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1.
Cell Physiol Biochem ; 54(2): 195-210, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32083406

RESUMO

BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-ß1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-ß1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. METHODS: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. RESULTS: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-ß1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-ß1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. CONCLUSION: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.


Assuntos
Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteína Smad3/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Isoquinolinas/farmacologia , Cetonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Piridinas/farmacologia , Pirróis/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/genética , Ativação Transcricional/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
2.
Vasa ; 49(2): 141-146, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31920171

RESUMO

Background: A 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor type 1 (PAI-1) gene has been reported to enhance the plasma levels of PAI-1, which plays an important role in fibrinolysis disorders and venous thromboembolism, but a large number of studies have reported inconclusive results. Therefore, we performed a meta-analysis to analysis these associations. Materials and methods: We performed a publication search for articles published before April 2019 by using the electronic databases of web of Science, Embase, PubMed, CNKI, CBM and WanFang data with the following terms "PAI-1", "polymorphism", "Venous Thromboembolism". Two investigators independently extracted data and assessed study quality. Statistical analyses were undertaken using Stata 14.0. Results: A total of 27 studies, with 3135 patients and 5346 controls were included. Overall, the variant PAI-1 4G/4G and PAI-1 4G/5G was associated with venous thromboembolism risk, compared with the PAI-1 5G/5G allele in the populations included in the analysis. Stratified analysis revealed that PAI-1 4G/4G and PAI-1 4G/5G genotypes were associated with an increased VTE risk among Asia populations in all five genetic models. Conclusions: The PAI-1 4G/5G polymorphism may be a potential biomarker of VTE risk, particularly in Asia populations. Further larger studies with multi-ethnic populations are required to further assess the association between PAI-1 4G/4G polymorphisms and VTE risk.


Assuntos
Inibidor 1 de Ativador de Plasminogênio/genética , Tromboembolia Venosa , Predisposição Genética para Doença , Humanos , Plasminogênio , Polimorfismo Genético , Regiões Promotoras Genéticas , Tromboembolia Venosa/genética
3.
Yonsei Med J ; 61(1): 85-93, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31887804

RESUMO

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


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cicatriz/metabolismo , Cicatriz/patologia , Colágeno Tipo I/biossíntese , Fibroblastos/metabolismo , Folistatina/metabolismo , Miofibroblastos/patologia , Traumatismos dos Tendões/patologia , Actinas/metabolismo , Animais , Células Cultivadas , Desmina/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Regulação da Expressão Gênica , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Tendões/patologia
4.
Nat Genet ; 51(11): 1574-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Doenças Vasculares/genética , Tromboembolia Venosa/genética , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/patologia
5.
Life Sci ; 239: 117092, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31760103

RESUMO

AIMS: Type 2 diabetes mellitus (DM2) is associated with coronary heart disease (CHD) and is characterized by high levels of plasminogen activator inhibitor (PAI)-1. Circulating microRNAs have been reported as potential diagnostic biomarkers for DM2 and CHD. However, the underlying mechanisms have largely remained unclear. MAIN METHODS: The changes of circulating miR-30c, PAI-1 and vitronetin (VN) in plasma from CHD, noncomplicated (NC) + DM2, CHD + DM2 subjects and control individuals were assessed by quantitative reverse transcription PCR (qRT-PCR) and ELISA assays, respectively. The effects of miR-30c on VN expression by targeting PAI-1 were assessed in vitro SMC and in ex vivo plasma, using bioinformatic analysis, miRNA transfection, luciferase assays, qRT-PCR and western blot, respectively. KEY FINDINGS: We found that decreased circulating miR-30c was negatively correlated with the severity of coronary lesions and the resulting elevated PAI-1 and VN levels. Circulating miR-30c significantly distinguished between patients with CHD + DM2, NC + DM2, CHD and control subjects, and that were significantly associated with certain risk factors for progression from a normal individual to one with CHD + DM2. Furthermore, we also showed that miR-30c plays a previously unrecognized role in regulating the expression of VN levels via regulating PAI-1 levels in vitro SMC and in ex vivo plasma. SIGNIFICANCE: These findings provide a novel regulatory mechanism of miR-30c in regulating PAI-1/VN interactions and that may serve as a diagnostic biomarker of DM2 that is complicated with CHD.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , MicroRNAs/genética , Idoso , Biomarcadores/sangue , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Células Cultivadas , Doença das Coronárias/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Vitronectina/genética , Vitronectina/metabolismo
6.
Cancer Metastasis Rev ; 38(3): 483-492, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31734763

RESUMO

The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.


Assuntos
Neoplasias/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Humanos , Modelos Moleculares , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neoplasias/patologia , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Int Arch Allergy Immunol ; 180(4): 255-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31574527

RESUMO

INTRODUCTION: In recent years, many studies have focused on the association between plasminogen activator inhibitor (PAI)-1 gene 4G/5G polymorphism and risk of allergic diseases, but the results have been inconclusive. OBJECTIVE: We conducted this meta-analysis to study the exact relationship between PAI-1 polymorphism and susceptibility to allergic diseases. METHODS: All eligible studies were determined by an electronic literature search. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association under all of the models. RESULTS: A total of 14 studies involving 2,327 cases and 2,838 controls were included in this meta-analysis. Overall, we found a significant association between PAI-1 polymorphism and risk of allergic diseases (4G/4G + 4G/5G vs. 5G/5G: OR 1.76, 95% CI 1.39-2.22, p < 0.00001). In a subgroup analysis by ethnicity, we found a markedly increased risk in Asians (OR 1.62, 95% CI 1.26-2.09, p = 0.0002) and Caucasians (OR 1.78, 95% CI 1.26-2.52, p = 0.001). In addition, significant associations between PAI-1 polymorphism and risk of allergic diseases were observed in both adults (OR 1.71, 95% CI 1.23-2.38, p = 0.001) and children (OR 1.87, 95% CI 1.42-2.46, p < 0.00001). In a subgroup analysis by different allergic diseases, a significantly increased risk was found for asthma (OR 1.78, 95% CI 1.33-2.39, p = 0.001) but not for rhinitis (OR 1.51, 95% CI 0.79-2.89, p = 0.22). CONCLUSION: This meta-analysis demonstrated that PAI-1 gene 4G/5G polymorphism was associated with an increased risk of allergic diseases.


Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Risco
8.
Int J Low Extrem Wounds ; 18(3): 339-341, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31409160

RESUMO

Leg ulcers may occur due to many autoimmune, hereditary, inflammatory, and infectious causes including venous, arterial, and neuropathic ulcers. Hyperhomocysteinemia is a metabolic disorder caused by various enzyme defects in methionine metabolism. The most common cause is methylenetetrahydrofolatreductase (MTHFR) enzyme gene mutations. Hyperhomocysteinemia is an independent risk factor for deep vein thrombosis and peripheral arterial disease. The effects of endothelial cell damage on smooth muscle hypertrophy, platelet aggregation, coagulation, and fibrinolysis cause atherogenesis and thrombosis, leading to venous and arterial lower extremity ulcers. In this article, we report the case of a 47-year-old male patient who was admitted to our clinic due to painful leg ulcers that started 1 year ago. He had a history of vena cava inferior thrombosis, deep vein thrombosis, and 40 pack-year smoking. Histopathological examination of punch biopsy taken from ulcerative lesion showed intense inflammatory infiltration in the middle dermis, erythrocyte extravasation, leukocytoclasia, and thrombus formation in a small diameter venule lumen. There were nonspecific findings in direct immunofluorescence examination. He was found as having MTHFR C677T homozygote and plasminogen activator inhibitor-1 4G/5G heterozygote gene mutation with high homocysteine level of 22.90 µmol/L, and he was diagnosed as hyperhomocysteinemia. He was recommended to quit smoking because it triggered thrombosis in hyperhomocysteinemia. Herein, we present a case of hyperhomocysteinemia due to MTHFR mutation, which is one of the rare hereditary thrombophilia causes.


Assuntos
Enoxaparina/administração & dosagem , Hiper-Homocisteinemia , Úlcera da Perna , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Compostos de Prata/administração & dosagem , Trombose Venosa , Talassemia beta , Bandagens , Biópsia/métodos , Diagnóstico Diferencial , Fibrinolíticos/administração & dosagem , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/genética , Úlcera da Perna/sangue , Úlcera da Perna/etiologia , Úlcera da Perna/patologia , Úlcera da Perna/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Trombofilia/diagnóstico , Trombofilia/etiologia , Trombose Venosa/complicações , Trombose Venosa/diagnóstico , Cicatrização , Talassemia beta/complicações , Talassemia beta/diagnóstico
9.
Mol Med Rep ; 20(2): 1509-1522, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257474

RESUMO

The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin­induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear models for microarray data method and mRNA targets of DEMs were predicted using the miRWalk2.0 database. The crucial DEGs were screened by constructing a protein­protein interaction (PPI) network and module analysis. Functions of target genes were analyzed using the database for annotation, visualization and integrated discovery. Small molecule drugs were predicted using the connectivity map database. As a result, 5 DEMs were identified to be shared and oppositely expressed in comparisons between AKI model and control groups, and between MSC treatment and AKI model groups. The 103 DEGs were overlapped with the target genes of 5 common DEMs, and the resulting list was used for constructing the miRNA­mRNA regulatory network, including rno­miR­210/Serpine1 and rno­miR­378/Fos. Serpine1 (degree=17) and Fos (degree=42) were predicted to be hub genes according to the topological characteristic of degree in the PPI network. Function analysis indicated Serpine1 and Fos may be inflammation­related. Furthermore, gliclazide was suggested to be a potential drug for the treatment of AKI because the enrichment score was the closest to ­1 (­0.9). In conclusion, it can be speculated that gliclazide may have a similar mechanism to MSC as a potential therapeutic agent for cisplatin­induced AKI, by regulating miR­210/Serpine1 and miR­378­/Fos­mediated inflammation and cell apoptosis.


Assuntos
Lesão Renal Aguda/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Proteínas Oncogênicas v-fos/genética , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Mensageiro/genética , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Lesão Renal Aguda/prevenção & controle , Animais , Cisplatino/administração & dosagem , Biologia Computacional/métodos , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Gliclazida/farmacologia , Hipoglicemiantes/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Oncogênicas v-fos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Mapeamento de Interação de Proteínas , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Croat Med J ; 60(3): 212-220, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187948

RESUMO

AIM: To investigate the prevalence of common genetic variants that can serve as markers of thrombophilia and warfarin pharmacogenetics in Bosnia and Herzegovina. METHODS: The study was performed between August and October 2017 on 130 healthy unrelated adult volunteers from Bosnian-Herzegovinian population sample. The prevalence of the following genetic variants was determined: F5 c.1601G>A (factor V Leiden), F2 c.*97G>A (factor II or prothrombin mutation), F13A1 (factor XIII) c.103G>T, MTHFR (methylenetetrahydrofolate reductase) c.665C>T and c.1286A>C, as well as PAI-1 (plasminogen activator inhibitor 1) c.-816A>G and c.-844G>A as markers of thrombophilia risk, and *2 and *3 alleles of CYP2C9 (cytochrome P450 2C9) and five variants of VKORC1 (vitamin K epoxide reductase complex subunit 1) as markers of warfarin pharmacogenetics. DNA was isolated from buccal swabs using salting out method, while genotyping was performed using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. RESULTS: Minor allele frequencies for two main thrombophilia risk factors, F5 c.1601G>A and F2 c.*97G>A were 0.023 and 0.008, respectively. Combined data for the markers of warfarin pharmacogenetics imply that 57.4% study participants can be expected to metabolize warfarin at an extensive, 40.3% at intermediate, and 2.3% at a poor rate. CONCLUSION: This study reports the first extensive population genetic data for thrombophilia and warfarin pharmacogenetic markers in Bosnia and Herzegovina. Allele frequencies of genetic variants are within the general average for European populations, and their presence implies the necessity of introduction of personalized medicine in warfarin-mediated antithrombotic therapy.


Assuntos
Anticoagulantes/metabolismo , Fatores de Coagulação Sanguínea/genética , Trombofilia/genética , Varfarina/metabolismo , Adolescente , Adulto , Alelos , Biomarcadores , Bósnia e Herzegóvina , Citocromo P-450 CYP2C9/genética , Fator V/genética , Fator XIII/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Gravidez , Protrombina/genética , Vitamina K Epóxido Redutases/genética , Adulto Jovem
11.
J Biol Regul Homeost Agents ; 33(3): 895-903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189303

RESUMO

Hypoxia is one of the most obvious environmental characteristics of the Qinghai-Tibet Plateau. Increasing tissue microvessel density is an important mechanism for plateau animals to adapt to the hypoxic environment.


Assuntos
Hipóxia , Inibidor 1 de Ativador de Plasminogênio/genética , Roedores/genética , Serpinas/genética , Altitude , Animais , China
12.
Hum Cell ; 32(3): 297-305, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054069

RESUMO

Renal fibrosis is the major feature of end-stage renal disease with high mortality. Chloride (Cl-) moving along Cl- channels has been suggested to play to an important role in renal function. This study aims to investigate the role of ClC-5 in renal fibrosis in unilateral ureteral occlusion (UUO) mice. C57BL/6 mice received UUO surgery followed by delivery of adeno-associated virus encoding ClC-5 cDNA (AAVClC-5). Western blotting, real-time PCR and histological analysis were used to investigate the effects of ClC-5 on renal fibrosis and underlying mechanisms. The expression of ClC-5 was significantly decreased in renal cortex of UUO mice and transforming growth factor-ß1 (TGF-ß1)-stimulated HK2 cells. Overexpression of ClC-5 in vivo markedly ameliorated UUO-induced renal injury and fibrosis. The increased expressions of plasminogen activator inhibitor type 1, connective tissue growth factor, collagen III and collagen IV were also inhibited by ClC-5 upregulation. Moreover, UUO-induced immune cell infiltration and inflammatory cytokines release were attenuated in mice infected with AAVClC-5. In addition, the in vivo and in vitro results showed that ClC-5 overexpression prevented epithelial-to-mesenchymal transition (EMT), concomitantly with a restoration of E-cadherin expression and a decrease of vimentin, α-SMA and S100A4 expressions. Furthermore, ClC-5 overexpression inhibited UUO- or TGF-ß1-induced increase in nuclear factor kappa B (NF-κB) acetylation and matrix metalloproteinases-9 (MMP-9) expression. However, downregulation of ClC-5 in HK2 cells further potentiated TGF-ß1-induced EMT and increase in NF-κB acetylation and MMP-9 expression. ClC-5 upregulation ameliorates renal fibrosis via inhibiting NF-κB/MMP-9 pathway signaling activation, suggesting that ClC-5 may be a novel therapeutic target for treating renal fibrosis and chronic kidney disease.


Assuntos
Canais de Cloreto/genética , Canais de Cloreto/fisiologia , Expressão Gênica , Rim/metabolismo , Rim/patologia , Regulação para Cima , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Animais , Caderinas/metabolismo , Células Cultivadas , Canais de Cloreto/metabolismo , Canais de Cloreto/uso terapêutico , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibrose , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , NF-kappa B/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/tratamento farmacológico
13.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142059

RESUMO

The interactions of cancer cells with neighboring non-malignant cells in the microenvironment play an important role for progressive neoplastic development and metastasis. Long-term direct co-culture of human MDA-MB-231cherry breast cancer cells with benign human mesenchymal stroma/stem-like cells (MSC) MSC544GFP stably expressing mCherry and eGFP fluorescence proteins, respectively, was associated with the formation of three-dimensional (3D) tumor spheroids in vitro. The quantification of the breast tumor marker urokinase plasminogen activator (uPA) in mono-cultured MDA-MB-231 cells revealed an approximately 14-fold enhanced expression when compared to five different normal human MSC mono-cultures. Moreover, uPA levels in 3D tumor spheroids remained elevated 9.4-fold above the average of five different human MSC cultures. In contrast, the expression of the corresponding plasminogen activator inhibitor type-1 (PAI-1) declined by 2.6-fold in the breast cancer cells and was even further reduced by 3.2-fold in the MDA-MB-231cherry/MSC544GFP 3D co-culture spheroids when compared to the various MSC populations. The supportive data were obtained for the production of TGF-ß1, which is an important growth factor in the regulation of tumor growth and metastasis formation. Whereas, TGF-ß1 release in MDA-MB-231cherry/MSC544GFP co-cultures was elevated by 1.56-fold as compared to MSC544 mono-cultures after 24 h; this ratio further increased to 2.19-fold after 72 h. Quantitative PCR analyses in MSC544 and MDA-MB-231 cells revealed that MSC, rather than the breast cancer cells, are responsible for TGF-ß1 synthesis and that TGF-ß1 contributes to its own synthesis in these cells. These findings suggested potential synergistic effects in the expression/secretion of uPA, PAI-1, and TGF-ß during the co-culture of breast cancer cells with MSC.


Assuntos
Neoplasias da Mama/metabolismo , Células-Tronco Mesenquimais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativadores de Plasminogênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Comunicação Celular , Linhagem Celular Tumoral , Feminino , Humanos , Inibidor 1 de Ativador de Plasminogênio/genética , Ativadores de Plasminogênio/genética , Esferoides Celulares/metabolismo , Células Tumorais Cultivadas
14.
Int J Clin Oncol ; 24(9): 1030-1041, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30937621

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the six leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains less than 65% due to lack of symptoms in the early stage. Hence, biomarkers which can improve detection of HNSCC should improve clinical outcome. METHODS: Gene expression profiles (GSE6631, GSE58911) and the Cancer Genome Atlas (TCGA) HNSCC data were used for integrated bioinformatics analysis; the differentially expressed genes (DEGs) were then subjected to functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction. Subsequently, module analysis of the PPI network was performed and overall survival (OS) analysis of hub genes in subnetwork was studied. Finally, immunohistochemistry was used to verify the selected markers. RESULTS: A total of 52 up-regulated and 80 down-regulated DEGs were identified, which were mainly associated with ECM-receptor interaction and focal adhesion signaling pathways. Importantly, a set of prognostic signatures including SERPINE1, PLAU and ACTA1 were screened from DEGs, which could predict OS in HNSCC patients from TCGA cohort. Experiment of clinical samples further successfully validated that these three signature genes were aberrantly expressed in the oral epithelial dysplasia and HNSCC, and correlated with aggressiveness of HNSCC patients. CONCLUSIONS: SERPINE1, PLAU and ACTA1 played important roles in regulating the initiation and progression of HNSCC, and could be identified as key biomarkers for precise diagnosis and prognosis of HNSCC, which will provide potential targets for clinical therapies.


Assuntos
Actinas/genética , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Membrana/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Actinas/metabolismo , Biomarcadores Tumorais/genética , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Prognóstico , Mapas de Interação de Proteínas/genética , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
15.
Crit Rev Eukaryot Gene Expr ; 29(1): 85-94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002598

RESUMO

Plasminogen activator inhibitor type 1 (PAI-1) correlates with the risk and progression of systemic lupus erythematosus (SLE). We aimed to assess the relationship between the PAI-1 4G/5G gene polymorphism and SLE/lupus nephritis risk. We identified the eligible studies regarding the association between the PAI-1 4G/5G gene polymorphism and the risk of SLE/lupus nephritis. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects model or, in the presence of heterogeneity, a random-effects model. A total of six studies were enrolled in our pooled analysis. The PAI-1 4G/5G gene polymorphism had no significant association with the risk of SLE among overall populations, Asians and Caucasians. Nor was it associated with susceptibility to lupus nephritis among overall populations, Asians and Caucasians. Sensitivity analysis yielded similar results. No marked publication bias was noted. In conclusion, the PAI-1 4G/5G gene polymorphism is not associated with susceptibility to SLE/lupus nephritis among overall populations, Asians and Caucasians. However, more studies should be conducted in the future.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1313-1322, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710617

RESUMO

Activation of the renin-angiotensin system (RAS) plays a pivotal role in mediating hypertension, chronic kidney and cardiovascular diseases. As Wnt/ß-catenin regulates multiple RAS genes, we speculated that this developmental signaling pathway might also participate in blood pressure (BP) regulation. To test this, we utilized two rat models of experimental hypertension: chronic angiotensin II infusion and remnant kidney after 5/6 nephrectomy. Inhibition of Wnt/ß-catenin by ICG-001 blunted angiotensin II-induced hypertension. Interestingly, angiotensin II was able to induce the expression of multiple Wnt genes in vivo and in vitro, thereby creating a vicious cycle between Wnt/ß-catenin and RAS activation. In the remnant kidney model, renal ß-catenin was upregulated, and delayed administration of ICG-001 also blunted BP elevation and abolished the induction of angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II type 1 receptor. ICG-001 also reduced albuminuria, serum creatinine and blood urea nitrogen, and inhibited renal expression of fibronectin, collagen I and plasminogen activator inhibitor-1, and suppressed the infiltration of CD3+ T cells and CD68+ monocytes/macrophages. In vitro, incubation with losartan prevented Wnt/ß-catenin-mediated fibronectin, α-smooth muscle actin and Snail1 expression, suggesting that the fibrogenic action of Wnt/ß-catenin is dependent on RAS activation. Taken together, these results suggest an intrinsic linkage of Wnt/ß-catenin signaling with BP regulation. Our studies also demonstrate that hyperactive Wnt/ß-catenin can drive hypertension and kidney damage via RAS activation.


Assuntos
Albuminúria/genética , Hipertensão/genética , Rim/metabolismo , Proteínas Wnt/genética , beta Catenina/genética , Albuminúria/tratamento farmacológico , Albuminúria/etiologia , Albuminúria/fisiopatologia , Angiotensina II/administração & dosagem , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Creatinina/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Nefrectomia/métodos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirimidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
17.
BMC Neurol ; 19(1): 13, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30669988

RESUMO

BACKGROUND: Epilepsy is one of the most common chronic disabling neurologic diseases. The purpose of our study was to investigate whether there is an association between t-PA (tissue plasminogen activator, rs2020918 and rs4646972), PAI-1 (plasminogen activator inhibitor 1, rs1799768) polymorphisms and susceptibility to temporal lobe epilepsy (TLE) in Chinese Han population. METHOD: One hundred and twenty-one cases of patients who were diagnosed as TLE and 146 normal controls were enrolled and the genotypes of t-PA and PAI-1 were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR) method after the genomic DNA being extracted from peripheral blood. RESULT: There were significant differences for the genotypic frequencies at the two polymorphic sites in t-PA gene between TLE patients and controls (P = 0.019; P = 0.001). Furthermore, the frequency of rs2020918 (C > T) with T (CT + TT) and rs4646972 (311 bp insertion/-) with 311 bp deletion (311 bp/- + -/-) was significantly higher among TLE patients relative to controls respectively (P = 0.006; P = 0.001). However, no significant difference in genotypic and allelic frequency was found at the polymorphic site in PAI-1 gene between TLE patients and controls (P = 0.735). CONCLUSION: We reported for the first time to our knowledge the significant role of the two SNPs in t-PA gene (rs2020918 and rs4646972) in developing susceptibility to TLE in Chinese Han population.


Assuntos
Epilepsia do Lobo Temporal/genética , Predisposição Genética para Doença/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Ativador de Plasminogênio Tecidual/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
J Surg Res ; 235: 22-33, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30691798

RESUMO

BACKGROUND: Accumulating evidence indicated that long noncoding RNAs (lncRNAs) have a wide range of biological functions and may play significant roles in tumorigenesis and progression. However, the understanding of its functions and related competitive endogenous RNAs (ceRNAs) networks is much less than that of protein-coding genes, particularly in colon adenocarcinoma. METHODS: We comprehensively analyzed the sequencing data of protein-coding and noncoding RNAs in colon adenocarcinoma patients from The Cancer Genome Atlas (TCGA) database. Next, we constructed colon adenocarcinoma-specific ceRNA network and evaluated the effect of these RNAs on overall survival (OS) for colon adenocarcinoma patients. RESULTS: Totally, 1138 differentially expressed lncRNAs (DElncRNAs), 245 microRNAs (DEmiRNAs), and 2081 mRNAs (DEmRNAs) were identified using a threshold of |log2FoldChange| >2.0 and adjusted P-value < 0.01. Subsequently, a colon adenocarcinoma-specific ceRNA network was successfully established with133 DElncRNAs, 29 DEmiRNAs, and 55 DEmRNAs. Among ceRNA network, seven DElncRNAs (AL590483.1, AP004609.1, ARHGEF26-AS1, HOX transcript antisense RNA (HOTAIR), ITCH-IT1, KCNQ1OT1, and LINC00491), four DEmiRNAs (hsa-mir-143, hsa-mir-183, hsa-mir-216a, and hsa-mir-424), and six DEmRNAs (FJX1, TPM2, ULBP2, PDCD4, PLAU, and SERPINE1) significantly correlated with OS (all P-value < 0.05). Notably, several interactions were highlighted in the ceRNA network, such as "KCNQ1OT1-hsa-mir-183-PDCD4", "KCNQ1OT1-hsa-mir-424-TPM2", "HOTAIR-hsa-mir-143-SERPINE1", and "ARHGEF26-AS1-hsa-mir-143-SERPINE1". CONCLUSIONS: These findings reveal several molecules might be novel important prognostic factors and potential treatment targets for colon adenocarcinoma. In addition, these observations contribute to a more comprehensive understanding of lncRNA-related ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in colon adenocarcinoma.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais , Neoplasias do Colo/mortalidade , Redes Reguladoras de Genes , Humanos , Canal de Potássio KCNQ1/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Prognóstico , RNA Mensageiro/genética , Tropomiosina/genética
19.
BMC Cancer ; 19(1): 71, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646864

RESUMO

BACKGROUND: The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated. PATIENTS AND METHODS: This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position - 675 of the PAI-1 gene was detected by PCR-RFLP analysis. RESULTS: Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, - 675 4G/5G and - 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (- 675 4G/4G). CONCLUSION: Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proteínas de Membrana/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Prognóstico , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
20.
Clin Exp Nephrol ; 23(4): 448-454, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30341573

RESUMO

BACKGROUND: Chloroquine, an antimalarial agent, has been reported to prevent the risk of thrombosis and decrease renal damage in patients with systemic lupus erythematosus (SLE); however, its detailed mechanisms remain unclear. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis and is involved in fibrin deposition in glomeruli. Since upregulation of glomerular Toll-like receptor 3 (TLR3) signaling reportedly plays a pivotal role in the pathogenesis of lupus nephritis (LN), we examined whether chloroquine affects TLR3-mediated expression of PAI-1 in cultured human glomerular endothelial cells (GECs). METHODS: We examined the effect of polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, on PAI-1 and tissue plasminogen activator (t-PA) expression in GECs. Then, we analyzed whether pretreatment of chloroquine or dexamethasone inhibits poly IC-induced expression of these proteins using reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Poly IC increased PAI-1 expression in a time- and concentration-dependent manner, but did not affect t-PA expression in GECs. RNA interference against TLR3 inhibited poly IC-induced PAI-1 expression. Interestingly, pretreating cells with chloroquine, and also hydroxychloroquine, but not dexamethasone, attenuated poly IC-induced PAI-1 expression in GECs. CONCLUSION: Considering that TLR3 signaling is implicated in LN pathogenesis, our results suggest that chloroquine exert postulated renoprotective effects by inhibiting PAI-1 expression.


Assuntos
Antimaláricos/farmacologia , Antivirais/farmacologia , Cloroquina/farmacologia , Células Endoteliais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética , Anti-Inflamatórios/farmacologia , Linhagem Celular , Dexametasona/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Helicase IFIH1 Induzida por Interferon/genética , Interleucina-6/genética , Glomérulos Renais/citologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Receptores do Ácido Retinoico/genética , Transdução de Sinais/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/genética
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