RESUMO
BACKGROUND AND AIM: Secreted frizzled-related protein 2 (sFRP2) has been reported to be involved in cardiovascular diseases. However, its role in cardiac hypertrophy induced by pressure overload is still elusive. We aimed to examine the role of sFRP2 in the development of cardiac hypertrophy in vivo and in vitro. METHODS AND RESULTS: Following cardiac hypertrophy stimulated by aortic banding (AB), the expression of sFRP2 was downregulated in the hypertrophic ventricle. Adeno-associated virus 9 (AAV9) was injected through the tail vein to overexpress sFRP2 in the mouse myocardium. Overexpression of sFRP2 alleviated cardiomyocyte hypertrophy and interstitial fibrosis, as identified by the reduced cardiomyocyte cross-sectional area, heart weight/body weight ratio, and left ventricular (LV) collagen ratio. Additionally, sFRP2 decreased cardiomyocyte apoptosis induced by pressure overload. Western blot showed that sFRP2 prevented the expression of active ß-catenin. The Wnt/ß-catenin agonist LiCl (1 mmol/kg) abolished the inhibitory effects of sFRP2 on cardiac hypertrophy and apoptosis, as evidenced by the increased cross-sectional area and LV collagen ratio and the deterioration of echocardiographic data. CONCLUSION: Our study indicated that decreased sFRP2 levels were observed in failing mouse hearts. Overexpression of sFRP2 attenuated myocyte hypertrophy and interstitial fibrosis induced by hypertrophic stimuli by inhibiting the Wnt/ß-catenin pathway. We revealed that sFRP2 may be a promising therapeutic target for the development of cardiac remodeling.
Assuntos
Cardiomegalia/prevenção & controle , Proteínas de Membrana/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Modelos Animais de Doenças , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pressão , Ratos , Ratos Sprague-Dawley , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
AIMS: Recently, accumulating evidence indicates that dysregulation of microRNAs is associated with the initiation and progression of cancer. Oncogenic miR-301a has been reported upregulation and associated with tumorigenesis and progression in various types of cancer. The aim of this study was to investigate the expression of miR-301a in nonsmall-cell lung cancer. (NSCLC), and to assess its association with malignancy, metastasis and prognosis. SUBJECTS AND METHODS: total of 88 NSCLC patients (females = 21 and males = 67), aged 15-81 years were included in the study. miR-301a expression in tumor tissue was estimated by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: miR-301a was significantly upregulated in NSCLC tissues compared with their paired adjacent nontumor tissues. (P < 0.001). Increased expression of miR-301a was detected in tumors with lymph node metastases. (P =0.003). In addition, high miR-301a expression was significantly associated with poorly differentiation. (P =0.015), lymph node metastasis. (P =0.013) and advanced tumor-node-metastasis. (TNM) stage. (P =0.018). A. comparison of survival curves of low versus high expressers of miR-301a revealed a highly significant difference in NSCLC, which suggests that overexpression of miR-301a is associated with a poorer disease-free survival (DFS) (P =0.002). Moreover, multivariate Cox proportional hazard regression analyses revealed that the miR-301a overexpression was an unfavorable prognostic factor for disease-free survival in addition to TNM stage. CONCLUSIONS: miR-301a may represent a novel prognostic indicator, a biomarker for the early detection of lymph node metastasis and a therapeutic target in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Fatores de RiscoRESUMO
The present study aimed to investigate the effects of Wenyangbushen formula on the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), osteoprotegerin (OPG), receptor activator of nuclear factor (NF)κß ligand (RANK), and RANK ligand (RANKL) in a rabbit model of steroidinduced avascular necrosis of the femoral head (SANFH). The present study also aimed to examine the potential mechanism underlying the effect of this formula on the treatment of SANFH. A total of 136 New Zealand rabbits were randomly divided into five groups: Normal group, model group, and three groups treated with the traditional Chinese medicine (TCM), Wenyangbushen decoction, at a low, moderate and high dose, respectively. The normal group and positive control group were intragastrically administered with saline. The TCM groups were treated with Wenyangbushen decoction at the indicated dosage. Following treatment for 8 weeks, the mRNA and protein expression levels of VEGF, OPG, RANK and RANKL in the femoral head tissues were determined using reverse transcriptionquantitative polymerase chain reaction and western blot analyses, respectively. The data revealed that Wenyangbushen decoction effectively promoted the growth of bone cells, osteoblasts and chondrocytes, and prevented cell apoptosis in the SANFH. The mRNA and protein expression levels of OPG and VEGF were increased, while the levels of RANK and RANKL were reduced in the necrotic tissue of the model group, compared with those in the normal rabbits. Wenyangbushen treatment prevented these changes, manifested by an upregulation in the expression levels of VEGF and OPG, and downregulation in the expression levels of RANK and RANKL in a dosedependent manner. It was concluded that treatment with Wenyangbushen formula alleviated necrosis of the femoral head induced by steroids. It was observed to promote bone cell, osteoblast and chondrocyte growth, as well as prevent cell apoptosis. In addition, it upregulated the expression levels of OPG and VEGF, and inhibited the expression levels of RANK and RANKL. These results suggest the potential use of Wenyangbushen formula as a possible approach for the effective treatment of SANFH.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Necrose da Cabeça do Fêmur/tratamento farmacológico , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fatores de Necrose Tumoral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Cabeça do Fêmur/efeitos dos fármacos , Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoprotegerina/genética , Ligante RANK/genética , RNA Mensageiro/metabolismo , Coelhos , Receptor Ativador de Fator Nuclear kappa-B/genética , Fatores de Necrose Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
A new limonoid, named Citriolide-A (1), along with the known structurally related compounds 2-5, was isolated from the liposoluble extract of the seeds of Citrus reticulata Blanco. The structure of Citriolide-A (1) was elucidated by means of EI, 1D- and 2D-NMR techniques. Compounds 1, 2 and 4 exhibited medium cytotoxicity against P-388 and A-549 cell lines.
Assuntos
Antineoplásicos Fitogênicos/análise , Citrus/química , Limoninas/isolamento & purificação , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Limoninas/química , Camundongos , Estrutura Molecular , Sementes/químicaRESUMO
A gastric cancer (GC) cell line, AGS, has high-level expression of CD40, a tumor necrosis factor receptor (TNFR) family member. CD40 is present on the surfaces of a large variety of cells, including B cells, endothelial cells, dendritic cells and some carcinoma cells, and delivers signals regulating diverse cellular responses, such as proliferation, differentiation, growth suppression, and cell death. In this research, we studied the effects of different forms of CD40 stimulation on AGS cells by flow cytometry, Western blotting and siRNA transfection. We found that different forms of CD40 stimulation, either recombinant soluble CD40L (sCD40L, ligation) or agonist anti-CD40 antibody (cross-linking), induced different effects in AGS gastric cancer cells, proliferation or apoptosis. We also showed that VEGF provided a significant contribution to sCD40L-induced proliferation, while agonist anti-CD40 antibody induced GADD45 upregulation and promoted apoptosis.
Assuntos
Antígenos CD40/imunologia , Ligante de CD40/imunologia , Neoplasias Gástricas/imunologia , Apoptose/imunologia , Antígenos CD40/farmacologia , Ligante de CD40/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Cromonas/farmacologia , Citometria de Fluxo , Humanos , Indóis/farmacologia , Morfolinas/farmacologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , RNA/química , RNA/genética , RNA Interferente Pequeno/genética , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
OBJECTIVE: To evaluate the effect of surgical manipulation on the dissemination of cancer cells into blood circulation in patients with gastric cancer and to analyze its risk factors. METHODS: This study included 45 consecutive patients with gastric cancer undergoing curative resection and 13 control cases (10 healthy persons and 3 patients with peptic ulcer receiving gastrectomy). Peripheral blood was obtained preoperatively and just after surgical manipulation. The mRNA levels of carcinoembryonic antigen (CEA) from the blood samples were assayed by reverse transcription-polymerase chain reaction(RT-PCR) and compared between the 2 groups. RESULTS: CEA mRNA was negative in all control cases. Of the 45 gastric cancer patients, the preoperative positive rate of CEA mRNA was 8.9%, while the postoperative positive rate was 48.9%, which was significantly higher than that of preoperation (P=0.000). Multivariable Logistic regression analysis showed that operative duration (P=0.014) and tumor depth (P=0.010) were independent risk factors for cancer cell dissemination. Furthermore, the operative duration in patients with positive postoperative CEA mRNA was markedly longer than that in patients with negative postoperative CEA mRNA (P=0.000), and positive rate of postoperative CEA mRNA in advanced gastric cancer was higher compared with that in early gastric cancer (P=0.034). CONCLUSIONS: Surgical manipulation of curative gastrectomy can provoke dissemination of cancer cells into blood circulation, and the operative duration and tumor invasion depth may be 2 of the risk factors for cancer cell dissemination.