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World J Gastroenterol ; 25(24): 3044-3055, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31293340


BACKGROUND: The formation of liver fibrosis is mainly caused by the activation of hepatic stellate cells (HSCs) and the imbalance of extracellular matrix (ECM) production and degradation. The treatment of liver fibrosis mainly includes removing the cause, inhibiting the activation of HSCs, and inhibiting inflammation. NOD-like receptor (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5/NOD27/CLR16.1 (NLRC5) is a highly conserved member of the NLR family and is involved in inflammation and immune responses by regulating various signaling pathways such as nuclear factor-κB (NF-κB) signaling. It has been found that NLRC5 plays an important role in liver fibrosis, but its specific effect and possible mechanism remain to be fully elucidated. AIM: To investigate the role of NLRC5 in the activation and reversion of HSCs induced with transforming growth factor-ß (TGF-ß) and MDI, and to explore its relationship with liver fibrosis. METHODS: A total of 24 male C57BL/6 mice were randomly divided into three groups, including normal, fibrosis, and recovery groups. Twenty-four hours after a liver fibrosis and spontaneous reversion model was established, the mice were sacrificed and pathological examination of liver tissue was performed to observe the degree of liver fibrosis in each group. LX-2 cells were cultured in vitro and treated with TGF-ß1 and MDI. Real-time quantitative PCR (qPCR) and Western blot were used to analyze the expression levels of NLRC5, α-smooth muscle actin (α-SMA), and collagen type I alpha1 (Col1a1) in each group. The activity of NF-κB in each group of cells transfected with NLRC5-siRNA was detected. RESULTS: Compared with the normal mice, the expression level of NLRC5 increased significantly (P < 0.01) in the fibrosis group, but decreased significantly in the recovery group (P < 0.01). In in vitro experiments, the content of NLRC5 was enhanced after TGF-ß1 stimulation and decreased to a lower level when treated with MDI (P < 0.01). The expression of α-SMA and Col1a1 proteins and mRNAs in TGF-ß1-mediated cells was suppressed by transfection with NLRC5-siRNA (P < 0.01). Western blot analysis showed that the expression of NF-κB p65 protein and phosphorylated IκBα (p-IκBα) was increased in the liver of mice in the fibrosis group but decreased in the recovery group (P < 0.01), and the protein level of nuclear p65 and p-IκBα was significantly increased after treatment with NLRC5-siRNA (P < 0.01). CONCLUSION: NLRC5 may play a key role in the development and reversal of hepatic fibrosis through the NF-κB signaling pathway, and it is expected to be one of the clinical therapeutic targets.

Células Estreladas do Fígado/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cirrose Hepática Experimental/patologia , NF-kappa B/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Matriz Extracelular/patologia , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/citologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Masculino , Camundongos , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
Invest New Drugs ; 37(6): 1300-1308, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30929157


Background Gastric cancer (GC) is the second most common cause of cancer-related death worldwide. Novel anticancer drugs against gastric cancer are urgently needed. Methods Compound 10 was designed and synthesized via a molecular hybridization strategy based on the natural product formononetin. It was evaluated for their antiproliferative activity against three gastric cancer cell lines (SGC7901, MKN45 and MGC803). Results Derivative 10 displayed potently antiproliferative activity with an IC50 value of 1.07 µM against SGC7901 cells. Derivative 10 could inhibit the growth and migration against gastric cancer SGC7901 cells through the Wnt/ß-Catenin and AKT/mTOR pathways. From the in vivo expremints, it could effectively inhibited SGC7901 xenograft tumor growth in vivo without significant loss of the body weight. Conclusion Derivative 10 is an novel antitumor agent with potential for further clinical applications to treat gastric cancer. Graphical abstract.

Antineoplásicos Fitogênicos/uso terapêutico , Cumarínicos/uso terapêutico , Isoflavonas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
Arch Biochem Biophys ; 657: 23-30, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30222949


microRNA (miR)-141-3p has context-dependent effects on tumor progression. In this study, we attempted to explore the expression and function of miR-141-3p in cervical cancer. We found that miR-141-3p expression was significantly increased in cervical cancer specimens relative to normal cervical tissues. Moreover, miR-141-3p levels were associated with tumor size and lymph node metastasis status. Ectopic expression of miR-141-3p significantly increased cervical cancer cell proliferation, colony formation, invasion, and epithelial to mesenchymal transition, whereas depletion of miR-141-3p suppressed cervical cancer cell proliferation and invasion. FOXA2 was identified to be a target of miR-141-3p. Overexpression of miR-141-3p led to a marked inhibition of endogenous FOXA2 in cervical cancer cells. FOXA2 silencing phenocopied the effects of miR-141-3p overexpression on cervical cancer cell proliferation and invasion. Enforced expression of FOXA2 blocked the effects of miR-141-3p on cervical cancer cell proliferation and invasion. miR-141-3p overexpression significantly accelerated the growth of xenograft tumors, which was accompanied by a striking reduction in FOXA2 expression. miR-141-3p acts as an oncogene in cervical cancer largely through repression of FOXA2. Targeting miR-141-3p may represent a potential therapeutic strategy for cervical cancer.

Carcinogênese/genética , Fator 3-beta Nuclear de Hepatócito/genética , MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Regulação para Cima , Neoplasias do Colo do Útero/patologia
Oncol Rep ; 38(4): 2123-2131, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849234


Sanggenon C is a well-known, major active agent of the flavonoid derivative of benzopyrone with valuable biological properties, including anticancer, anti-inflammatory, antimicrobial, antiviral, antithrombotic, and immune-modulatory activities. In this study, we investigated the molecular mechanisms by which sanggenon C mediated the induction of cell death in colorectal cancer cells (CRC). Treatment of colorectal cancer cells (LoVo, HT-29 and SW480) with sanggenon C (0, 5, 10, 20, 40 and 80 µM) resulted in inhibited proliferation of colon cancer cells. In addition, Sanggenon C (10, 20, 40 µM) induces apoptosis of HT-29 colon cancer cells as well as the increased ROS generation. Furthermore, treatment with sanggenon C increased the level of intracellular Ca2+ and ATP, while inhibited the nitric oxide production via inhibiting inducible nitric oxide synthase expression. This resulted in the activation of mitochondrial apoptosis pathway as evidenced by the decrease in Bcl-2 protein expression. Consistently, the anti-growth and pro-apoptosis effects of sanggenon C on xenograft colon tumor were further confirmed in vivo. Collectively, our results demonstrated sanggenon C induced apoptosis of colon cancer cells by increased reactive oxygen species generation and decreased nitric oxide production, which is associated with inhibition of inducible nitric oxide synthase expression and activation of mitochondrial apoptosis pathway.

Benzofuranos/administração & dosagem , Cromonas/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico/genética , Animais , Apoptose/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto