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1.
Nutr Cancer ; 62(4): 525-32, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20432174

RESUMO

Recent surveys indicate that Pi intake has increased steadily as Pi-containing foods have increased. Our previous study demonstrated that high dietary Pi strongly stimulated lung tumorigeneis. In order to answer the issue whether low Pi may be chemopreventive, we examined the effects of low Pi on lung cancer. Eighteen 5-wk-old male K-ras(LA1) lung cancer model mice were randomly allocated to 2 groups. One group was fed a normal diet (0.5% Pi) and other group was fed low Pi (0.1% Pi) diet for 4 wk. Lung cancer development was evaluated by histopathological examination, Western blot, kinase assay, and immunohistochemistry. Low Pi increased the expression of sodium-dependent phosphate co-transporter 2b, and activated Akt signal with decreased PTEN expression in the lungs of K-ras(LA1) mice. Low Pi increased the Akt/mTOR-mediated protein translation through upregulating the phosphorylation of p70S6K and 4E-BP1. In addition, low Pi stimulated cell cycling as evidenced by altered cell cycle regulators such as cyclin D1 and D3. Finally, low Pi increased lung tumorigenesis in K-ras(LA1) mice compared to the normal diet group. Our results clearly demonstrated that low Pi also promoted lung tumorigenesis, thus suggesting that an appropriate intake of dietary Pi may be critical for lung cancer prevention as well as treatment.


Assuntos
Ciclo Celular , Genes ras , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fósforo na Dieta/administração & dosagem , Biossíntese de Proteínas , Proteínas Adaptadoras de Transdução de Sinal , Adenoma/patologia , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fatores de Iniciação em Eucariotos , Hiperplasia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/prevenção & controle , Masculino , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Serina-Treonina Quinases TOR , Carga Tumoral
2.
J Nutr Biochem ; 19(1): 16-25, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17509857

RESUMO

Inorganic phosphate (Pi) plays a key role in diverse physiologic functions. In a previous study, we showed that high dietary Pi perturbs brain growth through Akt/ERK signaling in developing mice. However, no study has investigated the response of the brain to low dietary Pi. In this study, we addressed this question by studying the effects of low dietary Pi on the cerebrum of developing mice. Two-week-old weaned mice were fed with a low phosphate diet for 4 weeks. At the end of the study, their cerebrum was dissected and signals important for protein translation, apoptosis and cell cycle were examined. The low phosphate diet did not cause physiologically significant changes; it increased the protein expression of phosphatase and tensin homolog deleted on chromosome 10 but decreased Akt activity. In addition, expression of eukaryotic translation initiation factor binding protein coupled with increased complex formation of eukaryotic translation initiation factor 4E/eukaryotic translation initiation factor binding protein 1 was induced in the cerebrum by low phosphate, leading to reduced cap-dependent protein translation. Finally, low phosphate facilitated apoptosis and suppressed signals important for the cell cycle in the cerebrum of dual-luciferase reporter mice. In summary, our results showed that a low phosphate diet affects the brain by controlling protein translation, apoptosis and cell cycle in developing mice. Our results support the hypothesis that Pi works as a stimulus capable of increasing or decreasing several pivotal genes for normal development and suggest that regulation of Pi consumption is important in maintaining a healthy life.


Assuntos
Apoptose/fisiologia , Encéfalo/metabolismo , Ciclo Celular/fisiologia , Fosfatos/administração & dosagem , Fosfatos/fisiologia , Biossíntese de Proteínas/fisiologia , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Química Encefálica , Dieta , Regulação da Expressão Gênica no Desenvolvimento , Luciferases de Vaga-Lume/genética , Luciferases de Renilla/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/análise , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/análise
3.
Toxicol Sci ; 100(1): 215-23, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17698515

RESUMO

Inorganic phosphate (Pi) plays a key role in diverse physiological functions. Several studies indicate that Pi may affect lung cell development through Na/Pi cotransporter (NPT). Several NPT subtypes have been identified in mammalian lung, and considerable progress has been made in our understanding of their function and regulation. Therefore, current study was performed to elucidate the potential effects of high dietary Pi on lungs of developing mice. Our results clearly demonstrate that high dietary Pi may affect the lung of developing mice through Akt-related cap-dependent protein translation, cell cycle regulation, and angiogenesis. Our results support the hypothesis that Pi works as a critical signal molecule for normal lung growth and suggest that careful restriction of Pi consumption may be important in maintaining a normal development.


Assuntos
Ciclo Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fósforo na Dieta/administração & dosagem , Biossíntese de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fatores de Iniciação em Eucariotos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Pulmão/irrigação sanguínea , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Pulmão/patologia , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação ao Cap de RNA/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Serina-Treonina Quinases TOR
4.
J Aerosol Med Pulm Drug Deliv ; 23(5): 285-93, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20455770

RESUMO

BACKGROUND: Programmed cell death 4 (PDCD4), a protein that binds to eukaryotic initiation factor 4A (eIF4A), inhibits the initiation of translation. Although a number of tumor suppressors target transcription, Pdcd4 is the first suppressor targeting protein translation, and has also been suggested to function as a tumor suppressor gene in human cancer. The majority of tumor suppressors are mutationally inactivated, but the expression of Pdcd4 is downregulated with progression in a number of human cancer sites, including the lung. METHODS: An aerosol of lentivirus-shRNA Pdcd4 was delivered into A/J mice, through a nose-only inhalation system twice a week for 1 month. RESULTS AND CONCLUSIONS: Downregulated Pdcd4 resulted in increase levels of antiapoptotic and uPA-regulated proteins. We also found that downregulated Pdcd4 induced the mTOR/p70S6K pathway and cell-cycle proteins. Our results suggest that Pdcd4 may perform a critical function in the regulation of lung cancer cell proliferation.


Assuntos
Proteínas Reguladoras de Apoptose/administração & dosagem , Regulação para Baixo , Pulmão/metabolismo , RNA Interferente Pequeno/administração & dosagem , Proteínas de Ligação a RNA/administração & dosagem , Administração por Inalação , Administração Intranasal , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular , Proliferação de Células , Vetores Genéticos , Humanos , Lentivirus/genética , Masculino , Camundongos , Camundongos Endogâmicos A , Proteínas de Ligação a RNA/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
5.
Mol Med Rep ; 3(6): 1007-13, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21472347

RESUMO

Let-7g miRNAs, short non-coding RNAs approximately 21 nucleotides long, repress protein translation by binding to the 3'UTR of target mRNAs. Aberrant expression of let-7g is associated with the poor prognosis of lung cancer patients. Compared to normal lung cells, let-7g expression is absent in non-small cell lung cancer (NSCLC) cells. Furthermore, K-Ras and HMGA2 are well known as targets of let-7g. In this study, we evaluated the potential role of precursor (pre)-let-7g in lung cancer cell metastasis, focusing on the two targets of let-7g, HMGA2 and K-Ras. We found that pre-let-7g inhibited the migration of A549 lung cancer cells through HMGA2-mediated E2F1 down-regulation. Thus, our results suggest that pre-let-7g could be used as a suitable target for the suppression of lung cancer cell migration.

6.
J Vet Sci ; 10(2): 105-13, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19461205

RESUMO

Inorganic phosphate (Pi) plays a critical role in diverse cellular functions, and regulating the Pi balance is accomplished by sodium-dependent Pi co-transporter (NPT). Pulmonary NPT has recently been identified in mammalian lungs. However, to date, many of the studies that have involved Pi have mainly focused on its effect on bone and kidney. Therefore, current study was performed to discover the potential effects of low Pi on the lung of developing transgenic mice expressing the renilla/firefly luciferase dual reporter gene. Two-weeks old male mice divided into 2 groups and these groups were fed either a low PI diet or a normal control diet (normal: 0.5% Pi, low: 0.1% Pi) for 4 weeks. After 4 weeks of the diet, all the mice were sacrificed. Their lungs were harvested and analyzed by performing luciferase assay, Western blotting, kinase assay and immunohistochemistry. Our results demonstrate that low Pi affects the lungs of developing mice by disturbing protein translation, the cell cycle and the expression of fibroblast growth factor-2. These results suggest that optimally regulating Pi consumption may be important to maintain health.


Assuntos
Pulmão/crescimento & desenvolvimento , Fósforo na Dieta/administração & dosagem , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Western Blotting , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Fatores de Iniciação em Eucariotos , Imuno-Histoquímica , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR
7.
J Occup Health ; 51(5): 423-31, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19706996

RESUMO

OBJECTIVES: Nanomaterials are used in a wide variety of industrial materials such as semiconductors, magnetic resonance imaging, gene delivery carriers for gene therapy and many others; thus, human seems to be frequently exposed to them. Such diverse applications of nanoparticles elicit the need to identify the positive aspects of nanomaterials while avoiding the potential toxic effects. In this study, inhalation toxicity of manufactured nanomaterials using fluorescent magnetic nanoparticles (FMNPs) was assessed to address the issue of potential nanoparticle toxicity. METHODS: Biological samples from a previous mouse FMNP exposure experiment were analyzed for potential FMNP toxicity. Mice inhaled FMNPs for 4 wk through a nose-only exposure chamber developed by our group for 4 wk and the potential toxicity of FMNPs was analyzed. RESULTS: The nanoparticle distribution by scanning mobility particle sizer (SMPS) analysis showed that the mean values of number concentration (mass concentrations) in the nose-only exposure chamber were maintained at 4.89 x 10(5)/cm3 (approximately 159.4 microg/m3) for the low concentration and 9.34 x 10(5)/cm3 (approximately 319.5 microg/m3) for the high concentration, respectively. Inhalation of FMNPs caused a decrease of body weight and significant changes of white blood cells (WBCs) levels in whole blood. The FMNPs induced extramedullary hematopoiesis in the spleen without having a pulmonary effect. CONCLUSIONS: Our results support the proposition that extensive toxicity evaluation is needed for practical applications of anthropogenic nanomaterials and suggest that careful regulation of nanoparticle applications may be necessary to maintain a high quality of life as well as for facilitating the development of nanotechnology.


Assuntos
Óxido Ferroso-Férrico/toxicidade , Hematopoese Extramedular/efeitos dos fármacos , Inalação , Baço/fisiopatologia , Animais , Feminino , Óxido Ferroso-Férrico/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos
8.
Am J Respir Cell Mol Biol ; 35(5): 528-39, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16763222

RESUMO

Inorganic phosphate (Pi) plays a critical role in diverse cellular functions. Among three classes of sodium/phosphate co-transporters (NPTs), two types have been identified in mammalian lung. The potential importance of Pi as a novel signaling molecule and pulmonary expression of NPTs with poor prognosis of diverse lung diseases including cancer have prompted us to begin to define the pathways by which Pi regulates nontumorigenic human bronchial epithelial cells. Pi activates Akt phosphorylation on Thr308 specifically, and activated signal transmits on the Raf/MEK/ERK signaling. Here, we report that Pi controls cell growth by activating ERK cascades and by facilitating the translocation of Mnk1 from cytosol into nucleus through an Akt-mediated MEK pathway. Sequentially, translocated Mnk1 increases eIF4E-BP1 phosphorylation. As a result, Pi stimulates cap-dependent protein translation. Such Akt-mediated signaling of inorganic phosphate may provide critical clues for treatment as well as prevention of diverse lung diseases.


Assuntos
Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Mucosa Respiratória/citologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Fracionamento Celular , Células Cultivadas , Ativação Enzimática , Inibidores Enzimáticos/metabolismo , Células Epiteliais/citologia , Foscarnet/metabolismo , Regulação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Fosfoproteínas/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/fisiologia , Treonina/metabolismo
9.
Biotechnol Lett ; 25(10): 767-71, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12882005

RESUMO

Xanthophyllomyces dendrorhous (Phaffia rhodozyma) is used as a colorant for aquaculture, egg yolks, and crustaceans but its carotenoids can only be absorbed by animals when its cell wall is degraded. Conditions that degraded the cell wall of X. dendrorhous were developed. To measure the degrees of cell wall degradation, the carotenoid extractability (extracted carotenoid by acetone/total carotenoid) unit was used. Treatment with HCl (0.2 M, 9 h, 90 degrees C) followed by neutralization to pH 3 by NaOH and spray-drying increased carotenoid extractability to 100% with minimal decomposition.


Assuntos
Basidiomycota/química , Basidiomycota/metabolismo , Aditivos Alimentares/síntese química , Ácido Clorídrico/farmacologia , beta Caroteno/análogos & derivados , beta Caroteno/biossíntese , Basidiomycota/efeitos dos fármacos , Disponibilidade Biológica , Técnicas de Cultura de Células/métodos , Extratos Celulares/síntese química , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Desidratação , Relação Dose-Resposta a Droga , Aromatizantes/síntese química , Aromatizantes/metabolismo , Aditivos Alimentares/metabolismo , Temperatura Alta , Concentração de Íons de Hidrogênio , Xantofilas/biossíntese
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