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1.
Biochem Biophys Res Commun ; 399(4): 593-9, 2010 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-20682291

RESUMO

Alzheimer's disease (AD) is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid beta-peptide (Abeta) is the main component of senile plaques, and the pathological load of Abeta in the brain has been shown to be a marker of the severity of AD. Abeta is produced from the amyloid precursor protein by membrane proteases and is known to aggregate. Recently, immune-mediated cerebral clearance of Abeta has been studied extensively as potential therapeutic strategy. In previous studies that used a purified Abeta challenge in a mouse model of AD, symptomatic improvement was reported. However, a clinical Alzheimer's vaccine trial in the United States was stopped because of severe side effects. Immunization with the strong adjuvant used in these trials might have activated an inflammatory Th1 response. In this study, to establish a novel, safer, lower-cost therapy for AD, we tested an oral vaccination in a wild-type and a transgenic mouse model of AD administered via green pepper leaves expressing GFP-Abeta. Anti-Abeta antibodies were effectively induced after oral immunization. We examined the immunological effects in detail and identified no inflammatory reactions. Furthermore, we demonstrated a reduction of Abeta in the immunized AD-model mice. These results suggest this edible vehicle for Abeta vaccination has a potential clinical application in the treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/administração & dosagem , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/imunologia , Administração Oral , Peptídeos beta-Amiloides/biossíntese , Animais , Anticorpos/metabolismo , Encéfalo/metabolismo , Capsicum/genética , Capsicum/metabolismo , Imunoglobulina G/biossíntese , Camundongos , Camundongos Transgênicos , Folhas de Planta/genética , Folhas de Planta/metabolismo , Vacinação
2.
Circ Res ; 102(5): 607-14, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18218984

RESUMO

Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element-dependent and the E-box enhancer element-dependent pathways. Both phosphorylation and S-nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.


Assuntos
Envelhecimento/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Óxido Nítrico/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Células Cultivadas , Transtornos Cronobiológicos/tratamento farmacológico , Transtornos Cronobiológicos/etiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Meios de Cultura Livres de Soro/farmacologia , Elementos Facilitadores Genéticos/efeitos dos fármacos , Elementos Facilitadores Genéticos/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Nucleares/genética , Proteínas Circadianas Period , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Fatores de Tempo , Transfecção , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
3.
Circ Res ; 98(4): 532-9, 2006 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-16424366

RESUMO

Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity.


Assuntos
Senescência Celular , Ritmo Circadiano , Regulação da Expressão Gênica , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Transativadores/genética , Animais , Proteínas CLOCK , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Telômero , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
4.
Circulation ; 114(9): 953-60, 2006 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-16908765

RESUMO

BACKGROUND: Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined. METHODS AND RESULTS: Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II. CONCLUSIONS: We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.


Assuntos
Senilidade Prematura/fisiopatologia , Angiotensina II/farmacologia , Aterosclerose/fisiopatologia , Músculo Liso Vascular/crescimento & desenvolvimento , Animais , Aorta , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Pressão Sanguínea , Células Cultivadas , Modelos Animais de Doenças , Genes Reporter , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Transfecção
5.
Microbes Infect ; 15(1): 11-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23116945

RESUMO

Adipose tissue inflammation induces systemic insulin resistance in persons with obesity and heart failure, and has a crucial role in the progression of these diseases. Chronic inflammatory processes share a common mechanism in which increased production of reactive oxygen species activates p53 and NF-κB signaling, leading to up-regulation of pro-inflammatory cytokine expression and impairment of glucose metabolism. Since inhibition of these processes could slow the progression of various diseases, targeting adipose inflammation has the potential to become a new therapeutic approach for diabetes and heart failure.


Assuntos
Tecido Adiposo/patologia , Diabetes Mellitus/patologia , Insuficiência Cardíaca/patologia , Inflamação/patologia , Animais , Humanos
6.
Cell Metab ; 15(1): 51-64, 2012 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-22225876

RESUMO

Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.


Assuntos
Tecido Adiposo/metabolismo , Insuficiência Cardíaca/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/patologia , Isoproterenol/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pressão , Sistema Nervoso Simpático/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Regulação para Cima
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