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1.
J Immunol ; 201(12): 3677-3682, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30413670

RESUMO

RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell-specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow-derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ∼2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at -1961/-1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand-generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo.


Assuntos
Células Dendríticas/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T Reguladores/imunologia , Transativadores/metabolismo , Família Aldeído Desidrogenase 1 , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Animais , Células Cultivadas , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fatores Reguladores de Interferon/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , Retinal Desidrogenase , Transativadores/genética , Ativação Transcricional , Tirosina Quinase 3 Semelhante a fms/imunologia
2.
Toxicol In Vitro ; 25(8): 1581-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21664962

RESUMO

Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. However, recent studies have now demonstrated that chelerythrine can induce the loss of mitochondrial membrane potential (ΔΨm), a membrane permeability transition (MPT), and the subsequent activation of the mitochondrial apoptotic pathway, even in the cells deficient in Bax and Bak. This suggests the existence of an alternative Bax/Bak-independent pathway for apoptosis. The generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC) is also implicated in the cytotoxity elicited by chelerythrine. In our current study, we show that chelerythrine induces the rapid apoptotic death of H9c2 cardiomyocyte-derived cells within 8 min of treatment. The proteolytic activation of caspase9 and caspase3, crucial mediators of the mitochondrial apoptotic pathway, are also observed within 6 min of exposure to this drug. The generation of ROS is detected but at only marginal levels in the treated cells. The inhibition of the mitochondrial ETC by rotenone and malonate had almost no effects on ROS generation but in both cases effectively inhibited both cell death and the caspase activation induced by chelerythrine. Hence, chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria.


Assuntos
Antineoplásicos/toxicidade , Benzofenantridinas/toxicidade , Neoplasias Cardíacas/patologia , Neoplasias de Tecido Muscular/patologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cardíacas/metabolismo , Malonatos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias de Tecido Muscular/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia , Desacopladores/farmacologia
3.
Leg Med (Tokyo) ; 13(3): 148-50, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21277247

RESUMO

A 54-year-old man, who lived alone, was hospitalized due to rapid deterioration of the general condition over a three-week period caused by alcoholic cirrhosis. One month after he left hospital, he was found dead in his house by his friend. Three days before he was found dead, he had met his friend and seemed to be in poor condition. Autopsy was conducted by a medical examiner to clarify the cause of death. Externally, signs of severe jaundice were apparent over the whole body, along with extensive abdominal swelling and edema of the extremities. Autopsy findings demonstrated that the abdominal cavity contained an amount of massive turbid and slight pale reddish brown ascites (23 l). There were no findings of severe peritoneal inflammation. The liver (650 g) was elastic hard and had a micro-nodular surface, which showed severe atrophy. Microscopic examination of the liver showed clear pseudolobule with severe fibrosis in the stroma. There were no significant changes in the heart or brain. The stomach was empty and only a slight amount of intestinal contents. There was no ethanol detected in the blood or urine. The direct cause of his death was circulatory dysfunction due to massive accumulation of the ascites. The reasons for the massive ascites accumulation over 20 l in this case were (1) that he had no serious complications other than ascites; and (2) he did not have any medical treatment just before his death.


Assuntos
Ascite/etiologia , Cirrose Hepática Alcoólica/complicações , Autopsia , Evolução Fatal , Humanos , Japão , Cirrose Hepática Alcoólica/patologia , Masculino , Pessoa de Meia-Idade
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