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首页> 外文期刊>Biochemical Pharmacology >Inhibition of nitric oxide production by the carbazole compound LCY-2-CHO via blockade of activator protein-1 and CCAAT/enhancer-binding protein activation in microglia.
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Inhibition of nitric oxide production by the carbazole compound LCY-2-CHO via blockade of activator protein-1 and CCAAT/enhancer-binding protein activation in microglia.

机译:咔唑化合物LCY-2-CHO通过阻断小胶质细胞中活化蛋白1和CCAAT /增强子结合蛋白的活化来抑制一氧化氮的产生。

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摘要

Excessive nitric oxide (NO) production by activated microglia plays a critical role in neurodegenerative disorders. In this study, we found that 9-(2-chlorobenyl)-9H-carbazole-3-carbaldehyde (LCY-2-CHO) suppressed the NO production in lipopolysaccharide (LPS)/interferon-gamma (IFNgamma)-stimulated murine microglial N9 and BV-2 cells and in LPS-stimulated N9 cells and rat primary microglia. LCY-2-CHO had no cytotoxic effect on microglia. In activated N9 cells, LCY-2-CHO abolished the expression of inducible nitric oxide synthase (iNOS) protein and mRNA but failed to alter the stability of expressed iNOS mRNA and the enzymatic activity of expressed iNOS protein. LCY-2-CHO did not block DNA-binding activity of nuclear factor-kappaB (NF-kappaB) or cyclic AMP response element-binding protein (CREB), but abolished that of activator protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP) and nuclear factor IL6 (NF-IL6). LCY-2-CHO attenuated the nuclear levels of c-Jun and C/EBPbeta, but not those of p65, p50, C/EBPdelta, signal transducer and activator of transcription-1 (STAT-1) or the nuclear expression of IFN regulatory factor-1 (IRF-1). LCY-2-CHO had no effect on the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), MAPK-activated protein kinase-2 (MAPKAPK-2), STAT-1, CREB or c-Jun in LPS/IFNgamma-stimulated N9 cells, whereas it attenuated the phosphorylation of C/EBPbeta at Ser105 and Thr235 residues, which occurred concomitantly with LCY-2-CHO inhibition of C/EBPbeta expression and phosphorylation. Taken together, these results suggest that LCY-2-CHO inhibits NO production in microglia through the blockade of AP-1 and C/EBP activation.
机译:活化的小胶质细胞过量生成一氧化氮(NO)在神经变性疾病中起关键作用。在这项研究中,我们发现9-(2-氯苯基)-9H-咔唑-3-甲醛(LCY-2-CHO)抑制了脂多糖(LPS)/干扰素-γ(IFNγ)刺激的鼠小神经胶质N9中NO的产生。和BV-2细胞,以及LPS刺激的N9细胞和大鼠原发性小胶质细胞。 LCY-2-CHO对小胶质细胞没有细胞毒性作用。在活化的N9细胞中,LCY-2-CHO废除了诱导型一氧化氮合酶(iNOS)蛋白和mRNA的表达,但未能改变表达的iNOS mRNA的稳定性和表达的iNOS蛋白的酶活性。 LCY-2-CHO不会阻断核因子-kappaB(NF-kappaB)或环状AMP反应元件结合蛋白(CREB)的DNA结合活性,但废除了激活蛋白1(AP-1),CCAAT /增强子结合蛋白(C / EBP)和核因子IL6(NF-IL6)。 LCY-2-CHO减弱c-Jun和C / EBPbeta的核水平,但不减弱p65,p50,C / EBPdelta,信号转导子和转录激活因子1(STAT-1)或IFN调节子的核表达。因子1(IRF-1)。 LCY-2-CHO对p38丝裂原活化蛋白激酶(MAPK),细胞外信号调节激酶(ERK),c-Jun NH(2)-末端激酶(JNK),MAPK活化蛋白激酶的磷酸化没有影响-2(MAPKAPK-2),STAT-1,CREB或c-Jun在LPS /IFNγ刺激的N9细胞中,而它减弱了Ser105和Thr235残基处C / EBPbeta的磷酸化,这与LCY-2-CHO同时发生抑制C / EBPbeta表达和磷酸化。综上所述,这些结果表明,LCY-2-CHO通过阻断AP-1和C / EBP的活化来抑制小胶质细胞中NO的产生。

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