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Research on a novel mechanism for oxidative stress mediated by NO-induced nucleic acid nitration.

NO诱导核酸硝化介导的氧化应激新机制研究。

基本信息

批准号：
15390107
负责人：
AKAIKE Takaaki
金额：
$ 2.69万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Nitric oxide(NO) plays important roles in the pathogenesis and defense mechanism involved in various diseases, including microbial infections, inflammation, cardiovascular and neurodegenerative diseases, and cancer.We currently explored NO-induced nucleic acid modifications with a focus on guanine nitration(e.g., 8-nitroguanine formation) and its signaling potential contributing to host defense against microbial pathogens(Akaike T.et al.Proc.Natl.Acad.Sci.USA,100:685-690,2003). Formation of 8-nitroguanine and its related compounds in vivo and in cultured cells was assessed immunochemically with an antibody for 8-nitroguanosine. Wild-type mice and littermate mice deficient in inducible NO synthase(iNOS) were infected with various pathogens including influenza virus and Salm onella.Strong 8-nitroguanosine immunostaining was observed primarily in the cytosol of epithelial cells and inflammatory cells such as exudate macrophages in the infectious foci of wild-type mice but not iNOS-deficie … More nt mice. This staining generally co-localized with iNOS immunostaining in the tissues and cells. NO was generated in excess in wild-type mice but was eliminated in iNOS-deficient mice after infections ; this result also correlated well with formation of 8-nitroguanosine. Similar immunostaining for 8-nitroguanosine was evident with various cells in culture depending on endogenous and exogenous NO production. It is intriguing that 8-nitroguanosine shows unique redox activity affecting NADPH-dependent reductases including NADPH-cytochrome P450 reductase and all isoforms of NOS to produce superoxide. More importantly, 8-nitroguanosine stimulated the cultured cells to significantly increase the expression of a cytoprotective enzyme heme oxygenase-1, so that the cells became resistant to apoptosis and cell death induced by infection-associated cytotoxicity and nutrient starvation.The present results prompt us a new paradigm for redox signaling via guanine nitration caused by oxidative and nitrative stress(i.e., nitrative signaling), which may thus contribute in a critical way to the cytoprotection and host defense occurring during many disease processes. Less

一氧化氮 (NO) 在多种疾病的发病机制和防御机制中发挥着重要作用，包括微生物感染、炎症、心血管和神经退行性疾病以及癌症。我们目前探索 NO 诱导的核酸修饰，重点关注鸟嘌呤硝化（例如 8-硝基鸟嘌呤形成）及其有助于宿主防御微生物的信号潜力。病原体(Akaike T.等人.Proc.Natl.Acad.Sci.USA,100:685-690,2003)。使用 8-硝基鸟苷抗体对体内和培养细胞中 8-硝基鸟嘌呤及其相关化合物的形成进行免疫化学评估。缺乏诱导型一氧化氮合酶（iNOS）的野生型小鼠和同窝小鼠感染了包括流感病毒和沙门氏菌在内的多种病原体。在野生型小鼠的感染灶中，主要在上皮细胞和炎症细胞（例如渗出性巨噬细胞）的细胞质中观察到强的8-硝基鸟苷免疫染色，但在iNOS缺陷型小鼠中没有观察到强8-硝基鸟苷免疫染色。 ... 更多 nt 小鼠。这种染色通常与组织和细胞中的 iNOS 免疫染色共定位。在野生型小鼠中，NO 产生过量，但在 iNOS 缺陷型小鼠中，感染后 NO 被消除；该结果也与8-硝基鸟苷的形成密切相关。根据内源性和外源性 NO 的产生，8-硝基鸟苷的类似免疫染色在培养的各种细胞中是明显的。有趣的是，8-硝基鸟苷表现出独特的氧化还原活性，影响 NADPH 依赖性还原酶，包括 NADPH-细胞色素 P450 还原酶和所有 NOS 亚型，以产生超氧化物。更重要的是，8-硝基鸟苷刺激培养的细胞显着增加细胞保护酶血红素加氧酶-1的表达，从而使细胞对感染相关的细胞毒性和营养饥饿诱导的细胞凋亡和细胞死亡具有抵抗力。目前的结果为我们提供了通过氧化和硝化引起的鸟嘌呤硝化的氧化还原信号传导的新范例。因此，这可能对许多疾病过程中发生的细胞保护和宿主防御发挥关键作用。较少的