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

一氧化氮（NO）在各种疾病的发病机制和防御机制中起着重要作用，包括微生物感染、炎症、心血管和神经退行性疾病以及癌症。8-硝基鸟嘌呤形成）和其有助于宿主防御微生物病原体的信号传导潜力（Akaike T.et. Proc. Natl. Acad. Sci. USA，100：685- 690，2003）。8-硝基鸟嘌呤及其相关化合物在体内和培养细胞中的形成用8-硝基鸟苷的抗体进行免疫化学评估。用流感病毒和沙门氏菌等多种病原体感染诱导型一氧化氮合酶（inducible NO synthase，iNOS）缺陷的野生型小鼠和同窝小鼠，在野生型小鼠感染灶的上皮细胞和炎性细胞如渗出液巨噬细胞的胞浆中观察到较强的8-硝基鸟苷免疫染色，而iNOS缺陷小鼠则无此免疫染色。 关于我们 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。NO在野生型小鼠中过量产生，但在感染后iNOS缺陷小鼠中被消除;该结果也与8-硝基鸟苷的形成密切相关。类似的免疫染色8-硝基鸟苷是显而易见的，与各种细胞培养取决于内源性和外源性NO的生产。有趣的是，8-硝基鸟苷显示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NOS的所有亚型产生超氧化物。更重要的是，8-硝基鸟苷刺激培养的细胞显著增加细胞保护酶血红素加氧酶-1的表达，使得细胞变得抵抗由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。硝化信号传导），其因此可能以关键的方式有助于在许多疾病过程中发生的细胞保护和宿主防御。少

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