| Budget Amount *help |
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
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
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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
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