Redox regulation by glutathione and the roles of reactive oxygen and nitrogen species

活性氧（ROS）如超氧阴离子（O_2^-）、过氧化氢（H_2O_2）和羟基自由基（OH）等，过量存在时是公认的生物危害物质，这种情况被称为“氧化应激”。ROS作为生物氧化的副产物在细胞内产生，并且被认为在几种病理生理事件中起重要作用，包括炎症、诱变和衰老。近年来，活性氧和氧化还原平衡被认为是细胞内信号，具有广泛的生物学作用。因此，在本项目中，我们展示了ROS、谷胱甘肽和氧化还原平衡的新生物学功能。1）还原糖和二羰基化合物对谷胱甘肽过氧化物酶的灭活2）过氧化物酶家族的新生物学功能：Peroxiredoxin IV的纯化、克隆及其在细胞外空间的抗氧化特性3）铜蓝蛋白（Cp）具有谷胱甘肽过氧化物酶-类似的活性连同其铁氧化酶活性，并将完全除去芬顿化学和脂质过氧化所需的主要反应物。Cp与细胞外髓过氧化物酶（MPO）结合，阻止MPO产生HOC 1，HOC 1是一种强氧化剂，可导致分子损伤。4）在缺乏从头蛋白合成的情况下，羟基自由基加速中性粒细胞和癌细胞与内皮细胞的粘附5）谷胱甘肽、谷胱甘肽过氧化物酶和γ GCS的抗氧化功能机制，6）一氧化氮使谷胱甘肽过氧化物酶失活，积累的过氧化氢诱导肝素结合EGF样生长因子（HB-EGF）作为大鼠主动脉平滑肌细胞通过JNK途径的自分泌保护因子。

Reactive oxygen species(ROS) such as the superoxide anion (O_2^-), hydrogen peroxide (H_2O_2) and the hydroxyl radical (OH) are represent putative biohazards when present in excess, a condition which,is referred to as "oxidative stress". ROS are generated within cells as byproducts of biological oxidations and are thought to play important roles in several pathophysiologic events, including inflammation, mutagenesis, and aging. Recently ROS and redox balance are thought to act as an intracellular signal and have a wide variety of biological action. So in this project we have demonstrated new biological functions of ROS, glutathione and redox balance.1)Inactivation of glutathine peroxidase by reducing sugars and dicarbonyl compounds2)New biological faction of peroxiredixin family : Purification and cloning of peroxiredoxin IV and its antioxidative property in extracellular space3)Ceruloplasmin(Cp) has a glutathione peroxidase-like activity together with its ferroxidase activity and would completely remove the primary reactants required for both Fenton chemistry and lipid peroxidation. And Cp binds to extracellular myeloperoxidase(MPO) and prevents MPO making HOC1, a powerful oxidant which will lead to molecular damage.4)Hydroxyl radicals accelerates the adhesion of neutrophils and cancer cells to endothelial cells in the absence of de novo protein synthesis5)Mechanisms of anti-oxidative functions of glutathione, giutathione peroxidase and γ GCS, especially involvement of signal transduction.6)Nitric oxide inactivates glutathione peroxidase and the accumulated hydrogen peroxide induces Heparin-binding EGF-like growth factor(HB-EGF) as an autocrine protective factor in rat aortic smooth muscle cells via the JNK pathway.