Continuous presence of H₂O₂ induces mitochondrial-mediated, MAPK- and caspase-independent growth inhibition and cytotoxicity in human gingival fibroblasts.
Continuous presence of H₂O₂ induces mitochondrial-mediated, MAPK- and caspase-independent growth inhibition and cytotoxicity in human gingival fibroblasts.
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DOI：
10.1016/j.tiv.2012.01.022
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
Ji-Yeon Yu;Seung‐Youp Lee;Young-Ok Son;Xianglin Shi;Soon-Sun Park;Jeong-Chae Lee
中科院分区：
文献类型：
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作者：
Ji-Yeon Yu;Seung‐Youp Lee;Young-Ok Son;Xianglin Shi;Soon-Sun Park;Jeong-Chae Lee
活性氧（ROS）的持续生成是牙周炎症过程中最重要的事件之一。过氧化氢（H2O2）广泛应用于牙科诊所。许多研究者试图阐明h2o2对人牙龈成纤维细胞（HGFs）的确切影响。这些研究表明h2o2诱导细胞生长抑制和凋亡。然而，h2o2诱导hgf细胞死亡的机制尚不完全清楚。在这项研究中，我们研究了连续生成的h2o2如何影响葡萄糖氧化酶（GO）对hgf的活力和增殖的影响。我们还探讨了持续存在的h2o2诱导细胞死亡的机制。氧化石墨烯处理不仅抑制了HGF的生长和增殖，而且在没有典型凋亡特征（如核DNA阶梯）的HGF中诱导细胞死亡。氧化石墨烯介导的细胞毒性与生成的细胞内ROS水平成正比，而不是与细胞抗氧化活性的变化成正比。氧化石墨烯处理还导致线粒体膜电位的丧失和线粒体凋亡因子的重新定位。也有一个急性和严重的消耗细胞ATP水平。然而，没有一种针对丝裂原活化蛋白激酶（MAPKs）或pancaspase的药物抑制剂能阻止氧化石墨烯诱导的细胞死亡。过氧化氢酶或牛油果苷均可显著减弱氧化石墨烯介导的HGFs细胞毒性，从而提示抗氧化剂对氧化石墨烯介导的牙龈损伤具有保护作用。本研究表明，持续生成的h2o2不仅抑制hgf的活力和增殖，还通过线粒体应激介导的、不依赖于MAPK和caspase的途径导致细胞收缩/坏死死亡。
The continuous generation of reactive oxygen species (ROS) is one of the most important events that occur during periodontal inflammation. Hydrogen peroxide (H2O2) is widely used in dental clinics. Many investigators have tried to elucidate the exact effect of H2O2on human gingival fibroblasts (HGFs). These studies have shown that H2O2induces growth inhibition and apoptosis in cells. However, the mechanisms involved in H2O2-induced cell death in HGFs are not completely understood. In this study, we examine how continuously generated H2O2affects the viability and proliferation of HGFs using glucose oxidase (GO). We also explored the mechanisms by which the continuous presence of H2O2induces cell death. GO treatment not only inhibited HGF growth and proliferation, but it also induced cell death in HGFs without typical apoptotic features such as nuclear DNA laddering. This GO-mediated cytotoxicity was proportional to the levels of intracellular ROS that were generated, rather than proportional to changes of cellular antioxidant activities. GO treatment also resulted in the loss of mitochondrial membrane potential and the relocation of mitochondrial apoptogenic factors. There was also an acute and severe depletion of cellular ATP levels. However, none of the pharmacological inhibitors specific for mitogen-activated protein kinases (MAPKs) or pancaspase prevented GO-induced cell death. Treatment with either catalase or acteoside significantly attenuated the GO-mediated cytotoxicity in the HGFs, thereby suggesting a protective effect of antioxidants against ROS-mediated gingival damage. Here we demonstrate that continuously generated H2O2not only inhibits the viability and proliferation of HGFs, but also causes pyknotic/necrotic cell death through mitochondrial stress-mediated, MAPK- and caspase-independent pathways.