Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul 120-749, Korea.
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo 113-8519, Japan.
Free Radic Biol Med. 2012 Feb 1;52(3):607-615. doi: 10.1016/j.freeradbiomed.2011.11.010. Epub 2011 Nov 20.
Oxidative stress linked to DNA damage is involved in the pathogenesis of Helicobacter pylori-associated gastric diseases. The DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair, and apoptosis through the activation of ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) and their target proteins. However, neither H. pylori-induced DDR nor the effects of antioxidants on the DNA damage have been established. This study aimed to investigate the detailed process of H. pylori-induced DNA damage and to examine whether lycopene, a natural antioxidant, inhibits DNA damage and cellular response of gastric epithelial AGS cells infected with H. pylori. AGS cells were cultured with H. pylori in Korean isolates and treated with or without lycopene. Cell viability, DNA damage indices, levels of 8-OH-dG, and reactive oxygen species (ROS) as well as cell-cycle distributions were determined. The activation of ATM, ATR, Chk1, and Chk2; histone H2AX focus formation; activation and induction of p53; and levels of Bax and Bcl-2 and poly(ADP-ribose) polymerase-1 (PARP-1) were assessed. The results showed that H. pylori induced apoptosis in AGS cells with increased Bax and decreased Bcl-2 expression as well as PARP-1 cleavage. Culture with H. pylori led to increases in intracellular ROS, 8-OH-dG, double-strand DNA breaks (DSBs), and DNA fragmentation. H. pylori induced activation of the ATM/Chk2 and ATR/Chk1 pathways, phosphorylation of H2AX and p53, and a delay in the progression of the cells entering the S phase. Lycopene inhibited H. pylori-induced increases in ROS, apoptosis, alterations in cell-cycle distribution, DSBs, and ATM- and ATR-mediated DDR in AGS cells. In conclusion, lycopene may be beneficial for treatment of H. pylori-induced gastric diseases associated with oxidative DNA damage.
氧化应激与 DNA 损伤有关,参与了幽门螺杆菌相关胃疾病的发病机制。DNA 损伤反应 (DDR) 通过激活共济失调毛细血管扩张突变 (ATM) 和 ATM 与 Rad3 相关 (ATR) 及其靶蛋白,协调细胞周期转变、DNA 修复和细胞凋亡。然而,幽门螺杆菌诱导的 DDR 以及抗氧化剂对 DNA 损伤的影响尚未确定。本研究旨在探讨幽门螺杆菌诱导的 DNA 损伤的详细过程,并研究番茄红素(一种天然抗氧化剂)是否抑制感染幽门螺杆菌的胃上皮 AGS 细胞的 DNA 损伤和细胞反应。将 AGS 细胞与幽门螺杆菌在韩国分离株中共同培养,并加入或不加入番茄红素进行处理。测定细胞活力、DNA 损伤指数、8-OH-dG 水平和活性氧 (ROS) 以及细胞周期分布。评估 ATM、ATR、Chk1 和 Chk2 的激活;组蛋白 H2AX 焦点形成;p53 的激活和诱导;以及 Bax 和 Bcl-2 的水平和多聚(ADP-核糖)聚合酶-1 (PARP-1)。结果表明,幽门螺杆菌诱导 AGS 细胞凋亡,Bax 表达增加,Bcl-2 表达减少,PARP-1 裂解。与幽门螺杆菌共培养导致细胞内 ROS、8-OH-dG、双链 DNA 断裂 (DSBs) 和 DNA 片段化增加。幽门螺杆菌诱导 ATM/Chk2 和 ATR/Chk1 通路的激活、H2AX 和 p53 的磷酸化以及细胞进入 S 期的进程延迟。番茄红素抑制了幽门螺杆菌诱导的 ROS 增加、凋亡、细胞周期分布改变、DSBs 以及 ATM 和 ATR 介导的 AGS 细胞 DDR。总之,番茄红素可能有益于治疗与氧化应激诱导的 DNA 损伤相关的幽门螺杆菌引起的胃部疾病。