Department of Periodontology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
Free Radic Biol Med. 2022 Sep;190:62-74. doi: 10.1016/j.freeradbiomed.2022.08.001. Epub 2022 Aug 5.
Periodontitis is a recognized multifactorial inflammatory chronic disease, however, the exact role of oxidative stress in the pathogenesis of periodontitis is undefined. This study aims to imply the mechanism of NRF2-regulated oxidative stress and inflammatory responses under periodontitis and explored the novelty therapeutic targets. We first demonstrate that redox imbalance caused by inhibited NRF2 signaling pathway is induced in periodontium during hypoxia and bacterial events. Then we propose that LPS from P. gingivalis and hypoxia stimuli could inhibit hPDLCs proliferation and GSH level, promote ROS production, lipid peroxidation level, and pro-inflammatory cytokines such as IL-6, TNF-α, and IL-17 level caused by the inhibited PI3K/AKT/mTOR pathway and sequential sequestered crosstalk between selective autophagy SQSTM1/p62 and Keap1/NRF2 axis accompanied by the reinforced NRF2 ubiquitination degradation and inactivated NRF2 nuclear translocation. Overexpression of NRF2 and SQSTM1 can protect hPDLCs from oxidative stress and inflammation exacerbation because of enhanced NRF2 activity. Further, the antioxidant and anti-inflammation potential of puerarin is verified in vitro and in experimental periodontitis in mice through diminishing above negative feedback loop mechanically. Altogether, we speculate that NRF2-mediated redox homeostasis is a profound candidate for one of the prominent roles in periodontitis pathogenesis and suggest puerarin as a promising therapeutic target.
牙周炎是一种公认的多因素炎症性慢性疾病，然而，氧化应激在牙周炎发病机制中的确切作用尚不清楚。本研究旨在探讨 NRF2 调控的氧化应激和炎症反应在牙周炎中的作用机制，并探索新的治疗靶点。我们首先证明，在缺氧和细菌事件期间，NRF2 信号通路受到抑制会导致牙周组织中的氧化还原失衡。然后，我们提出牙龈卟啉单胞菌 LPS 和缺氧刺激可以通过抑制 PI3K/AKT/mTOR 通路，以及选择性自噬 SQSTM1/p62 和 Keap1/NRF2 轴之间的顺序隔离串扰，抑制 hPDLCs 的增殖和 GSH 水平，促进 ROS 产生、脂质过氧化水平以及促炎细胞因子如 IL-6、TNF-α 和 IL-17 的产生，从而导致 NRF2 泛素化降解增强和 NRF2 核转位失活。NRF2 和 SQSTM1 的过表达可以通过增强 NRF2 活性来保护 hPDLCs 免受氧化应激和炎症加重。此外，我们通过机械地减弱上述负反馈环，在体外和实验性牙周炎小鼠中验证了葛根素的抗氧化和抗炎潜力。综上所述，我们推测 NRF2 介导的氧化还原平衡是牙周炎发病机制中的一个重要候选因素，并提出葛根素是一种有前途的治疗靶点。
