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  3. Sequestered SQSTM1/p62 crosstalk with Keap1/NRF2 axis in hPDLCs promotes oxidative stress injury induced by periodontitis

Sequestered SQSTM1/p62 crosstalk with Keap1/NRF2 axis in hPDLCs promotes oxidative stress injury induced by periodontitis

  • Free Radic Biol Med. 2022 Sep;190:62-74. doi: 10.1016/j.freeradbiomed.2022.08.001.
Huiqing Gou 1,  Xu Chen 2,  Xiaoming Zhu 3,  Lu Li 4,  Liguang Hou 5,  Yi Zhou 6,  Yan Xu 7
Affiliations

Affiliations

  • 1 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. Electronic address: huiqing0708@foxmail.com.
  • 2 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. Electronic address: chenxu.hei@outlook.com.
  • 3 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. Electronic address: zhuxm1993@foxmail.com.
  • 4 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. Electronic address: lululi521@163.com.
  • 5 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. Electronic address: houliguang18@163.com.
  • 6 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. Electronic address: dentistjoey@hotmail.com.
  • 7 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. Electronic address: yanxu@njmu.edu.cn.
PMID: 35940517 DOI: 10.1016/j.freeradbiomed.2022.08.001
Abstract

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.

Keywords

NRF2 signaling pathway; Oxidative stress; Periodontitis; Puerarin; SQSTM1/p62.

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