Bomidin attenuates inflammation of periodontal ligament stem cells and periodontitis in mice via inhibiting ferroptosis

  • Int Immunopharmacol. 2023 Dec 22:127:111423. doi: 10.1016/j.intimp.2023.111423.
Wei Wu  1 ,  Guoqing Li  1 ,  Shuo Dong  1 ,  Catherine Huihan Chu  2 ,  Shanshan Ma  1 ,  Zhewei Zhang  1 ,  Shanshan Yuan  1 ,  Jin Wu  1 ,  Zixiang Guo  1 ,  Yue Shen  1 ,  Jiaohong Wang  1 ,  Chunbo Tang  3
Affiliations
  • 1. Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
  • 2. Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China; Department of Orthodontic, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 3. Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. Electronic address: [email protected].
PMID: 38141410 DOI: 10.1016/j.intimp.2023.111423
Abstract

Aim: Periodontitis is a prevalent oral immunoinflammatory condition that is distinguished by the compromised functionality of periodontal ligament stem cells (PDLSCs). Bomidin, a new Recombinant antimicrobial peptide (AMP), exhibits Antibacterial properties and modulates immune responses. Nevertheless, the precise anti-inflammatory impact of bomidin in periodontitis has yet to be fully elucidated. Thus, the study aimed to clarified the role of bomidin in modulating inflammation and its underlying mechanisms.

Methods: TNF-α was applied to treating PDLSCs for establishing a cell model of periodontitis. Bomidin, RSL3, ML385 and cycloheximide were also used to treat PDLSCs. Transcriptome Sequencing, RT-qPCR, western blot, immunofluorescence, immunohistochemistry, Fe2+ detection probe, molecular docking, Co-IP assay, ubiquitination assay and murine models of periodontitis were used.

Results: Our study demonstrated that bomidin effectively suppressed inflammation in PDLSCs stimulated by TNF-α, through down-regulating the MAPK and NF-κB signaling pathways. Furthermore, bomidin exerted inhibitory effects on Ferroptosis and activated the KEAP1/Nrf2 pathway in the TNF-α group. There is a strong likelihood of bonding bomidin with KEAP1 protein, which facilitated the degradation of KEAP1 protein via the ubiquitin-proteasome pathway, leading to an enhanced translocation of Nrf2 protein to the nucleus.

Conclusions: Bomidin can directly bond to KEAP1 protein, resulting in the degradation of KEAP1 through the ubiquitin-proteasome pathway, thereby further activating the KEAP1/Nrf2 pathway. The upregulation of the KEAP1/Nrf2 signaling pathway was found to contribute to the suppression of Ferroptosis, ultimately alleviating inflammation in treatment of periodontitis.

Keywords
Bomidin; Ferroptosis; Keap1; Periodontitis; Ubiquitylation.
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