Abstract
BACKGROUND: Periodontitis is an inflammatory disease causing destruction of periodontal tissues. Controlling inflammation is crucial for periodontitis treatment. Prohibitins (PHBs) are emerging targets in the treatment of inflammatory diseases. To identify compounds that would alleviate periodontitis, several small molecules that directly target PHBs and display various pharmacological activities were screened to decrease Porphyromonas gingivalis induced inflammation. Indeed, IN44, a new PHB ligand that has been shown to inhibit STAT3 and NF-kB signaling, suggesting that it may alleviate periodontitis. This study aimed to assess IN44's impact on inflammation elicited by P. gingivalis. METHODS: In vitro, IN44 cytotoxicity was tested on periodontal cells with AlamarBlue and Live/Dead assays. Its effect on cytokines and mitochondrial ROS production were evaluated using ELISA and Mitosox assay. In mouse, systemic inflammation and experimental periodontitis were induced to assess IN44's therapeutic effects. RESULTS: In vitro, IN44 (50 µM) showed no cytotoxicity on periodontal cells. It significantly reduced pro-inflammatory cytokine secretion and mitochondrial ROS in P. gingivalis-infected epithelial cells. Proteome analysis on infected epithelial cells revealed modulation of HSP60 and Akt expression by IN44. In vivo, IN44 demonstrated anti-inflammatory effects in a mouse model of systemic inflammation induced by P. gingivalis, and it improved periodontal healing. CONCLUSION: These findings suggest that PHBs may warrant consideration as therapeutic targets for periodontitis and possibly other inflammatory disorders.