The roles of stress‐induced premature senescence and Akt/FoxO1 signaling in periapical lesions.

Objectives: There is little knowledge about oxidative stress‐induced senescence involvement in apical periodontitis. Here, we explored its molecular mechanism in periapical lesions. Methods: Ten cases of radicular cysts and five cases of periapical granulomas were randomly selected. Immunohistochemical analysis was performed to detect the expression and correlation between Senescence‐associated factor polymerase I and transcript release factor (PTRF) and Akt/FoxO1 signaling. Human periodontal ligament cells (hPDLCs) pretreated with LY294002 were exposed to H2O2‐induced oxidative stress conditions and then cell proliferation, senescence, apoptosis, and associated signaling were evaluated by EdU labeling, β‐galactosidase assay, RT‐qPCR, and western blot analysis, respectively. Results: Polymerase I and transcript release factor and Akt/FoxO1 signaling were more frequently expressed in the radicular cyst than in periapical granulomas. Notably, cells in radicular cysts showed Akt activation, FoxO1 phosphorylation, and cytoplasmic translocation. In vitro, prominent H2O2‐induced senescence was observed in hPDLCs. LY294002, a PI3K inhibitor, attenuated the expression levels of senescence (Klotho, P16INK4), apoptosis (Bad, Fas), phosphorylated Akt, and phosphorylated FoxO1; however, did not affect cell proliferation. Conclusions: Our data indicated that senescence is present in clinical periapical lesions, and Akt/FoxO1 signaling is involved in the H2O2‐induced cellular senescence, which could serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]