TY  - JOUR
AU  - Xin, Liangjing
AU  - Zhou, Fuyuan
AU  - Zhang, Chuangwei
AU  - Zhong, Wenjie
AU  - Xu, Shihan
AU  - Jing, Xuan
AU  - Wang, Dong
AU  - Wang, Si
AU  - Chen, Tao
AU  - Song, Jinlin
PY  - 2022
TI  - Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system
JO  - International Journal of Oral Science
SN  - 1674-2818
SP  - 27
VL  - 14
AB  - Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate (4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time, the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2−/− mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment. Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction, ameliorate local inflammation for more predictable periodontitis.
UR  - https://doi.org/10.1038/s41368-022-00177-1
DO  - 10.1038/s41368-022-00177-1