Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system

Abstract

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.

Clostridium butyricum MIYAIRI 588 alleviates periodontal bone loss in mice with diabetes mellitus

“…Oxidative damage because of Nrf2 knockout leads to more severe periodontitis 43 . Our group previously performed in vivo and in vitro experiments to confirm the protection of Nrf2 against periodontitis development 44 . Additionally, activation of Nrf2 and the downstream genes such as Hmox1 and Nqo1 can ameliorate DMP 45 .…”

“…43 Our group previously performed in vivo and in vitro experiments to confirm the protection of Nrf2 against periodontitis development. 44 Additionally, activation of Nrf2 and the downstream genes such as Hmox1 and Nqo1 can amelio-rate DMP. 45 Inspired by the finding that 4-HBA attenuated periodontal bone loss and systemic oxidative damage, we next tried to ascertain whether 4-HBA exerted a protective effect by promoting Nrf2 activation.…”

Itaconate: A Potent Macrophage Immunomodulator

“…Another study also showed that 4-OI significantly inhibited ROS production by activating Nrf2, which in turn caused downregulation of AMPK phosphorylation levels, and improved free fatty acid-induced oxidative stress and lipid metabolism disorders in hepatocytes [ 43 ]. Itaconate has also attenuated inflammatory damage through activation of Nrf2 in other diseases such as osteoarthritis [ 44 – 47 ], nerve injury [ 48 , 49 ], cardiovascular disease [ 50 , 51 ], systemic lupus erythematosus [ 52 ], vitiligo [ 53 ], periodontitis [ 54 ], fungal keratitis [ 55 ], and diabetic wound repair [ 56 ]. Consequently, itaconate, as an Nrf2 agonist, may present new therapeutic opportunities for many inflammatory diseases.…”

The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases

“…As described in ‘5.2.1 Regulating KEAP1 activity’, itaconate increases the alkylation of cysteine residues 151, 257, 273, 288, and 297 on KEAP1, enhances the degradation of KEAP1 and leads to the dissociation and activation of Nrf2. Bambouskova et al demonstrated that itaconate and DI reacted with glutathione and activated Nrf2 [ 21 ], then in the process of periodontal destruction [ 179 ], liver fibrosis [ 72 ], vitiligo [ 180 ], pulmonary fibrosis [ 181 ], renal injury [ 175 ], osteoporosis [ 182 ], and neurodegenerative diseases [ 183 ], itaconate and its derivatives functioned as activators of the Nrf2 pathway and attenuated oxidative stress. Moreover, Yi et al reported that itaconate activated Nrf2 to mitigate oxidative stress in liver IRI, which demonstrated the antioxidant effect in nonimmune cells [ 163 ].…”