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Modulating the Affinity of KEAP1-Nrf2 Complex as a New Target for Periodontitis

Liangjing Xin, Fuyuan Zhou, Tao Chen*, Jinlin Song*

Department of Oral Diseases and Biomedical Sciences, University of Chongqing Medical, Chongqing, China

*Corresponding Author:
Tao Chen
Department of Oral Diseases and Biomedical Sciences,
University of Chongqing Medical,
Chongqing,
China
E-mail: [email protected]
Jinlin Song
Department of Oral Diseases and Biomedical Sciences,
University of Chongqing Medical,
Chongqing,
China
E-mail: [email protected];

Received: 12-Sep-2022, Manuscript No. JDS-22-71985; Editor assigned: 15-Sep-2022, PreQC No. JDS-22-71985 (PQ); Reviewed: 29-Sep-2022, QC No. JDS-22-71985; Revised: 06-Oct-2022, Manuscript No. JDS-22-71985 (R); Published: 12-Oct-2022, DOI: 10.4172/2320-7949.10.6.002

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About the Study

In the development of periodontitis, Damage-Associated Molecular Patterns (DAMPs) trigger innate immune response by affecting the metabolic adaptation, while Pathogen-Associated Molecular Patterns (PAMPs) bind to Pattern Recognition Receptors (PRRs) and activate the adaptive immune response, directly or indirectly driving a permanent pro-inflammatory state and leading to oxidative damage [1-5]. Recently, there has been increasing interest in the role of oxidative stress triggered by DAMPs and PAMPs in establishing the microenvironment that underlies the progression of periodontitis and increased attachment loss. Effector cells (e.g., macrophages) in periodontal tissue have specialized defense systems to minimize oxidative damage. A key step in preventing oxidative damage involves the activation of antioxidants, which is mainly regulated by the Antioxidant Response Elements (AREs) downstream of the Nuclear factor E2-related factor 2 (Nrf2) [3,6]. Under physiological conditions, cytoplasmic Nrf2 binds to Kelch-like ECH-associated protein 1 (KEAP1), a cytoskeletal binding protein that mediates the degradation of Nrf2 protein through the CUL3 ubiquitin-proteasome system, thereby avoiding the unneeded transcription of AREs and maintaining cellular redox homeostasis. During periods of periodontitis, Nrf2 is released from KEAP1, allowing its translocation to the nucleus and initiating the antioxidant response cascade. As an adaptor protein of Nrf2, KEAP1 serves as the primary Nrf2 regulatory mechanism [7]. Therefore, modulating the interaction between Keap1 and Nrf2 could provide new therapeutic options for alleviating oxidative stress and improving periodontal treatments. Metabolites emerged as immune effector molecules that play specific roles in the regulation of the immune system. They act as second messengers associated with transcription factors, modifying the structure and function of proteins and altering cellular signaling pathways. Immunometabolism treatment is the latest proposed therapeutic concept, in which an endogenous metabolite itaconate has been proven to possess a prominent immunomodulatory function. Itaconate is diverted from the tricarboxylic acid (TCA) cycle and is synthesized from aconitate via IRG1/aconitate decarboxylase 1 (ACOD1) [8]. Four-octyl itaconate (4-OI), a cell-permeable itaconate derivative, has been used as a substitute for itaconate for immunomodulation. 4-OI induces alkylation of cysteine residues on KEAP1, including cysteine 151 (C151). Alkylation of C151 inactivates KEAP1 and subsequently initiates Nrf2-dependent antioxidant cascade [9]. As expected, our previous study innovatively proposed that 4-OI can be a novel option for periodontitis treatment. In vitro, we have shown that 4-OI exerted protective effects on inflammation control and oxidative damage [10]. Molecular docking simulation and co-immunoprecipitation assay revealed the binding sites and potential mechanism of 4-OI for periodontitis management. This was confirmed as silencing Nrf2 to down regulate the expression of AREs blocked the therapeutic effect of 4-OI. Meanwhile, we applied Nrf2-/- mice for the first time to verify in vivo that 4-OI has no salvage effect on alveolar bone loss, underlining the importance of modulating the affinity of KEAP1-Nrf2 complex in 4-OI-mediated periodontitis treatment. Taken together, as a novel Nrf2 agonist, 4-OI shows promising immunometabolic modulation in periodontitis treatment (Figure 1).The metabolite 4-OI plays a crucial regulatory role in periodontitis process and modulating the affinity of KEAP1 and Nrf2 may help as a new target for periodontitis treatment.

dental-sciences-periodontal

Figure 1: Preferred choice of higher learning institution.

References

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