Sinensetin protects against periodontitis through binding to Bach1 enhancing its ubiquitination degradation and improving oxidative stress

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Zhiyao Yuan, Junjie Li, Fuyu Xiao, Yu Wu, Zhiting Zhang, Jiahong Shi, Jun Qian, Xudong Wu, Fuhua Yan
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Abstract

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm. The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress. Sinensetin (Sin) is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities. Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms. We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells (PDLCs) under inflammatory conditions. Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo. By molecular docking, we identified Bach1 as a strong binding target of Sin, and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays. Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter, subsequently upregulating the expression of the key antioxidant factor HO-1. Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects. Additionally, we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1, thereby inducing HO-1 expression and inhibiting oxidative stress. Overall, Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

Abstract Image

Sinensetin 通过与 Bach1 结合,增强其泛素化降解并改善氧化应激,从而预防牙周炎
牙周炎是一种由龈下生物膜诱发的慢性炎症和免疫反应性疾病。由于过度的炎症反应和氧化应激,对易感患者的治疗效果往往不尽人意。西奈素(Sin)是一种具有抗炎和抗氧化活性的天然多甲氧基黄酮类化合物。我们的研究旨在探讨 Sin 对牙周炎的有益作用及其具体的分子机制。我们发现,在炎症条件下,Sin 可减轻氧化应激和牙周韧带细胞(PDLCs)的炎症水平。给结扎诱导的牙周炎模型大鼠服用 Sin 对体内牙周炎有保护作用。通过分子对接,我们发现Bach1是Sin的强结合靶点,并通过细胞热位移实验和免疫荧光实验进一步验证了这种结合。染色质免疫沉淀-定量聚合酶链反应结果也显示,Sin阻碍了Bach1与HMOX1启动子的结合,从而上调了关键抗氧化因子HO-1的表达。在敲除和过表达 Bach1 的进一步功能实验中,我们验证了 Bach1 是 Sin 发挥抗氧化作用的关键靶点。此外,我们还证明,Sin 通过增强 Bach1 的泛素化降解,促使 Bach1 的减少,从而诱导 HO-1 的表达,抑制氧化应激。总之,通过与 Bach1 的靶向结合,Sin 可以成为治疗牙周炎的一种有前途的候选药物。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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