Cao Niuben, Liu Xiaomeng, Hou Yubo, Deng Yu, Xin Yu, Xin Xirui, Xiang Xinchen, Liu Xinchan, Yu Weixian
Department of Periodontics, Hospital of Stomatology, Jilin University, Changchun, China.
Department of Dental Implantology, Hospital of Stomatology, Jilin University, Changchun, China.
Front Pharmacol. 2023 Jul 19;14:1221053. doi: 10.3389/fphar.2023.1221053. eCollection 2023.
Periodontitis is a common chronic inflammatory disease in which oxidative stress is one of the key pathogenic factors. Connexin43 (Cx43) is the most critical and widely distributed connexin isoform. When the organism undergoes a severe and sustained stress response, Cx43-mediated gap junctions (GJs) are believed to underlie the biology of tissue injury exacerbation and amplification. Notably, 18-α-glycyrrhetinic acid (GA) is a classical pharmacological inhibitor of GJs and has antioxidant potential. However, the regulatory role of GA in the redox signaling of periodontal tissues and the potential mechanisms of Cx43 in the pathogenesis of periodontitis remain uncertain. In this study, we evaluated the effects and mechanisms of GA in alleviating oxidative damage of periodontal tissues and cells by constructing an HO-induced oxidative stress model in human periodontal ligament cells (hPDLCs) and a periodontitis model in rats. Cellular experiments showed that GA effectively attenuated HO-induced oxidative damage in hPDLCs by inhibiting the expression and function of Cx43. In addition, pretreatment of hPDLCs with either GA or SP600125 (a JNK inhibitor) inhibited the Cx43/JNK/NF-κB pathway, restored cell viability, and reduced apoptosis. Animal experiment results showed that GA intervention reduced alveolar bone resorption and periodontal tissue destruction, inhibited osteoclast differentiation, improved mitochondrial structural abnormalities and dysfunction in periodontal tissue, and decreased oxidative stress levels and apoptosis in rats with periodontitis. Overall, our findings suggest that the Cx43/JNK/NF-κB pathway may play a vital role to promote periodontitis progression, while GA reduces oxidative stress and apoptosis by inhibiting the interaction of Cx43 and JNK/NF-κB pathways, thus alleviating oxidative damage in the periodontal tissues.
牙周炎是一种常见的慢性炎症性疾病，其中氧化应激是关键的致病因素之一。连接蛋白43（Cx43）是最关键且分布最广泛的连接蛋白亚型。当机体经历严重且持续的应激反应时，Cx43介导的缝隙连接（GJs）被认为是组织损伤加剧和放大生物学过程的基础。值得注意的是，18-α-甘草次酸（GA）是一种经典的GJs药理学抑制剂，具有抗氧化潜力。然而，GA在牙周组织氧化还原信号传导中的调节作用以及Cx43在牙周炎发病机制中的潜在机制仍不明确。在本研究中，我们通过构建人牙周膜细胞（hPDLCs）中HO诱导的氧化应激模型和大鼠牙周炎模型，评估了GA在减轻牙周组织和细胞氧化损伤方面的作用及机制。细胞实验表明，GA通过抑制Cx43的表达和功能，有效减轻了HO诱导的hPDLCs氧化损伤。此外，用GA或SP600125（一种JNK抑制剂）预处理hPDLCs可抑制Cx43/JNK/NF-κB通路，恢复细胞活力并减少细胞凋亡。动物实验结果显示，GA干预减少了牙槽骨吸收和牙周组织破坏，抑制了破骨细胞分化，改善了牙周组织中线粒体的结构异常和功能障碍，并降低了牙周炎大鼠的氧化应激水平和细胞凋亡。总体而言，我们的研究结果表明，Cx43/JNK/NF-κB通路可能在促进牙周炎进展中起关键作用，而GA通过抑制Cx43与JNK/NF-κB通路的相互作用来降低氧化应激和细胞凋亡，从而减轻牙周组织的氧化损伤。
