基于NF-κB信号通路探索青蒿琥酯对伴糖尿病牙周炎炎症反应及成骨调控的效应和机制研究

Both diabetes and periodontitis can activate the NF-κB signaling pathway to promote the expression of inflammatory factors during inflammation, in which the NF-κB signaling pathway plays an important role, resulting in the destruction of periodontal soft and hard tissues. Clinically, the treatment of diabetic periodontitis is particularly intractable. Artemisinins have a variety of pharmacological effects, such as immunomodulatory, anti-inflammatory, osteoclast inhibiting, hypoglycemic activity, and NF-κB signaling pathway inhibiting. We hypothesis: Artesunate might inhibit the expression of downstream genes by inhibiting the NF-κB signaling pathway, regulate the expression of inflammatory factors, control blood glucose, improve the state of diabetes, and treat periodontal inflammation along with the soft and hard tissue damage caused by the inflammation, to achieve multi-target, multi-effect treatment of diabetic periodontitis. Experimental diabetes and periodontitis animal and periodontal ligament stem cells models, histology, and molecular biology experiments and transcriptome sequencing technique would be used to assess artesunate therapeutic intervention from both in vitro and in vivo levels and evaluate artesunate treatment of periodontal inflammation, blood glucose control and the protection of the related target organs in this study. Also, the role of signaling pathways in the regulation of diabetes and the development of periodontitis would be studied based on NF-κB signaling pathways and the molecular mechanisms and targets were explored. The research would provide experimental basis and expand the application of artemisinins in diabetic periodontitis treatment.

糖尿病和牙周炎均可激活在炎症过程发挥重要作用的NF-κB信号通路促进炎症因子表达，造成牙周软硬组织破坏，临床上伴糖尿病牙周炎治疗尤其棘手。青蒿素类药具有免疫调节、抗炎、抑制破骨细胞、降血糖、抑制NF-κB信号通路等作用。本研究提出青蒿琥酯可通过抑制NF-κB信号传导通路抑制其下游基因的表达，调节炎症因子的表达，控制血糖，改善糖尿病状态并可治疗牙周局部的炎症反应及其导致的软硬组织损害，达到多靶点、多效应治疗伴糖尿病牙周炎的效果的假说。研究将通过动物模型、组织学、细胞、分子生物学实验、转录组测序表达从体内外层面设计青蒿琥酯治疗干预实验，评估青蒿琥酯对牙周局部炎症的治疗、血糖控制及相关靶器官的保护作用，并基于NF-κB信号通路研究其在调控糖尿病及牙周炎炎症细胞、介质及成骨因子与相关机制调控中的作用，探讨其分子机制和作用靶点，为探索青蒿素类药物在牙周炎及伴糖尿病牙周炎的治疗应用提供实验和理论依据。

糖尿病牙周炎联合病变能激活并加速炎症发展的进程，NF-κB信号通路是介导炎症因子表达的主要信号通路之一。青蒿素类药具有免疫调节、抗炎、抑制破骨细胞、降血糖、抑制NF-κB信号通路等作用。本研究通过大鼠动物模型实验，采用影像学、组织病理学、分子生物学、16S、18S扩增子测序、代谢分析、行为学观察等方法研究青蒿琥酯对伴1型糖尿病牙周炎的炎症调节能力、骨代谢调控效应及靶器官保护作用；结果显示：牙周炎可以提高大鼠胰腺组织的氧化应激水平，青蒿琥酯干预能有效降低 MDA，增加 SOD 和 CAT 的水平，从而起到降低胰腺氧化应激水平，保护胰岛细胞损伤的作用。青蒿琥酯还可改善牙槽骨、颌骨、眼球、泪腺、胰腺、肾脏、肝脏、心脏、脑等脏器的炎症状态，调控颌骨、牙槽骨以及股骨等骨组织OPG/RANKL/RANK通路及ALP、OCN、Runx2因子，改善口腔、肠道微生态和菌群结构，调节骨代谢及血清钙磷含量减轻牙龈炎症及破骨改变，可能是青蒿琥酯发挥抗炎及调节骨代谢、保护器官作用的机制之一。同时，青蒿琥酯与胰岛素的联合应用还可有效缓解靶器官肠道、肝脏、腹主动脉中NF-κB信号通路基因的表达及脏器纤维化改变；调控胰腺组织及海马体Casepase3/Bax/Bcl-2通路、肾脏及脑组织中自噬反应；逆转组织细胞凋亡。体外实验也提示：青蒿琥酯可帮助高糖环境下骨髓间充质干细胞提高增殖和成骨分化能力。本研究首次提出青蒿琥酯具有改善口腔微生态、体液及机体代谢指标，调节牙槽、颌骨骨代谢，改善牙周炎的炎症状况，治疗伴糖尿病牙周炎及其伴发全身重要脏器并发症的潜能，为进一步深入研究和临床应用提供了研究基础。