脂肪来源间充质干细胞通过激活Nrf2/Keap1信号通路缓解化疗诱导的小鼠口腔黏膜炎的机制研究
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(上海市同济口腔医院牙体牙髓科,同济大学口腔医学院,上海牙组织修复与再生工程技术研究中心,同济大学口腔医学研究所,上海200072)

作者简介:

李媛媛(1999—),女,硕士研究生,E-mail: 1443837324@qq.com;赵琛(1989—),女,主治医师,博士,E-mail: tjkqnm@163.com;*为共同第一作者

通讯作者:

何园,E-mail: drheyuan@tongji.edu.cn

中图分类号:

R781.5

基金项目:

国家自然科学基金(82170961,82370970)


Mechanistic investigation of adipose-derived mesenchymal stem cells in alleviating chemotherapy-induced oral mucositis in mice by activating the Nrf2/Keap1 signaling pathway
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(Department of Endodontics, Stomatological Hospital and Dental School, Tongji University & Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology, Shanghai 200072, China)

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    摘要:

    目的探讨小鼠脂肪来源间充质干细胞(mouse adipose-derived mesenchymal stem cells, mADSCs)对化疗所致口腔黏膜炎(chemotherapy induced-oral mucositis, CIOM)的治疗作用及其可能机制。 方法腹腔注射5-氟尿嘧啶(5-Fluorouracil, 5-FU)并局部使用70%乙酸化学灼伤舌黏膜建立化疗性口腔黏膜炎模型,小鼠溃疡区域局部注射mADSCs。苏木精-伊红染色观察组织学变化,qRT-PCR检测炎症细胞因子和氧化应激相关因子的表达。免疫组织化学染色评价氧化应激相关蛋白的表达。 结果局部注射mADSCs 9 d后,实验组较对照组溃疡面积减少,上皮结构恢复,炎性细胞浸润减少,IL-6和TNF-α表达降低。此外,mADSCs治疗后氧化应激相关因子血红素加氧酶1(heme oxygenase 1, HO-1)、超氧化物歧化酶1(superoxide dismutase 1, SOD-1)和核因子E2相关因子2[nuclear factor(erythroid-derived 2)-like 2(NFE2L2), Nrf2]在病变组织中的表达增加,而Kelch样ECH关联蛋白1(Kelch-like ECH-associated protein 1, Keap1)表达减少。 结论mADSCs可能通过Nrf2/Keap1信号通路减轻氧化应激改善CIOM的作用,为CIOM的治疗策略提供了理论依据。

    Abstract:

    ObjectiveTo investigater the therapeutic effects of mouse adipose-derived mesenchymal stem cells(mADSCs) on chemotherapy-induced oral mucositis(CIOM), along with their potential mechanisms. MethodsA mouse CIOM model was established by intraperitoneally injecting 5-fluorouracil(5-FU) and chemically damaging the tongue mucosa with 70% acetic acid, followed by the injection of mADSCs into the ulcerated area. Hematoxylin and eosin(H-E) staining was performed to observe histological changes, while qRT-PCR was used to measure the expression of inflammatory cytokines and oxidative stress-related factors. Immunohistochemical staining assessed the expression of oxidative stress-related proteins. ResultsAfter local injection of mADSCs, the ulcer area in the experimental group was reduced compared to the control group on the ninth day of the experiment., along with restoration of the epithelial structure, decreased inflammatory cell infiltration, and lowered expression of interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), indicating therapeutic effects on CIOM. Additionally, treatment with mADSCs resulted in elevated expression of oxidative stress-related factors heme oxygenase 1(HO-1), superoxide dismutase 1(SOD-1), and Nuclear factor(erythroid-derived 2) -like 2(NFE2L2)(Nrf2) in the lesions, while Kelch-like ECH-associated protein 1(Keap1) expression decreased, indicating that these therapies may alleviate oxidative stress through the Nrf2/Keap1 signaling pathway in the treatment of CIOM. ConclusionThis study provides preliminary insights into the roles and mechanisms of mADSCs in treating chemotherapy-induced oral mucositis, offering a theoretical foundation for new treatment strategies for CIOM.

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李媛媛,赵琛,朱平怡,等.脂肪来源间充质干细胞通过激活Nrf2/Keap1信号通路缓解化疗诱导的小鼠口腔黏膜炎的机制研究[J].同济大学学报(医学版),2025,46(6):819-827.

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  • 收稿日期:2025-04-26
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  • 录用日期:2025-06-20
  • 在线发布日期: 2026-01-07
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