Autophagy in resin monomer-initiated toxicity of dental mesenchymal cells: a novel therapeutic target of N-acetyl cysteine.
Autophagy in resin monomer-initiated toxicity of dental mesenchymal cells: a novel therapeutic target of N-acetyl cysteine.
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DOI：
10.1039/c5tb00894h
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Lingxin Zhu;Jie Zhang;Lan Xiao;Shan Liu;Jingjing Yu;Weihai Chen;Xianzheng Zhang;B. Peng
中科院分区：
文献类型：
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作者：
Lingxin Zhu;Jie Zhang;Lan Xiao;Shan Liu;Jingjing Yu;Weihai Chen;Xianzheng Zhang;B. Peng
牙科修复生物材料通常用于修复因龋齿、侵蚀或骨折而受损的牙齿。聚合修复复合材料释放的树脂单体会干扰口腔真核细胞的活力并引起细胞毒性，这仍然是医学上的一个挑战。然而，树脂单体介导的毒性的细胞内过程或潜在机制以及潜在的预防/治疗策略仍远未清楚。本研究旨在确定自噬在树脂单体三甘醇二甲基丙烯酸酯（TEGDMA）诱导的细胞毒性中的作用，并探索自噬作为抗氧化剂N-乙酰半胱氨酸（NAC）的潜在治疗靶点的体外和离体研究。结果表明，TEGDMA暴露导致人牙间充质细胞（DMC）自噬的几个特定特征，包括酸性囊泡细胞器的形成，自噬空泡的出现和LC 3-II的积累。通过药理学和遗传学的方法，抑制自噬显著地阻止了TEGDMA诱导的DMCs凋亡。此外，TEGDMA激活的自噬通过AMPK/mTOR途径发生，NAC预处理可消除该途径。更重要的是，牙齿切片器官培养模型提供了自噬参与TEGDMA触发的牙齿间充质组织毒性的进一步证据，并作为NAC离体治疗靶点。我们的研究结果为树脂单体介导的毒性机制提供了新的见解，并突出了自噬作为NAC改善牙科修复生物材料的有前途的治疗靶点，从而保护牙齿组织。
Dental restorative biomaterials are commonly used to restore the teeth impaired by caries, erosion, or fracture. Resin monomers released from polymerized restorative composite materials could disturb cell viability and cause toxicity of oral eukaryotic cells, which remains a medical challenge. However, the intracellular processes or underlying mechanisms of resin monomer-mediated toxicity and the potential preventive/therapeutic strategy are still far from clear. The present study aimed to determine the role of autophagy in resin monomer triethylene glycol dimethacrylate (TEGDMA)-induced cytotoxicity and explore autophagy as a potential therapeutic target of anti-oxidant N-acetyl cysteine (NAC) in vitro and ex vivo. The results showed that TEGDMA exposure resulted in several specific features of autophagy in human dental mesenchymal cells (DMCs), including the formation of acidic vesicular organelles, appearance of autophagic vacuoles, and LC3-II accumulation. By pharmacological and genetic approaches, the inhibition of autophagy significantly prevented TEGDMA-induced apoptosis in DMCs. Moreover, the autophagy activated by TEGDMA occurred via the AMPK/mTOR pathway, which could be abrogated by NAC pretreatment. More importantly, the tooth slice organ culture model provided further evidence of autophagy involvement in TEGDMA-triggered dental mesenchymal tissue toxicity and as a therapeutic target of NAC ex vivo. Our findings provide novel insights into the mechanisms of resin monomer-mediated toxicity and highlight autophagy as a promising therapeutic target of NAC for improving dental restorative biomaterials that enable dental tissue protection.