N-乙酰多巴胺二聚体通过 TLR4/NF-κB 和 NLRP3/Caspase-1 通路抑制神经炎症。,Acta Biochimica et Biophysica Sinica

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N-乙酰多巴胺二聚体通过 TLR4/NF-κB 和 NLRP3/Caspase-1 通路抑制神经炎症。
Acta Biochimica et Biophysica Sinica ( IF 3.3 ) Pub Date : 2022-08-25 , DOI: 10.3724/abbs.2022116
Lijun Huang ₁ , Leiqiang Gong ₁ , Xueyan Huo ₁ , Lirong Lei ₁ , Qi Zhang ₁ , Yunjie Hu ₁ , Qixuan Kuang ₁ , Yu Gui ₁ , Yifei Dai ₂ , Yucheng Gu ₃ , Yun Deng ₁ , Dong Wang ₁ , Dale Guo ₁

Affiliation

小胶质细胞介导的神经炎症是神经退行性疾病的重要病理生理机制。然而，目前还缺乏治疗神经炎症的有效药物。N-乙酰多巴胺二聚体 (NADD) 是一种来自中药蝉花的天然化合物。在我们之前的研究中，我们发现 NADD 可以通过抑制 NF-κB 和 MAPK 通路来减轻 DSS 诱导的溃疡性结肠炎。NADD 是否抑制神经炎症，NADD 的作用靶点是什么？为了回答这个问题，使用脂多糖 (LPS) 刺激的 BV-2 小胶质细胞作为细胞模型来研究 NADD 对神经炎症的影响。一氧化氮 (NO) 检测，活性氧 (ROS) 检测和酶联免疫吸附试验 (ELISA) 结果表明，NADD 可减弱 LPS 刺激的 BV-2 小胶质细胞中的炎症信号和促炎细胞因子，包括 NO、ROS、肿瘤坏死因子 (TNF)-α、白细胞介素(IL)-1β 和白细胞介素 6 (IL-6)。蛋白质印迹分析显示 NADD 抑制 Toll 样受体 4 (TLR4)、核因子 kappa-B (NF-κB)、NOD 样受体热蛋白结构域相关蛋白 3 (NLRP3)、ASC 和半胱氨酰天冬氨酸特异性蛋白水平蛋白酶 (Caspase)-1，表明 NADD 可能通过 TLR4/NF-κB 和 NLRP3/Caspase-1 信号通路抑制神经炎症。此外，表面等离子体共振分析和分子对接表明 NADD 直接与 TLR4 结合。

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N-acetyldopamine dimer inhibits neuroinflammation through the TLR4/NF-κB and NLRP3/Caspase-1 pathways.

Neuroinflammation mediated by microglia is an important pathophysiological mechanism in neurodegenerative diseases. However, there is a lack of effective drugs to treat neuroinflammation. N-acetyldopamine dimer (NADD) is a natural compound from the traditional Chinese medicine Isaria cicada. In our previous study, we found that NADD can attenuate DSS-induced ulcerative colitis by suppressing the NF-κB and MAPK pathways. Does NADD inhibit neuroinflammation, and what is the target of NADD? To answer this question, lipopolysaccharide (LPS)-stimulated BV-2 microglia was used as a cell model to investigate the effect of NADD on neuroinflammation. Nitric oxide (NO) detection, reactive oxygen species (ROS) detection and enzyme-linked immunosorbent assay (ELISA) results show that NADD attenuates inflammatory signals and proinflammatory cytokines in LPS-stimulated BV-2 microglia, including NO, ROS, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and interleukin-6 (IL-6). Western blot analysis show that NADD inhibits the protein levels of Toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC and cysteinyl aspartate specific proteinase (Caspase)-1, indicating that NADD may inhibit neuroinflammation through the TLR4/NF-κB and NLRP3/Caspase-1 signaling pathways. In addition, surface plasmon resonance assays and molecular docking demonstrate that NADD binds with TLR4 directly. Our study reveals a new role of NADD in inhibiting the TLR4/NF-κB and NLRP3/Caspase-1 pathways, and shows that TLR4-MD2 is the direct target of NADD, which may provide a potential therapeutic candidate for the treatment of neuroinflammation.

更新日期：2022-01-25

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