Liu Wanying, Li Ke, Zheng Menglin, He Ling, Chen Tong
Department of Pharmacology, China Pharmaceutical University, 639, Longmian Avenue, Nanjing 211198, China.
Antioxidants (Basel). 2022 Dec 29;12(1):74. doi: 10.3390/antiox12010074.
The present study was conducted to evaluate the effect of genipin (GEN) on the microglia of diabetic cognitive impairment and explore its potential mechanism. Diabetic mice were induced by STZ/HFD, while GEN was intragastrically and intraventricularly treated. The human microglia cell HMC3 was induced by LPS/HG/PA. As a result, GEN attenuated diabetic symptoms and diabetic cognitive impairment-related behavior in novel object recognition, Morris water maze and passive avoidance tests. GEN inhibited M1 microglia polarization, lipid accumulation, oxidative stress and promoted mitochondrial fusion via FABP4/Mfn1. FABP4 overexpression, Mfn1 overexpression, selective FABP4 inhibitor BMS, and Mfn1 SiRNA were employed for investigating the mechanism. The inhibitory effect of GEN on ROS may be associated with NOX2 signaling and the translocation of p47phox/p67phox to the cell membrane. With the ROS scavenger NAC, it was proved that ROS participated in GEN-mediated inflammation and lipid accumulation. GEN inhibited the phosphorylation and nucleus translocation of NF-κB. GEN inhibited the ubiquitination of Mfn1, which was mediated by the E3 ligase Hrd1. GEN also enhanced microglia phagocytosis. Molecular docking predicted that GEN may interact with FABP4 by hydrogen bond at the S53 and R78 residues. In conclusion, GEN attenuated diabetic cognitive impairment by inhibiting inflammation, lipid accumulation and promoting mitochondrial fusion via FABP4/Mfn1 signaling.
本研究旨在评估京尼平（GEN）对糖尿病认知障碍小鼠小胶质细胞的影响，并探讨其潜在机制。通过链脲佐菌素/高脂饮食（STZ/HFD）诱导糖尿病小鼠模型，对GEN进行灌胃和脑室内注射处理。采用脂多糖/高糖/棕榈酸（LPS/HG/PA）诱导人小胶质细胞系HMC3。结果显示，在新物体识别、莫里斯水迷宫和被动回避试验中，GEN减轻了糖尿病症状及与糖尿病认知障碍相关的行为。GEN通过脂肪酸结合蛋白4（FABP4）/线粒体融合蛋白1（Mfn1）抑制M1小胶质细胞极化、脂质蓄积和氧化应激，并促进线粒体融合。采用FABP4过表达、Mfn1过表达、选择性FABP4抑制剂BMS以及Mfn1小干扰RNA（SiRNA）研究其机制。GEN对活性氧（ROS）的抑制作用可能与NADPH氧化酶2（NOX2）信号通路以及p47phox/p67phox向细胞膜的转位有关。使用ROS清除剂N-乙酰半胱氨酸（NAC）证实，ROS参与了GEN介导的炎症反应和脂质蓄积。GEN抑制核因子κB（NF-κB）的磷酸化及其核转位。GEN抑制由E3泛素连接酶Hrd1介导的Mfn1泛素化。GEN还增强了小胶质细胞的吞噬作用。分子对接预测GEN可能通过S53和R78位点的氢键与FABP4相互作用。综上所述，GEN通过抑制炎症、脂质蓄积并通过FABP4/Mfn1信号通路促进线粒体融合，减轻糖尿病认知障碍。
