Genipin Attenuates Diabetic Cognitive Impairment by Reducing Lipid Accumulation and Promoting Mitochondrial Fusion via FABP4/Mfn1 Signaling in Microglia.
Genipin Attenuates Diabetic Cognitive Impairment by Reducing Lipid Accumulation and Promoting Mitochondrial Fusion via FABP4/Mfn1 Signaling in Microglia.
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Genipin通过在小胶质细胞中通过FABP4/Mfn1信号减少脂质堆积和促进线粒体融合来缓解糖尿病认知障碍。
DOI：
10.3390/antiox12010074
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发表时间：
2022-12-29
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本研究旨在观察京尼平（GEN）对糖尿病认知功能损害小胶质细胞的影响，并探讨其可能的作用机制。STZ/HFD诱导糖尿病小鼠模型，GEN灌胃和脑室内给药。用LPS/HG/PA诱导人小胶质细胞HMC 3。结果，GEN在新物体识别、Morris水迷宫和被动回避测试中减轻了糖尿病症状和糖尿病认知障碍相关行为。GEN通过FABP 4/Mfn 1抑制M1小胶质细胞极化、脂质积累、氧化应激并促进线粒体融合。采用FABP 4过表达、Mfn 1过表达、选择性FABP 4抑制剂BMS和Mfn 1 siRNA研究其机制。GEN对ROS的抑制作用可能与NOX 2信号通路和p47 phox/p67 phox向细胞膜的转位有关。活性氧清除剂NAC证实活性氧参与了GEN介导的炎症反应和脂质积聚。GEN可抑制NF-κB的磷酸化和核转位。GEN抑制Mfn 1的泛素化，这是由E3连接酶Hrd 1介导的。GEN还增强小胶质细胞的吞噬作用。分子对接预测GEN与FABP 4可能通过S53和R78残基上的氢键相互作用。总之，GEN通过FABP 4/Mfn 1信号通路抑制炎症、脂质蓄积和促进线粒体融合来减轻糖尿病认知障碍。
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.
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影响因子：
4.6
作者：
Rajab BS;Kassab S;Stonall CD;Daghistani H;Gibbons S;Mamas M;Smith D;Mironov A;AlBalawi Z;Zhang YH;Baudoin F;Zi M;Prehar S;Cartwright EJ;Kitmitto A
通讯作者：
Kitmitto A
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影响因子：
5.6
作者：
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通讯作者：
Wang, Xiaoying
影响因子：
6.9
作者：
Jackson, Ladonya;Dong, Guangkuo;Ergul, Adviye
通讯作者：
Ergul, Adviye
影响因子：
4.8
作者：
Nuotio-Antar, Alli M.;Poungvarin, Naravat;Chan, Lawrence
通讯作者：
Chan, Lawrence
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