BAK通过激活AMPK/Nrf2来抑制TXNIP/NLRP3/caspase-1轴，从而改善脑梗塞/缺血再灌注损伤。

IF 2.5 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters Pub Date : 2024-11-06 DOI:10.1016/j.neulet.2024.138037

Yue-Wei Xu , Chang-Heng Yao , Xiao-Ming Gao , Li Wang , Meng-Xiang Zhang , Xiao-Dan Yang , Jing Li , Wen-Ling Dai , Man-Qin Yang , Ming Cai

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引用次数: 0

摘要

背景：脑缺血再灌注（I/R）损伤是一种严重的血管疾病，死亡率和致残率极高。Bakuchiol (BAK)存在于Psoralea corylifolia Linn的叶子和种子中，已被证明能减少炎症和氧化应激，但BAK改善脑缺血再灌注损伤的机制仍不清楚：方法：采用大脑中动脉闭塞再灌注（MACO/R）建立小鼠模型。通过神经功能缺损测试、TTC染色和H&E染色检测BAK对MCAO/R小鼠的保护作用。氧气/葡萄糖剥夺和再灌注（OGD/R）用于体外刺激 SH-SY5Y 细胞。蛋白表达采用免疫印迹法检测，基因表达采用实时定量聚合酶链反应法检测，细胞凋亡采用免疫荧光法检测：结果：我们的研究表明，BAK能保护MACO/R小鼠缺血再灌注损伤，并上调超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的酶活性。BAK还能抑制TNF-α、IL-1β、IL-6和IL-18的表达，抑制MACO/R小鼠和OGD/R SH-SY5Y细胞的凋亡和热凋亡。进一步的研究结果表明，BAK能抑制TXNIP、ASC、NLRP3和caspase-1 mRNA水平，从而逆转炎性体的组装。BAK还能上调磷酸化AMP激活蛋白激酶（AMPK）和核因子红细胞2相关因子（Nrf2）的表达。此外，Nrf2抑制剂ML385逆转了BAK诱导的TXNIP、ASC、NLRP3的减少，AMPK抑制剂也取消了BAK对Nrf2 TXNIP、ASC、NLRP3、caspase-1和促炎细胞因子的调节作用。总之，药蜀葵叶和种子中的BAK可通过激活AMPK/Nrf2抑制NLRP3炎性体改善脑I/R损伤，为脑I/R损伤提供了新的治疗策略。

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BAK ameliorated cerebral infarction/ischemia–reperfusion injury by activating AMPK/Nrf2 to inhibit TXNIP/NLRP3/caspase-1 axis

Background

Cerebral ischemia/reperfusion (I/R) injury is a serious vascular disease with extremely high mortality and disability rate. Bakuchiol (BAK) was found in leaves and seeds of Psoralea corylifolia Linn and has been shown to decrease inflammation and reduce oxidative stress, while the mechanism of BAK in ameliorating cerebral I/R injury remains unclear.

Methods

Middle cerebral artery occlusion reperfusion (MACO/R) was used to establish mouse model. The protective effect of BAK in MCAO/R mices was detected by performing neurological deficit testing, TTC staining, and H&E staining. Oxygen/glucose deprivation and reperfusion (OGD/R) was used to stimulate SH-SY5Y cells in vitro. Protein expression was detected by western blotting, gene expression was detected by quantitative real-time polymerase chain reaction and apoptosis was detected by immunofluorescence.

Results

Our study indicated that BAK protected ischemia–reperfusion injury in MACO/R mice, and upregulated superoxide dismutase (SOD) and the catalase (CAT) enzyme activity. BAK also inhibited the expression of TNF-α, IL-1β, IL-6, and IL-18 and suppressed apoptosis and pyroptosis both in MACO/R mice and in OGD/R SH-SY5Y cells. Further results showed that BAK could suppress TXNIP, ASC, NLRP3, and caspase-1 mRNA levels to reverse assembly of inflammasome. And BAK could also upregulate the expression of phosphorylated AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor (Nrf2). In addition, Nrf2 inhibitor ML385 reversed the BAK induced reduction of TXNIP, ASC, NLRP3, and the AMPK inhibitor also abolished BAK’ the effect on the regulation of Nrf2, TXNIP, ASC, NLRP3, caspase-1, and pro-inflammatory cytokines. In conclusion, BAK, found in leaves and seeds of Psoralea corylifolia Linn, could ameliorated cerebral I/R injury through activating AMPK/Nrf2 to inhibit NLRP3 inflammasome, which might present new therapeutic strategy for cerebral I/R injury.

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来源期刊

Neuroscience Letters 医学-神经科学

CiteScore

5.20

自引率

0.00%

发文量

408

审稿时长

50 days

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