Acetaminophen alleviates ferroptosis in mice with sepsis-associated encephalopathy via the GPX4 pathway
Acetaminophen alleviates ferroptosis in mice with sepsis-associated encephalopathy via the GPX4 pathway
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DOI：
10.1177/09603271221133547
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发表时间：
2022-10-01
影响因子：
2.8
通讯作者：
Yu, Yonghao
中科院分区：
文献类型：
--
作者：
Chu, Jing;Jiang, Yi;Yu, Yonghao
脓毒症相关脑病（SAE）是脓毒症引起的认知功能障碍，与发病率和死亡率增加相关。对乙酰氨基酚（acetaminophen，APAP）是一种很有前途的SAE治疗药物。本研究旨在确定APAP是否通过减弱铁凋亡和介导谷胱甘肽过氧化物酶（GPX 4）途径来减轻SAE。采用盲肠结扎穿孔（CLP）法建立脓毒症小鼠模型。测定7天存活率。采用Morris水迷宫（MWM）评定认知功能。苏木精-伊红（HE）染色确定海马组织的组织病理学改变。透射电镜观察海马组织线粒体损伤。海马组织中的活性氧（ROS）水平的测定使用商业分析。使用与1 μ g/ml脂多糖（LPS）一起生长的HT 22细胞产生败血症细胞模型。使用免疫荧光定量ROS。Western blotting法检测海马组织和HT 22细胞中铁凋亡相关蛋白的表达水平。为了评估海马组织和HT 22细胞的铁含量，使用商业试剂盒。根据研究结果，APAP提高了存活率，降低了海马和线粒体损伤，并改善了认知障碍。在动物和细胞研究中，APAP降低铁含量、ROS、谷氨酸反向转运体（xCT）、4-羟基-2-壬烯醛（4-HNE）水平，但增加GPX 4表达。然而，RSL 3，一种GPX 4抑制剂，作为一种铁凋亡激活剂，降低了APAP在体外的保护性能。我们的研究结果表明，APAP通过减少由GPX 4信号通路介导的铁凋亡来减少脓毒症诱导的认知障碍。
Sepsis-associated encephalopathy (SAE) is a cognitive impairment caused by sepsis, associated with increased morbidity and death. And acetaminophen (APAP) is a promising therapeutic medicine for SAE treatment. This research was designed to determine whether APAP alleviates SAE by attenuating ferroptosis and mediating the glutathione peroxidase (GPX4) pathway. The cecal ligation and puncture (CLP) approach was used to establish septic mouse models. The survival rates for 7 days were determined. The Morris water maze (MWM) was utilized to assess cognitive function. Hematoxylin and eosin (HE) staining identified histopathologic alterations in hippocampal tissue. Mitochondrial damage was discovered in hippocampal tissue using transmission electron microscopy (TEM). The reactive oxygen (ROS) levels in hippocampal tissue were measured using commercial assays. Septic cell models were produced using HT22 cells grown with 1 mu g/ml lipopolysaccharide (LPS). ROS were quantified using immunofluorescence. Ferroptosis-related protein expression levels in hippocampal tissue and HT22 cells were measured using western blotting. To evaluate the iron content of hippocampal tissue and HT22 cells, commercial kits were employed. According to the findings, APAP improved survival rates, lowered hippocampal and mitochondrial damage, and improve cognitive impairment. In both animal and cell studies, APAP reduced iron content, ROS, glutamate antiporter (xCT), 4-hydroxy-2-nonenal (4-HNE) levels but increased GPX4 expression. However, RSL3, a GPX4 inhibitor that acts as a ferroptosis activator, decreased the protective properties of APAP in vitro. Our findings suggest that APAP reduces sepsis-induced cognitive impairment by reducing ferroptosis, which is mediated by the GPX4 signaling pathway.