ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation.

IF 1.7 4区 医学 Q2 MEDICINE, GENERAL & INTERNAL Open Medicine Pub Date : 2024-09-03 eCollection Date: 2024-01-01 DOI:10.1515/med-2024-0993
Ieng-Hou Lam, Chon-In Chan, Meixia Han, Lixuan Li, Hon-Ho Yu
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Abstract

Background: The pathogenesis of inflammatory bowel disease (IBD) is closely associated with the dysfunction of the intestinal epithelial barrier, leading to increased bacterial translocation, leukocyte infiltration, and mucosal injury, which may act as a pivotal or incipient event in the pathophysiology of the disorder. The primary objective of this study is to examine the key genes implicated in IBD and the perturbation of intestinal epithelial cell function.

Methods: The genes associated with ferroptosis were identified through the utilization of the Gene Expression Omnibus (GEO) database and the GeneCard database. Additionally, an in vitro model of IBD was established by stimulating Caco-2 cells with lipopolysaccharides (LPSs) to investigate the molecular mechanisms underlying intestinal epithelial cell dysfunction.

Results: We discovered evidence that establishes a connection between ferroptosis and the inflammatory responses associated with the development of IBD. This evidence suggests that IBD patients who exhibit an inflammatory response have higher expression of the acyl-CoA synthetase long-chain family member 4 (ACSL4) gene compared to IBD patients without an inflammatory response or healthy individuals. Exposure to LPS at concentrations of 1 or 10 μg/mL resulted in a significant upregulation of ferroptosis-related genes ACSL4, GPX4, and SLC7A11, as well as an increase in ferroptosis biomarkers MDA and a decrease in CAT and GSH-Px levels compared to the control group. Inhibition of ACSL4 using si-ACSL4 or rosiglitazone demonstrated protective effects against LPS-induced ferroptosis and NF-κB-mediated inflammatory response.

Conclusion: ACSL4 shows potential as a promising target for ferroptosis in the prevention and treatment of IBD and dysfunction of intestinal epithelial cells.

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ACSL4 介导炎症性肠病,并通过激活铁蛋白沉积和炎症促进 LPS 诱导的肠上皮细胞功能障碍。
背景:炎症性肠病(IBD)的发病机制与肠上皮屏障功能失调密切相关,导致细菌转运、白细胞浸润和黏膜损伤增加,这可能是该疾病病理生理学的关键或萌芽事件。本研究的主要目的是研究与 IBD 和肠上皮细胞功能紊乱有关的关键基因:方法:通过利用基因表达总库(GEO)数据库和基因卡数据库,确定了与铁变态反应相关的基因。此外,通过用脂多糖(LPSs)刺激 Caco-2 细胞建立了 IBD 体外模型,以研究肠上皮细胞功能障碍的分子机制:结果:我们发现了铁蛋白沉积与 IBD 发病相关的炎症反应之间存在联系的证据。这些证据表明,与没有炎症反应的 IBD 患者或健康人相比,表现出炎症反应的 IBD 患者的酰基-CoA 合成酶长链家族成员 4(ACSL4)基因表达量更高。与对照组相比,暴露于浓度为 1 或 10 μg/mL 的 LPS 会导致铁变态反应相关基因 ACSL4、GPX4 和 SLC7A11 的显著上调,以及铁变态反应生物标志物 MDA 的增加、CAT 和 GSH-Px 水平的降低。使用si-ACSL4或罗格列酮抑制ACSL4对LPS诱导的铁变态反应和NF-κB介导的炎症反应有保护作用:结论:ACSL4有望成为预防和治疗IBD和肠上皮细胞功能障碍的铁变态反应靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Open Medicine
Open Medicine Medicine-General Medicine
CiteScore
3.00
自引率
0.00%
发文量
153
审稿时长
20 weeks
期刊介绍: Open Medicine is an open access journal that provides users with free, instant, and continued access to all content worldwide. The primary goal of the journal has always been a focus on maintaining the high quality of its published content. Its mission is to facilitate the exchange of ideas between medical science researchers from different countries. Papers connected to all fields of medicine and public health are welcomed. Open Medicine accepts submissions of research articles, reviews, case reports, letters to editor and book reviews.
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