2-乙酰氨基苯酚(2-AAP)通过缓解高脂血症和减弱铁蛋白沉积途径抑制动脉粥样硬化的进展

IF 4.9 2区 医学 Q1 CHEMISTRY, MEDICINAL
Marine Drugs Pub Date : 2024-11-13 DOI:10.3390/md22110513
Xiaohan Zang, Yongcheng Wang, Cong Han, Lishuang Cui, Haojie Liu, Shuimiao Tian, Kechun Liu, Peihai Li, Chen Sun, Qing Xia, Yun Zhang
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引用次数: 0

摘要

高脂血症和随之而来的内皮炎症以及泡沫细胞的生成会促进动脉粥样硬化(AS)的进展。在此,我们旨在研究通过斑马鱼表型筛选出的2-乙酰胺基苯酚(2-AAP)通过缓解高脂血症和抑制泡沫细胞形成来减轻动脉粥样硬化的作用及其内在机制。在斑马鱼高脂血症模型中,2-AAP 增加了降脂疗效;缓解了 TC、TG、LDL-C 和 MDA 水平;提高了 HDL-C 和 T-SOD 水平;显著改善了血管内巨噬细胞聚集;改善了血流量。在氧化-LDL 诱导的 RAW264.7 模型中,2-AAP 可抑制 RAW264.7 细胞的脂质吞噬;降低细胞内 TC、TG、FC 和 CE 的含量;降低 CE/TC 比值,从而减缓泡沫细胞的生成。此外,2-AAP 还能缓解 RAW264.7 细胞内的 ROS 和亚铁离子积累,降低 MDA 含量,提高 GPX4 的活力。此外,转录组分析和基因表达验证显示,2-AAP 处理可上调与 GSH 合成和转运相关的基因,如 gclc、gclm、gss 和 gpx4a,并提高参与铁离子储存和转运的基因的表达水平,如 fpn1、fth 和 g6pd,表明 2-AAP 显著调节了铁变态反应和谷胱甘肽代谢途径。总之,我们的研究表明,2-AAP通过缓解高脂血症和减弱铁蛋白沉积途径,在强直性脊柱炎的治疗中具有潜力,并为2-AAP未来在强直性脊柱炎治疗中的应用提供了证据支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
2-Acetamidophenol (2-AAP) Suppresses the Progression of Atherosclerosis by Alleviating Hyperlipidemia and Attenuating the Ferroptosis Pathway.

Hyperlipidemia and consequent endothelial inflammation, along with foam cell generation, promote the progression of atherosclerosis (AS). Here, we aimed to investigate the effects of 2-acetamidophenol (2-AAP), which was selected by zebrafish phenotypic screening, in alleviating AS by relieving hyperlipidemia and inhibiting foam cell formation, as well as the underlying mechanisms. In a zebrafish hyperlipidemia model, 2-AAP increased lipid-lowering efficacy; alleviated TC, TG, LDL-C, and MDA levels; elevated HDL-C and T-SOD levels; significantly improved intravascular macrophage aggregation; and improved blood flow. In an ox-LDL-induced RAW264.7 model, 2-AAP inhibited lipid phagocytosis in RAW264.7 cells; reduced the intracellular TC, TG, FC, and CE contents; and decreased the CE/TC ratio, thus slowing foam cell generation. In addition, 2-AAP alleviated intracellular ROS and ferrous ion accumulation in RAW264.7 cells, reduced the MDA content, and increased GPX4 viability. Furthermore, transcriptome analyses and gene expression validation showed 2-AAP treatment upregulates genes related to GSH synthesis and transport, such as gclc, gclm, gss, and gpx4a, and enhanced the expression levels of genes involved in the storage and transportation of iron ions, such as fpn1, fth, and g6pd, indicating that 2-AAP dramatically regulated the ferroptosis and glutathione metabolic pathways. Overall, our study demonstrated that 2-AAP demonstrated potential in AS by alleviating hyperlipidemia and attenuating the ferroptosis pathway and provided evidence supporting the future application of 2-AAP in AS treatment.

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来源期刊
Marine Drugs
Marine Drugs 医学-医药化学
CiteScore
9.60
自引率
14.80%
发文量
671
审稿时长
1 months
期刊介绍: Marine Drugs (ISSN 1660-3397) publishes reviews, regular research papers and short notes on the research, development and production of drugs from the sea. Our aim is to encourage scientists to publish their experimental and theoretical research in as much detail as possible, particularly synthetic procedures and characterization information for bioactive compounds. There is no restriction on the length of the experimental section.
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