• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

EETs 通过 Trim25/Keap1/Nrf2 轴抑制内质网应激来减轻肺泡上皮细胞衰老。

EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis.

机构信息

Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, 410078, China.

Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.

出版信息

Redox Biol. 2023 Jul;63:102765. doi: 10.1016/j.redox.2023.102765. Epub 2023 May 28.

DOI:10.1016/j.redox.2023.102765
PMID:37269686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10249012/
Abstract

Alveolar epithelial cell (AEC) senescence is a key driver of a variety of chronic lung diseases. It remains a challenge how to alleviate AEC senescence and mitigate disease progression. Our study identified a critical role of epoxyeicosatrienoic acids (EETs), downstream metabolites of arachidonic acid (ARA) by cytochrome p450 (CYP), in alleviating AEC senescence. In vitro, we found that 14,15-EET content was significantly decreased in senescent AECs. Exogenous EETs supplementation, overexpression of CYP2J2, or inhibition of EETs degrading enzyme soluble epoxide hydrolase (sEH) to increase EETs alleviated AECs' senescence. Mechanistically, 14,15-EET promoted the expression of Trim25 to ubiquitinate and degrade Keap1 and promoted Nrf2 to enter the nucleus to exert an anti-oxidant effect, thereby inhibiting endoplasmic reticulum stress (ERS) and alleviating AEC senescence. Furthermore, in D-galactose (D-gal)-induced premature aging mouse model, inhibiting the degradation of EETs by Trifluoromethoxyphenyl propionylpiperidin urea (TPPU, an inhibitor of sEH) significantly inhibited the protein expression of p16, p21, and γH2AX. Meanwhile, TPPU reduced the degree of age-related pulmonary fibrosis in mice. Our study has confirmed that EETs are novel anti-senescence substances for AECs, providing new targets for the treatment of chronic lung diseases.

摘要

肺泡上皮细胞（AEC）衰老，是多种慢性肺部疾病的关键驱动因素。如何缓解 AEC 衰老并减轻疾病进展，仍是一个挑战。我们的研究发现，环氧二十碳三烯酸（EETs）在缓解 AEC 衰老方面起着关键作用，EETs 是花生四烯酸（ARA）经细胞色素 p450（CYP）代谢后的下游产物。在体外，我们发现衰老的 AEC 中 14,15-EET 含量明显下降。外源性 EETs 补充、CYP2J2 过表达或抑制 EETs 降解酶可溶性环氧化物水解酶（sEH）以增加 EETs，均能缓解 AEC 衰老。在机制上，14,15-EET 促进 Trim25 的表达，使其泛素化并降解 Keap1，并促进 Nrf2 进入细胞核发挥抗氧化作用，从而抑制内质网应激（ERS）并缓解 AEC 衰老。此外，在 D-半乳糖（D-gal）诱导的早衰小鼠模型中，用三氟甲氧基苯丙酰哌啶脲（TPPU，sEH 的抑制剂）抑制 EETs 的降解，可显著抑制 p16、p21 和 γH2AX 的蛋白表达。同时，TPPU 降低了小鼠与年龄相关的肺纤维化程度。本研究证实，EETs 是 AEC 新型抗衰老物质，为慢性肺部疾病的治疗提供了新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/2f91613aaf97/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/90b240c39c56/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/a0dfe66373ff/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/8a8be077f905/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/fd1e635f07fa/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/feda75551a11/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/54ef1c8231f0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/ba14be19be38/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/1cc51b6fae3d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/8bfaa930fb61/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/4aedddf34eb2/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/2f91613aaf97/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/90b240c39c56/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/a0dfe66373ff/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/8a8be077f905/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/fd1e635f07fa/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/feda75551a11/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/54ef1c8231f0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/ba14be19be38/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/1cc51b6fae3d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/8bfaa930fb61/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/4aedddf34eb2/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f66/10249012/2f91613aaf97/gr10.jpg

相似文献

1
EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis.EETs 通过 Trim25/Keap1/Nrf2 轴抑制内质网应激来减轻肺泡上皮细胞衰老。
Redox Biol. 2023 Jul;63:102765. doi: 10.1016/j.redox.2023.102765. Epub 2023 May 28.
2
Epoxyeicosatrienoic acids alleviate alveolar epithelial cell senescence by inhibiting mitophagy through NOX4/Nrf2 pathway.环氧二十碳三烯酸通过 NOX4/Nrf2 通路抑制细胞自噬来减轻肺泡上皮细胞衰老。
Biomed Pharmacother. 2023 Dec 31;169:115937. doi: 10.1016/j.biopha.2023.115937. Epub 2023 Nov 25.
3
COX-2/sEH dual inhibitor PTUPB alleviates bleomycin-induced pulmonary fibrosis in mice via inhibiting senescence.COX-2/sEH 双重抑制剂 PTUPB 通过抑制衰老缓解博来霉素诱导的小鼠肺纤维化。
FEBS J. 2020 Apr;287(8):1666-1680. doi: 10.1111/febs.15105. Epub 2019 Nov 8.
4
Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis.可溶性环氧化物水解酶的药理抑制作用通过调节宿主炎症反应、核因子-κB受体活化因子相关信号传导、内质网应激和细胞凋亡来减少牙槽骨丧失。
J Pharmacol Exp Ther. 2017 Jun;361(3):408-416. doi: 10.1124/jpet.116.238113. Epub 2017 Mar 29.
5
The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis.花生四烯酸代谢物 11,12-环氧二十碳三烯酸可缓解肺纤维化。
Exp Mol Med. 2021 May;53(5):864-874. doi: 10.1038/s12276-021-00618-7. Epub 2021 May 14.
6
14,15-epoxyeicosatrienoic Acid suppresses cigarette smoke extract-induced apoptosis in lung epithelial cells by inhibiting endoplasmic reticulum stress.14,15-环氧二十碳三烯酸通过抑制内质网应激来抑制香烟烟雾提取物诱导的肺上皮细胞凋亡。
Cell Physiol Biochem. 2015;36(2):474-86. doi: 10.1159/000430113. Epub 2015 May 11.
7
Soluble Epoxide Hydrolase Inhibitor Suppresses the Expression of Triggering Receptor Expressed on Myeloid Cells-1 by Inhibiting NF-kB Activation in Murine Macrophage.可溶性环氧化物水解酶抑制剂通过抑制小鼠巨噬细胞中的NF-κB活化来抑制髓样细胞表达的触发受体-1的表达。
Inflammation. 2017 Feb;40(1):13-20. doi: 10.1007/s10753-016-0448-6.
8
Loss of PTEN induces lung fibrosis via alveolar epithelial cell senescence depending on NF-κB activation.PTEN 缺失通过 NF-κB 激活诱导肺泡上皮细胞衰老导致肺纤维化。
Aging Cell. 2019 Feb;18(1):e12858. doi: 10.1111/acel.12858. Epub 2018 Dec 12.
9
Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.褪黑素通过激活NRF2和抑制内质网应激来预防犬脂肪间充质干细胞的衰老。
Aging (Albany NY). 2018 Oct 25;10(10):2954-2972. doi: 10.18632/aging.101602.
10
Epoxyeicosatrienoic acids inhibit the activation of NLRP3 inflammasome in murine macrophages.环氧二十碳三烯酸抑制小鼠巨噬细胞中 NLRP3 炎性体的激活。
J Cell Physiol. 2020 Dec;235(12):9910-9921. doi: 10.1002/jcp.29806. Epub 2020 May 26.

引用本文的文献

1
Yanghe Pingchuan granules inhibit cellular senescence in airway smooth muscle cells to improve bronchial asthma via modulating Nrf2 acetylation.阳和平喘颗粒通过调节Nrf2乙酰化抑制气道平滑肌细胞衰老以改善支气管哮喘。
Respir Res. 2025 Aug 31;26(1):266. doi: 10.1186/s12931-025-03345-z.
2
Targeted soluble epoxide hydrolase inhibits M1 macrophage polarization to improve cartilage injury in temporomandibular joint osteoarthritis.靶向可溶性环氧化物水解酶可抑制M1巨噬细胞极化，以改善颞下颌关节骨关节炎中的软骨损伤。
J Transl Med. 2025 Aug 28;23(1):969. doi: 10.1186/s12967-025-07003-2.
3
Ellagic Acid Mediates the Delay of Dermal Fibroblast Senescence via CSNK2A1.

本文引用的文献

1
TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury.TREM-1 通过激活急性肺损伤中的糖酵解来调控巨噬细胞中的 NLRP3 炎性小体激活。
Int J Biol Sci. 2023 Jan 1;19(1):242-257. doi: 10.7150/ijbs.77304. eCollection 2023.
2
Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury.线粒体柠檬酸积累驱动脂多糖诱导的急性肺损伤中肺泡上皮细胞坏死性凋亡。
Exp Mol Med. 2022 Nov;54(11):2077-2091. doi: 10.1038/s12276-022-00889-8. Epub 2022 Nov 28.
3
S-allylmercapto-N-acetylcysteine ameliorates pulmonary fibrosis in mice via Nrf2 pathway activation and NF-κB, TGF-β1/Smad2/3 pathway suppression.
鞣花酸通过酪蛋白激酶2α1介导真皮成纤维细胞衰老的延迟。
Clin Cosmet Investig Dermatol. 2025 Aug 20;18:1971-1983. doi: 10.2147/CCID.S523963. eCollection 2025.
4
Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis.木犀草素抑制SIRT7的双重作用重编程肝星状细胞命运：PRMT5琥珀酰化驱动的衰老和内质网应激蛋白依赖的自然杀伤细胞免疫清除在肝纤维化中的作用
Research (Wash D C). 2025 Aug 7;8:0808. doi: 10.34133/research.0808. eCollection 2025.
5
Targeting alveolar epithelial cell metabolism in pulmonary fibrosis: Pioneering an emerging therapeutic strategy.靶向肺纤维化中的肺泡上皮细胞代谢：开拓一种新兴治疗策略。
Front Cell Dev Biol. 2025 Jun 25;13:1608750. doi: 10.3389/fcell.2025.1608750. eCollection 2025.
6
Small molecule compound ZYZ-384 targets SMYD3 to alleviate aging.小分子化合物ZYZ - 384靶向SMYD3以缓解衰老。
Sci Rep. 2025 Jul 10;15(1):24802. doi: 10.1038/s41598-025-10345-y.
7
Research Progress on Anti-fibrotic Effects and Mechanisms of Tetrandrine.粉防己碱抗纤维化作用及其机制的研究进展
Chin J Integr Med. 2025 May 23. doi: 10.1007/s11655-025-4130-4.
8
Blocking triggering receptors expressed on myeloid cell-1 alleviates alveolar epithelial cell senescence by inhibiting oxidative stress in pulmonary fibrosis.阻断髓样细胞表达的触发受体-1通过抑制肺纤维化中的氧化应激减轻肺泡上皮细胞衰老。
Histochem Cell Biol. 2025 Apr 16;163(1):45. doi: 10.1007/s00418-025-02374-5.
9
GLSP mitigates vascular aging by promoting Sirt7-mediated Keap1 deacetylation and Keap1-Nrf2 dissociation.GLSP通过促进Sirt7介导的Keap1去乙酰化和Keap1-Nrf2解离来减轻血管衰老。
Theranostics. 2025 Mar 18;15(10):4345-4367. doi: 10.7150/thno.110324. eCollection 2025.
10
TRIM25: A Global Player of Cell Death Pathways and Promising Target of Tumor-Sensitizing Therapies.TRIM25：细胞死亡途径的全球参与者及肿瘤增敏治疗的潜在靶点
Cells. 2025 Jan 7;14(2):65. doi: 10.3390/cells14020065.
S-烯丙基巯基-N-乙酰半胱氨酸通过激活 Nrf2 通路和抑制 NF-κB、TGF-β1/Smad2/3 通路改善小鼠肺纤维化。
Biomed Pharmacother. 2023 Jan;157:114018. doi: 10.1016/j.biopha.2022.114018. Epub 2022 Nov 18.
4
Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats.番茄红素通过抑制氧化应激介导的内质网应激通路凋亡缓解大鼠慢性应激诱导的肝损伤。
J Agric Food Chem. 2022 Nov 16;70(45):14414-14426. doi: 10.1021/acs.jafc.2c06650. Epub 2022 Nov 1.
5
Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.未折叠蛋白反应 IRE1/XBP1 信号通路对于健康的哺乳动物大脑衰老至关重要。
EMBO J. 2022 Nov 17;41(22):e111952. doi: 10.15252/embj.2022111952. Epub 2022 Oct 31.
6
Epoxyeicosatrienoic Acids Inhibit the Activation of Murine Fibroblasts by Blocking the TGF-1-Smad2/3 Signaling in a PPAR-Dependent Manner.环氧二十碳三烯酸通过以 PPAR 依赖的方式阻断 TGF-β1-Smad2/3 信号转导抑制小鼠成纤维细胞的激活。
Oxid Med Cell Longev. 2022 Oct 13;2022:7265486. doi: 10.1155/2022/7265486. eCollection 2022.
7
Oxidative Stress and Cell Senescence Process.氧化应激与细胞衰老过程。
Antioxidants (Basel). 2022 Aug 30;11(9):1718. doi: 10.3390/antiox11091718.
8
Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.肺泡上皮细胞衰老影响小鼠肺纤维化间质性肺病的起始和慢性期。
Front Immunol. 2022 Aug 18;13:935114. doi: 10.3389/fimmu.2022.935114. eCollection 2022.
9
COX-2/sEH Dual Inhibitor Alleviates Hepatocyte Senescence in NAFLD Mice by Restoring Autophagy through Sirt1/PI3K/AKT/mTOR.COX-2/sEH 双重抑制剂通过 Sirt1/PI3K/AKT/mTOR 恢复自噬来减轻非酒精性脂肪性肝病小鼠的肝细胞衰老。
Int J Mol Sci. 2022 Jul 27;23(15):8267. doi: 10.3390/ijms23158267.
10
Endoplasmic Reticulum (ER) Stress and Its Role in Pancreatic β-Cell Dysfunction and Senescence in Type 2 Diabetes.内质网应激及其在 2 型糖尿病中胰岛β细胞功能障碍和衰老中的作用。
Int J Mol Sci. 2022 Apr 27;23(9):4843. doi: 10.3390/ijms23094843.