• 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

PKA 和 Epac1 降低 Nek7 以阻断视网膜血管中的 NLRP3 炎性小体蛋白。

PKA and Epac1 Reduce Nek7 to Block the NLRP3 Inflammasome Proteins in the Retinal Vasculature.

机构信息

Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States.

出版信息

Invest Ophthalmol Vis Sci. 2022 Jan 3;63(1):14. doi: 10.1167/iovs.63.1.14.

DOI:10.1167/iovs.63.1.14
PMID:35006270
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8762717/
Abstract

PURPOSE

To determine whether protein kinase a (PKA) and exchange protein for cAMP 1 (Epac1) inhibit NIMA-related kinase 7 (Nek7) to block the NOD-like receptor family pyrin domain-containing family member 3 (NLRP3) signaling pathway.

METHODS

Retinal endothelial cells (RECs) were grown in normal (5 mM) or high (25 mM) glucose. Some cells were treated with a Nek7 cDNA plasmid, Nek7 siRNA; an Epac1 agonist, forskolin; a PKA agonist; or an empty vector. Epac1 floxed and Cdh5-cre Epac1 mice and Nek7 floxed and Cdh5-cre Nek7 mice were also used. Western blot analyses were done on cell culture or whole retinal lysates for NLRP3, cleaved caspase 1, interleukin-1-beta (IL-1β). A PKA activity assay was also done.

RESULTS

Nek7 cDNA increased NLRP3 signaling proteins, but Nek7 siRNA inhibited high-glucose induction of these proteins in retinal endothelial cells. Epac1 and forskolin both reduced Nek7 and NLRP3 pathway proteins, even when given in combination with Nek7 cDNA. Elimination of Nek7 in endothelial cells reduced NLRP3 signaling proteins in whole retinal lysates from mice.

CONCLUSIONS

Nek7 regulated NLRP3 inflammasome protein levels both in vitro and in vivo. Both Epac1 and PKA lie upstream of Nek7 and NLRP3 and can overcome excessive Nek7 levels. These studies establish that cAMP proteins can inhibit Nek7 and block activation of the NLRP3 inflammasome proteins.

摘要

目的

确定蛋白激酶 A（PKA）和环腺苷酸交换蛋白 1（Epac1）是否通过抑制丝氨酸/苏氨酸激酶 NIMA 相关激酶 7（Nek7）来阻断 NOD 样受体家族含吡咯结构域蛋白 3（NLRP3）信号通路。

方法

培养视网膜血管内皮细胞（RECs）使其处于正常（5mM）或高（25mM）葡萄糖环境中。部分细胞用 Nek7 cDNA 质粒、Nek7 siRNA、Epac1 激动剂 forskolin、PKA 激动剂或空载体进行处理。此外，还使用了 Epac1 基因敲除和 Cdh5-cre Epac1 小鼠及 Nek7 基因敲除和 Cdh5-cre Nek7 小鼠。Western blot 分析用于检测细胞培养物或全视网膜裂解物中的 NLRP3、切割的半胱天冬酶 1、白细胞介素 1-β（IL-1β）。还进行了 PKA 活性测定。

结果

Nek7 cDNA 增加了 NLRP3 信号蛋白，但 Nek7 siRNA 抑制了高葡萄糖诱导的视网膜内皮细胞中这些蛋白的表达。Epac1 和 forskolin 均降低了 Nek7 和 NLRP3 通路蛋白，即使与 Nek7 cDNA 联合使用也是如此。内皮细胞中 Nek7 的缺失降低了来自小鼠的全视网膜裂解物中的 NLRP3 信号蛋白。

结论

Nek7 在线粒体和体内均调节 NLRP3 炎症小体蛋白水平。Epac1 和 PKA 均位于 Nek7 和 NLRP3 的上游，可克服过高的 Nek7 水平。这些研究确立了 cAMP 蛋白可抑制 Nek7 并阻断 NLRP3 炎症小体蛋白的激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/f721acadbb7e/iovs-63-1-14-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/9f335c4c937a/iovs-63-1-14-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/e61b2bcf0588/iovs-63-1-14-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/2ba390498e7c/iovs-63-1-14-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/fcec7e3ce769/iovs-63-1-14-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/721fdb6431ff/iovs-63-1-14-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/eb8da93a6b3a/iovs-63-1-14-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/33e97c79a910/iovs-63-1-14-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/06031c2d1929/iovs-63-1-14-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/f721acadbb7e/iovs-63-1-14-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/9f335c4c937a/iovs-63-1-14-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/e61b2bcf0588/iovs-63-1-14-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/2ba390498e7c/iovs-63-1-14-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/fcec7e3ce769/iovs-63-1-14-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/721fdb6431ff/iovs-63-1-14-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/eb8da93a6b3a/iovs-63-1-14-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/33e97c79a910/iovs-63-1-14-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/06031c2d1929/iovs-63-1-14-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7809/8762717/f721acadbb7e/iovs-63-1-14-f009.jpg

相似文献

1
PKA and Epac1 Reduce Nek7 to Block the NLRP3 Inflammasome Proteins in the Retinal Vasculature.PKA 和 Epac1 降低 Nek7 以阻断视网膜血管中的 NLRP3 炎性小体蛋白。
Invest Ophthalmol Vis Sci. 2022 Jan 3;63(1):14. doi: 10.1167/iovs.63.1.14.
2
Epac1 and PKA agonists inhibit ROS to reduce NLRP3 inflammasome proteins in retinal endothelial cells.Epac1 和 PKA 激动剂抑制 ROS 减少视网膜内皮细胞中 NLRP3 炎性小体蛋白。
Mol Vis. 2022 Dec 31;28:500-506. eCollection 2022.
3
Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1 in Retinal Endothelial Cells and Mouse Retinal Vasculature.Epac1阻断NLRP3炎性小体以减少视网膜内皮细胞和小鼠视网膜血管中的白细胞介素-1 。
Mediators Inflamm. 2017;2017:2860956. doi: 10.1155/2017/2860956. Epub 2017 Feb 28.
4
Epac1 and PKA regulate of P2X7 and NLRP3 inflammasome proteins in the retinal vasculature.Epac1 和 PKA 调节视网膜血管中的 P2X7 和 NLRP3 炎性小体蛋白。
Exp Eye Res. 2022 May;218:108987. doi: 10.1016/j.exer.2022.108987. Epub 2022 Feb 16.
5
Compound 49b Regulates ZO-1 and Occludin Levels in Human Retinal Endothelial Cells and in Mouse Retinal Vasculature.化合物49b调节人视网膜内皮细胞和小鼠视网膜血管中的紧密连接蛋白1（ZO-1）和闭合蛋白水平。
Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):185-189. doi: 10.1167/iovs.16-20412.
6
NIMA-related kinase 7 amplifies NLRP3 inflammasome pro-inflammatory signaling in microglia/macrophages and mice models of spinal cord injury.NIMA 相关激酶 7 在小胶质细胞/巨噬细胞和脊髓损伤小鼠模型中放大 NLRP3 炎性体炎症信号。
Exp Cell Res. 2021 Jan 15;398(2):112418. doi: 10.1016/j.yexcr.2020.112418. Epub 2020 Dec 9.
7
Recent advances in the NEK7-licensed NLRP3 inflammasome activation: Mechanisms, role in diseases and related inhibitors.NEK7 许可的 NLRP3 炎性小体激活的最新进展：机制、在疾病中的作用和相关抑制剂。
J Autoimmun. 2020 Sep;113:102515. doi: 10.1016/j.jaut.2020.102515. Epub 2020 Jul 20.
8
NEK7 mediated assembly and activation of NLRP3 inflammasome downstream of potassium efflux in ventilator-induced lung injury.NEK7 介导钾离子外流后呼吸机诱导肺损伤中 NLRP3 炎性小体的组装和激活。
Biochem Pharmacol. 2020 Jul;177:113998. doi: 10.1016/j.bcp.2020.113998. Epub 2020 Apr 27.
9
PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome.Spata2-CYLD 通过去泛素化 PLK4 抑制中心体处 NEK7 介导的 NLRP3 炎性小体激活。
EMBO J. 2020 Jan 15;39(2):e102201. doi: 10.15252/embj.2019102201. Epub 2019 Nov 25.
10
NEK7: a potential therapy target for NLRP3-related diseases.NEK7：NLRP3 相关疾病的潜在治疗靶点。
Biosci Trends. 2020 May 21;14(2):74-82. doi: 10.5582/bst.2020.01029. Epub 2020 Apr 16.

引用本文的文献

1
Caveolin-1 regulates inflammatory mediators in retinal endothelial cells.小窝蛋白-1调节视网膜内皮细胞中的炎症介质。
Mol Vis. 2024 Oct 5;30:298-303. eCollection 2024.
2
Ephrin B1 Regulates Inflammatory Pathways in Retinal Müller Cells.Ephrin B1调节视网膜穆勒细胞中的炎症通路。
J Diabetes Clin Res. 2024;6(1):1-7. doi: 10.33696/diabetes.6.056.
3
Semaphorin 7a regulates inflammatory mediators and permeability in retinal endothelial cells.Semaphorin 7a 在视网膜内皮细胞中调节炎症介质和通透性。

本文引用的文献

1
Ghrelin Ameliorates Diabetic Retinal Injury: Potential Therapeutic Avenues for Diabetic Retinopathy.胃饥饿素可改善糖尿病性视网膜损伤：糖尿病性视网膜病变的潜在治疗途径。
Oxid Med Cell Longev. 2021 Oct 26;2021:8043299. doi: 10.1155/2021/8043299. eCollection 2021.
2
Down-expression of the NLRP3 inflammasome delays the progression of diabetic retinopathy.NLRP3 炎性小体的下调可延缓糖尿病视网膜病变的进展。
Microvasc Res. 2022 Jan;139:104265. doi: 10.1016/j.mvr.2021.104265. Epub 2021 Oct 16.
3
Forskolin regulates retinal endothelial cell permeability through TLR4 actions in vitro.
Microvasc Res. 2023 Nov;150:104587. doi: 10.1016/j.mvr.2023.104587. Epub 2023 Jul 13.
4
Epac1 and PKA agonists inhibit ROS to reduce NLRP3 inflammasome proteins in retinal endothelial cells.Epac1 和 PKA 激动剂抑制 ROS 减少视网膜内皮细胞中 NLRP3 炎性小体蛋白。
Mol Vis. 2022 Dec 31;28:500-506. eCollection 2022.
5
Loss of cystatin C regulates permeability and inflammatory pathways in retina.胱抑素 C 的缺失调节视网膜的通透性和炎症途径。
Microvasc Res. 2023 Jul;148:104510. doi: 10.1016/j.mvr.2023.104510. Epub 2023 Feb 21.
6
TNFAIP3 may be key to TLR4-activation of the inflammasome in the retinal vasculature.肿瘤坏死因子-α 诱导蛋白 3 可能是 TLR4 在视网膜血管中激活炎症小体的关键。
Exp Eye Res. 2022 Jul;220:109108. doi: 10.1016/j.exer.2022.109108. Epub 2022 May 11.
福司可林通过 TLR4 作用体外调节视网膜内皮细胞通透性。
Mol Cell Biochem. 2021 Dec;476(12):4487-4492. doi: 10.1007/s11010-021-04252-9. Epub 2021 Aug 28.
4
Epac1 regulates TLR4 signaling in the diabetic retinal vasculature.Epac1 调控糖尿病视网膜血管中 TLR4 信号通路。
Cytokine. 2021 Aug;144:155576. doi: 10.1016/j.cyto.2021.155576. Epub 2021 May 18.
5
RACK1 Mediates NLRP3 Inflammasome Activation by Promoting NLRP3 Active Conformation and Inflammasome Assembly.RACK1 通过促进 NLRP3 活性构象和炎性小体组装来介导 NLRP3 炎性小体的激活。
Cell Rep. 2020 Nov 17;33(7):108405. doi: 10.1016/j.celrep.2020.108405.
6
The role of NLRP3 inflammasome in infection-related, immune-mediated and autoimmune skin diseases.NLRP3 炎性小体在感染相关、免疫介导和自身免疫性皮肤病中的作用。
J Dermatol Sci. 2020 Jun;98(3):146-151. doi: 10.1016/j.jdermsci.2020.03.001. Epub 2020 Mar 6.
7
Epac1 and Glycyrrhizin Both Inhibit HMGB1 Levels to Reduce Diabetes-Induced Neuronal and Vascular Damage in the Mouse Retina.Epac1和甘草甜素均可抑制高迁移率族蛋白B1水平，以减轻糖尿病诱导的小鼠视网膜神经元和血管损伤。
J Clin Med. 2019 May 31;8(6):772. doi: 10.3390/jcm8060772.
8
Epac1 deacetylates HMGB1 through increased IGFBP-3 and SIRT1 levels in the retinal vasculature.Epac1通过增加视网膜血管中IGFBP-3和SIRT1的水平使HMGB1去乙酰化。
Mol Vis. 2018 Nov 16;24:727-732. eCollection 2018.
9
PKA regulates HMGB1 through activation of IGFBP-3 and SIRT1 in human retinal endothelial cells cultured in high glucose.蛋白激酶 A 通过激活 IGFBP-3 和 SIRT1 调控高糖培养下人视网膜血管内皮细胞高迁移率族蛋白 B1
Inflamm Res. 2018 Dec;67(11-12):1013-1019. doi: 10.1007/s00011-018-1196-x. Epub 2018 Oct 17.
10
Prostaglandin E2 Activates NLRP3 Inflammasome in Endothelial Cells to Promote Diabetic Retinopathy.前列腺素 E2 激活内皮细胞中的 NLRP3 炎性小体促进糖尿病视网膜病变。
Horm Metab Res. 2018 Sep;50(9):704-710. doi: 10.1055/a-0664-0699. Epub 2018 Aug 24.