• 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

磷酸二酯酶4、5和9的选择性抑制诱导热休克蛋白20磷酸化并减轻β淀粉样蛋白1-42介导的细胞毒性。

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42-mediated cytotoxicity.

作者信息

Cameron Ryan T, Whiteley Ellanor, Day Jon P, Parachikova Anna I, Baillie George S

机构信息

Institute of Cardiovascular and Medical Sciences College of Veterinary Medical and Life Sciences University of Glasgow UK.

Synaptic Transmission H. Lundbeck A/S Valby Denmark.

出版信息

FEBS Open Bio. 2016 Dec 5;7(1):64-73. doi: 10.1002/2211-5463.12156. eCollection 2017 Jan.

DOI:10.1002/2211-5463.12156
PMID:28097089
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5221464/
Abstract

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1-42 (Aβ) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ cytotoxicity in our cell model.

摘要

磷酸二酯酶（PDE）抑制剂目前正在作为可能有助于改善与阿尔茨海默病相关的认知障碍的药物进行评估。我们的目的是确定PDE4、5和9的抑制剂是否可以通过涉及小分子热休克蛋白HSP20的机制减轻β淀粉样蛋白1-42（Aβ）的细胞毒性作用。我们发现，抑制PDE4、5和9而非PDE3可诱导HSP20磷酸化，进而增加伴侣蛋白与Aβ之间的共定位，从而显著降低该肽的毒性作用。我们得出结论，在我们的细胞模型中，抑制PDE9对抗Aβ细胞毒性最有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/3c8f52768730/FEB4-7-64-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/ea5b6411653d/FEB4-7-64-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/71dc93a62f75/FEB4-7-64-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/31e291c90868/FEB4-7-64-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/b5d5254c9e4b/FEB4-7-64-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/852a2e6e03ca/FEB4-7-64-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/3c8f52768730/FEB4-7-64-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/ea5b6411653d/FEB4-7-64-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/71dc93a62f75/FEB4-7-64-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/31e291c90868/FEB4-7-64-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/b5d5254c9e4b/FEB4-7-64-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/852a2e6e03ca/FEB4-7-64-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fba/5221464/3c8f52768730/FEB4-7-64-g006.jpg

相似文献

1
Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42-mediated cytotoxicity.磷酸二酯酶4、5和9的选择性抑制诱导热休克蛋白20磷酸化并减轻β淀粉样蛋白1-42介导的细胞毒性。
FEBS Open Bio. 2016 Dec 5;7(1):64-73. doi: 10.1002/2211-5463.12156. eCollection 2017 Jan.
2
A novel selective phosphodiesterase 9 inhibitor, irsenontrine (E2027), enhances GluA1 phosphorylation in neurons and improves learning and memory via cyclic GMP elevation.一种新型选择性磷酸二酯酶9抑制剂，艾司诺曲林（E2027），可增强神经元中GluA1的磷酸化，并通过环鸟苷酸水平升高改善学习和记忆。
Neuropharmacology. 2025 Aug 1;273:110428. doi: 10.1016/j.neuropharm.2025.110428. Epub 2025 Mar 25.
3
Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)-HSP20 complex attenuates the β-agonist induced hypertrophic response in cardiac myocytes.环腺苷酸磷酸二酯酶-4（PDE4）-热休克蛋白 20 复合物的破坏可减轻β-激动剂诱导的心肌细胞肥大反应。
J Mol Cell Cardiol. 2011 May;50(5):872-83. doi: 10.1016/j.yjmcc.2011.02.006. Epub 2011 Feb 18.
4
Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity.小分子热休克蛋白可抑制β-淀粉样蛋白聚集及脑血管β-淀粉样蛋白毒性。
Brain Res. 2006 May 17;1089(1):67-78. doi: 10.1016/j.brainres.2006.03.058. Epub 2006 Apr 24.
5
Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway.磷酸二酯酶之间在心脏β-肾上腺素能信号通路调节中的相互作用。
J Mol Cell Cardiol. 2015 Nov;88:29-38. doi: 10.1016/j.yjmcc.2015.09.011. Epub 2015 Sep 23.
6
Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer's disease.磷酸二酯酶抑制剂对阿尔茨海默病认知改善的治疗潜力。
Eur J Med Chem. 2022 Mar 15;232:114170. doi: 10.1016/j.ejmech.2022.114170. Epub 2022 Feb 3.
7
Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors.环核苷酸磷酸二酯酶抑制剂对大鼠主动脉的内皮依赖性和非内皮依赖性舒张作用。
Br J Pharmacol. 1991 Oct;104(2):495-503. doi: 10.1111/j.1476-5381.1991.tb12457.x.
8
Isoenzyme-selective cyclic nucleotide phosphodiesterase inhibitors: effects on airways smooth muscle.同工酶选择性环核苷酸磷酸二酯酶抑制剂：对气道平滑肌的作用
Int J Biochem Cell Biol. 1995 Jan;27(1):29-37. doi: 10.1016/1357-2725(94)00060-3.
9
Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis.磷酸二酯酶-2抑制剂Bay 60-7550通过调节下丘脑-垂体-肾上腺轴改善β-淀粉样蛋白诱导的认知和记忆障碍。
Front Cell Neurosci. 2019 Oct 2;13:432. doi: 10.3389/fncel.2019.00432. eCollection 2019.
10
Proteolysis of cyclic AMP phosphodiesterase-II attenuates its ability to be inhibited by compounds which exert positive inotropic actions in cardiac tissue.环磷酸腺苷磷酸二酯酶-II的蛋白水解作用减弱了其被在心脏组织中发挥正性肌力作用的化合物抑制的能力。
Biochem Pharmacol. 1987 Dec 1;36(23):4047-54. doi: 10.1016/0006-2952(87)90560-0.

引用本文的文献

1
Antibody-assisted selective isolation of Purkinje cell nuclei from mouse cerebellar tissue.抗体辅助的小鼠小脑组织浦肯野细胞核的选择性分离。
Cell Rep Methods. 2024 Jul 15;4(7):100816. doi: 10.1016/j.crmeth.2024.100816. Epub 2024 Jul 8.
2
PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity.抑制不同细胞类型中的 PDE 以恢复突触可塑性的平衡。
Theranostics. 2021 Jan 1;11(5):2080-2097. doi: 10.7150/thno.50701. eCollection 2021.
3
Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease.

本文引用的文献

1
The amyloid hypothesis of Alzheimer's disease at 25 years.阿尔茨海默病淀粉样蛋白假说25年回顾
EMBO Mol Med. 2016 Jun 1;8(6):595-608. doi: 10.15252/emmm.201606210. Print 2016 Jun.
2
Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer's disease.发现能够抑制β淀粉样蛋白聚集的新型磷酸二酯酶9抑制剂，作为治疗阿尔茨海默病的潜在候选药物。
Sci Rep. 2016 Feb 25;6:21826. doi: 10.1038/srep21826.
3
Global and local missions of cAMP signaling in neural plasticity, learning, and memory.
小分子热休克蛋白对神经退行性疾病中蛋白质聚集有重大影响。
Front Pharmacol. 2019 Sep 18;10:1047. doi: 10.3389/fphar.2019.01047. eCollection 2019.
4
Targeting Phosphodiesterases-Towards a Tailor-Made Approach in Multiple Sclerosis Treatment.靶向磷酸二酯酶——多发性硬化症治疗的个体化方法。
Front Immunol. 2019 Jul 24;10:1727. doi: 10.3389/fimmu.2019.01727. eCollection 2019.
5
Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease.利用组蛋白脱乙酰酶和磷酸二酯酶抑制剂的选择性来设计更好的治疗策略以治疗阿尔茨海默病。
Front Aging Neurosci. 2019 Jun 21;11:149. doi: 10.3389/fnagi.2019.00149. eCollection 2019.
6
Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A - C-Raf.针对携带新型穿透细胞肽扰乱 PDE8A-C-Raf 的 B-Raf 抑制剂耐药性黑色素瘤
BMC Cancer. 2019 Mar 25;19(1):266. doi: 10.1186/s12885-019-5489-4.
7
Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain.与正常衰老和与年龄相关的脑疾病相关的环核苷酸信号变化。
Cell Signal. 2018 Jan;42:281-291. doi: 10.1016/j.cellsig.2017.11.004. Epub 2017 Nov 23.
环磷酸腺苷（cAMP）信号在神经可塑性、学习和记忆中的全局及局部作用
Front Pharmacol. 2015 Aug 4;6:161. doi: 10.3389/fphar.2015.00161. eCollection 2015.
4
Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy.靶向破坏热休克蛋白 20-磷酸二酯酶 4D（PDE4D）相互作用可预防肥厚型小鼠病理性心脏重构。
FEBS Open Bio. 2014 Oct 28;4:923-7. doi: 10.1016/j.fob.2014.10.011. eCollection 2014.
5
The phosphorylation of Hsp20 enhances its association with amyloid-β to increase protection against neuronal cell death.热休克蛋白20（Hsp20）的磷酸化增强了它与β淀粉样蛋白的结合，从而增强对神经元细胞死亡的保护作用。
Mol Cell Neurosci. 2014 Jul;61:46-55. doi: 10.1016/j.mcn.2014.05.002. Epub 2014 May 20.
6
PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition.磷酸二酯酶9A（PDE9A）抑制可挽救β淀粉样蛋白诱导的突触可塑性和认知缺陷。
Neurobiol Aging. 2014 Sep;35(9):2072-8. doi: 10.1016/j.neurobiolaging.2014.03.023. Epub 2014 Mar 26.
7
Advances in targeting cyclic nucleotide phosphodiesterases.靶向环核苷酸磷酸二酯酶的研究进展。
Nat Rev Drug Discov. 2014 Apr;13(4):290-314. doi: 10.1038/nrd4228.
8
Real-time probing of β-amyloid self-assembly and inhibition using fluorescence self-quenching between neighbouring dyes.利用相邻染料间的荧光自猝灭对β-淀粉样蛋白自组装及抑制作用进行实时探测。
Mol Biosyst. 2014 Jan;10(1):34-44. doi: 10.1039/c3mb70272c. Epub 2013 Oct 29.
9
Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy.调节中枢神经系统中的一氧化氮信号传递用于阿尔茨海默病的治疗。
Future Med Chem. 2013 Aug;5(12):1451-68. doi: 10.4155/fmc.13.111.
10
Blockade of Ser16-Hsp20 phosphorylation attenuates neuroprotection dependent upon Bcl-2 and Bax.阻断 Ser16-Hsp20 磷酸化可减轻依赖 Bcl-2 和 Bax 的神经保护作用。
Curr Neurovasc Res. 2013 Aug;10(3):208-15. doi: 10.2174/15672026113109990006.