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Open AccessArticle
Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence
by
Jingyuan Ya
Jingyuan Ya
and
Ulvi Bayraktutan
Ulvi Bayraktutan *
Academic Stroke, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
*
Author to whom correspondence should be addressed.
Cells 2024, 13(15), 1292; https://doi.org/10.3390/cells13151292 (registering DOI)
Submission received: 13 June 2024
/
Revised: 19 July 2024
/
Accepted: 28 July 2024
/
Published: 31 July 2024
Abstract
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood–brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher β-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction.
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MDPI and ACS Style
Ya, J.; Bayraktutan, U.
Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence. Cells 2024, 13, 1292.
https://doi.org/10.3390/cells13151292
AMA Style
Ya J, Bayraktutan U.
Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence. Cells. 2024; 13(15):1292.
https://doi.org/10.3390/cells13151292
Chicago/Turabian Style
Ya, Jingyuan, and Ulvi Bayraktutan.
2024. "Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence" Cells 13, no. 15: 1292.
https://doi.org/10.3390/cells13151292
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