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SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury
BACKGROUND: Evidence exists uncovering that SRY-box transcription factor 9 (SOX9) plays a role in ischemic brain injury (IBI). Thus, the current study was conducted to elucidate the specific role of SOX9 and the mechanism by which SOX9 influenced IBI. METHODS: The IBI-associated regulatory factors w...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006459/ https://www.ncbi.nlm.nih.gov/pubmed/33791290 http://dx.doi.org/10.3389/fcell.2020.555175 |
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author | Deng, Yiming Ma, Gaoting Gao, Feng Sun, Xuan Liu, Lian Mo, Dapeng Ma, Ning Song, Ligang Huo, Xiaochuan He, Hongwei Miao, Zhongrong |
author_facet | Deng, Yiming Ma, Gaoting Gao, Feng Sun, Xuan Liu, Lian Mo, Dapeng Ma, Ning Song, Ligang Huo, Xiaochuan He, Hongwei Miao, Zhongrong |
author_sort | Deng, Yiming |
collection | PubMed |
description | BACKGROUND: Evidence exists uncovering that SRY-box transcription factor 9 (SOX9) plays a role in ischemic brain injury (IBI). Thus, the current study was conducted to elucidate the specific role of SOX9 and the mechanism by which SOX9 influenced IBI. METHODS: The IBI-associated regulatory factors were searched by bioinformatics analysis. The rat model of IBI was generated using middle cerebral artery occlusion (MCAO) treatment. Neuronal cells were exposed to oxygen-glucose deprivation (OGD). The expressions of SOX9, forkhead box O3 (FOXO3), transcription of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), and IκB kinase α (IKKα) in OGD-treated neuronal cells were characterized using reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. The interaction among CITED2, IKKα, and FOXO3 was identified by chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays. Gain- and loss-of-function experiments were performed to verify the relationship among SOX9, FOXO3, CITED2, and IKKα and to investigate their functional effects on apoptosis and the inflammatory response of OGD-treated neuronal cells as well as neurological deficit and infarct area of the rat brain. RESULTS: SOX9, FOXO3, CITED2, and IKKα were highly expressed in OGD-treated neuronal cells. Silencing of SOX9 inhibited OGD-induced neuronal apoptosis and inflammatory response and reduced the neurological deficit and infarct area of the brain in the rats, which were caused by MCAO but were reversed by overexpressing FOXO3, CITED2, or IKKα. CONCLUSION: Taken together, our study suggested that upregulation of SOX9 promoted IBI though upregulation of the FOXO3/CITED2/IKKα axis, highlighting a basic therapeutic consideration for IBI treatment. |
format | Online Article Text |
id | pubmed-8006459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80064592021-03-30 SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury Deng, Yiming Ma, Gaoting Gao, Feng Sun, Xuan Liu, Lian Mo, Dapeng Ma, Ning Song, Ligang Huo, Xiaochuan He, Hongwei Miao, Zhongrong Front Cell Dev Biol Cell and Developmental Biology BACKGROUND: Evidence exists uncovering that SRY-box transcription factor 9 (SOX9) plays a role in ischemic brain injury (IBI). Thus, the current study was conducted to elucidate the specific role of SOX9 and the mechanism by which SOX9 influenced IBI. METHODS: The IBI-associated regulatory factors were searched by bioinformatics analysis. The rat model of IBI was generated using middle cerebral artery occlusion (MCAO) treatment. Neuronal cells were exposed to oxygen-glucose deprivation (OGD). The expressions of SOX9, forkhead box O3 (FOXO3), transcription of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), and IκB kinase α (IKKα) in OGD-treated neuronal cells were characterized using reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. The interaction among CITED2, IKKα, and FOXO3 was identified by chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays. Gain- and loss-of-function experiments were performed to verify the relationship among SOX9, FOXO3, CITED2, and IKKα and to investigate their functional effects on apoptosis and the inflammatory response of OGD-treated neuronal cells as well as neurological deficit and infarct area of the rat brain. RESULTS: SOX9, FOXO3, CITED2, and IKKα were highly expressed in OGD-treated neuronal cells. Silencing of SOX9 inhibited OGD-induced neuronal apoptosis and inflammatory response and reduced the neurological deficit and infarct area of the brain in the rats, which were caused by MCAO but were reversed by overexpressing FOXO3, CITED2, or IKKα. CONCLUSION: Taken together, our study suggested that upregulation of SOX9 promoted IBI though upregulation of the FOXO3/CITED2/IKKα axis, highlighting a basic therapeutic consideration for IBI treatment. Frontiers Media S.A. 2021-03-12 /pmc/articles/PMC8006459/ /pubmed/33791290 http://dx.doi.org/10.3389/fcell.2020.555175 Text en Copyright © 2021 Deng, Ma, Gao, Sun, Liu, Mo, Ma, Song, Huo, He and Miao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Deng, Yiming Ma, Gaoting Gao, Feng Sun, Xuan Liu, Lian Mo, Dapeng Ma, Ning Song, Ligang Huo, Xiaochuan He, Hongwei Miao, Zhongrong SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title | SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title_full | SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title_fullStr | SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title_full_unstemmed | SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title_short | SOX9 Knockdown-Mediated FOXO3 Downregulation Confers Neuroprotection Against Ischemic Brain Injury |
title_sort | sox9 knockdown-mediated foxo3 downregulation confers neuroprotection against ischemic brain injury |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006459/ https://www.ncbi.nlm.nih.gov/pubmed/33791290 http://dx.doi.org/10.3389/fcell.2020.555175 |
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