Cargando…
Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells
BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Ou...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752267/ https://www.ncbi.nlm.nih.gov/pubmed/35028008 http://dx.doi.org/10.1155/2022/5583512 |
_version_ | 1784631851469504512 |
---|---|
author | Meng, Qingqi Chen, Zhiteng Gao, Qingyuan Hu, Liqiong Li, Qilong Li, Shutai Cui, Lili Feng, Zhencheng Zhang, Xingliang Cui, Shiyun Zhang, Haifeng |
author_facet | Meng, Qingqi Chen, Zhiteng Gao, Qingyuan Hu, Liqiong Li, Qilong Li, Shutai Cui, Lili Feng, Zhencheng Zhang, Xingliang Cui, Shiyun Zhang, Haifeng |
author_sort | Meng, Qingqi |
collection | PubMed |
description | BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. METHODS: SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. RESULTS: We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. CONCLUSIONS: Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation. |
format | Online Article Text |
id | pubmed-8752267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-87522672022-01-12 Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells Meng, Qingqi Chen, Zhiteng Gao, Qingyuan Hu, Liqiong Li, Qilong Li, Shutai Cui, Lili Feng, Zhencheng Zhang, Xingliang Cui, Shiyun Zhang, Haifeng Oxid Med Cell Longev Research Article BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. METHODS: SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. RESULTS: We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. CONCLUSIONS: Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation. Hindawi 2022-01-04 /pmc/articles/PMC8752267/ /pubmed/35028008 http://dx.doi.org/10.1155/2022/5583512 Text en Copyright © 2022 Qingqi Meng et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Meng, Qingqi Chen, Zhiteng Gao, Qingyuan Hu, Liqiong Li, Qilong Li, Shutai Cui, Lili Feng, Zhencheng Zhang, Xingliang Cui, Shiyun Zhang, Haifeng Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title | Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title_full | Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title_fullStr | Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title_full_unstemmed | Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title_short | Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells |
title_sort | rosiglitazone ameliorates spinal cord injury via inhibiting mitophagy and inflammation of neural stem cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752267/ https://www.ncbi.nlm.nih.gov/pubmed/35028008 http://dx.doi.org/10.1155/2022/5583512 |
work_keys_str_mv | AT mengqingqi rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT chenzhiteng rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT gaoqingyuan rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT huliqiong rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT liqilong rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT lishutai rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT cuilili rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT fengzhencheng rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT zhangxingliang rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT cuishiyun rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells AT zhanghaifeng rosiglitazoneamelioratesspinalcordinjuryviainhibitingmitophagyandinflammationofneuralstemcells |