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Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway

Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for...

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Autores principales: Peng, Fenfen, Li, Hongyu, Li, Shuting, Wang, Yuxian, Liu, Wenting, Gong, Wangqiu, Yin, Bohui, Chen, Sijia, Zhang, Ying, Luo, Congwei, Zhou, Weidong, Chen, Yihua, Li, Peilin, Huang, Qianyin, Xu, Zhaozhong, Long, Haibo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760645/
https://www.ncbi.nlm.nih.gov/pubmed/30976056
http://dx.doi.org/10.1038/s41374-019-0245-6
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author Peng, Fenfen
Li, Hongyu
Li, Shuting
Wang, Yuxian
Liu, Wenting
Gong, Wangqiu
Yin, Bohui
Chen, Sijia
Zhang, Ying
Luo, Congwei
Zhou, Weidong
Chen, Yihua
Li, Peilin
Huang, Qianyin
Xu, Zhaozhong
Long, Haibo
author_facet Peng, Fenfen
Li, Hongyu
Li, Shuting
Wang, Yuxian
Liu, Wenting
Gong, Wangqiu
Yin, Bohui
Chen, Sijia
Zhang, Ying
Luo, Congwei
Zhou, Weidong
Chen, Yihua
Li, Peilin
Huang, Qianyin
Xu, Zhaozhong
Long, Haibo
author_sort Peng, Fenfen
collection PubMed
description Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models–the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.
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spelling pubmed-67606452019-09-26 Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway Peng, Fenfen Li, Hongyu Li, Shuting Wang, Yuxian Liu, Wenting Gong, Wangqiu Yin, Bohui Chen, Sijia Zhang, Ying Luo, Congwei Zhou, Weidong Chen, Yihua Li, Peilin Huang, Qianyin Xu, Zhaozhong Long, Haibo Lab Invest Article Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models–the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway. Nature Publishing Group US 2019-04-11 2019 /pmc/articles/PMC6760645/ /pubmed/30976056 http://dx.doi.org/10.1038/s41374-019-0245-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Peng, Fenfen
Li, Hongyu
Li, Shuting
Wang, Yuxian
Liu, Wenting
Gong, Wangqiu
Yin, Bohui
Chen, Sijia
Zhang, Ying
Luo, Congwei
Zhou, Weidong
Chen, Yihua
Li, Peilin
Huang, Qianyin
Xu, Zhaozhong
Long, Haibo
Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title_full Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title_fullStr Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title_full_unstemmed Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title_short Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
title_sort micheliolide ameliorates renal fibrosis by suppressing the mtdh/bmp/mapk pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760645/
https://www.ncbi.nlm.nih.gov/pubmed/30976056
http://dx.doi.org/10.1038/s41374-019-0245-6
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