Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization
Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett (G. acuta) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against...
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Frontiers Media S.A.
2021-04-01
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Series: | Frontiers in Pharmacology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.644886/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hong-Xia Yang Hong-Xia Yang Jia-Huan Sun Ting-Ting Yao Yuan Li Geng-Rui Xu Chuang Zhang Xing-Chao Liu Wei-Wei Zhou Qiu-Hang Song Qiu-Hang Song Qiu-Hang Song Yue Zhang Yue Zhang Yue Zhang Ai-Ying Li Ai-Ying Li Ai-Ying Li |
spellingShingle |
Hong-Xia Yang Hong-Xia Yang Jia-Huan Sun Ting-Ting Yao Yuan Li Geng-Rui Xu Chuang Zhang Xing-Chao Liu Wei-Wei Zhou Qiu-Hang Song Qiu-Hang Song Qiu-Hang Song Yue Zhang Yue Zhang Yue Zhang Ai-Ying Li Ai-Ying Li Ai-Ying Li Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization Frontiers in Pharmacology bellidifolin Gentianella acuta myocardial fibrosis TGF-β1/smads pathway p38 orphan nuclear receptor NR4A1 |
author_facet |
Hong-Xia Yang Hong-Xia Yang Jia-Huan Sun Ting-Ting Yao Yuan Li Geng-Rui Xu Chuang Zhang Xing-Chao Liu Wei-Wei Zhou Qiu-Hang Song Qiu-Hang Song Qiu-Hang Song Yue Zhang Yue Zhang Yue Zhang Ai-Ying Li Ai-Ying Li Ai-Ying Li |
author_sort |
Hong-Xia Yang |
title |
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization |
title_short |
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization |
title_full |
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization |
title_fullStr |
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization |
title_full_unstemmed |
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization |
title_sort |
bellidifolin ameliorates isoprenaline-induced myocardial fibrosis by regulating tgf-β1/smads and p38 signaling and preventing nr4a1 cytoplasmic localization |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2021-04-01 |
description |
Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett (G. acuta) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against myocardial damage. However, the effects and mechanisms of BEL on myocardial fibrosis have not been reported. In vivo, BEL dampened isoprenaline (ISO)-induced cardiac structure disturbance and collagen deposition. In vitro, BEL inhibited transforming growth factor (TGF)-β1-induced cardiac fibroblast (CF) proliferation. In vivo and in vitro, BEL decreased the expression of α-smooth muscle actin (α-SMA), collagen Ⅰ and Ⅲ, and inhibited TGF-β1/Smads signaling. Additionally, BEL impeded p38 activation and NR4A1 (an endogenous inhibitor for pro-fibrogenic activities of TGF-β1) phosphorylation and inactivation in vitro. In CFs, inhibition of p38 by SB203580 inhibited the phosphorylation of NR4A1 and did not limit Smad3 phosphorylation, and blocking TGF-β signaling by LY2157299 and SB203580 could decrease the expression of α-SMA, collagen I and III. Overall, both cell and animal studies provide a potential role for BEL against myocardial fibrosis by inhibiting the proliferation and phenotypic transformation of CFs. These inhibitory effects might be related to regulating TGF-β1/Smads pathway and p38 signaling and preventing NR4A1 cytoplasmic localization. |
topic |
bellidifolin Gentianella acuta myocardial fibrosis TGF-β1/smads pathway p38 orphan nuclear receptor NR4A1 |
url |
https://www.frontiersin.org/articles/10.3389/fphar.2021.644886/full |
work_keys_str_mv |
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doaj-5ca83a0869494491b64296bcadf6d8cb2021-04-30T08:21:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-04-011210.3389/fphar.2021.644886644886Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic LocalizationHong-Xia Yang0Hong-Xia Yang1Jia-Huan Sun2Ting-Ting Yao3Yuan Li4Geng-Rui Xu5Chuang Zhang6Xing-Chao Liu7Wei-Wei Zhou8Qiu-Hang Song9Qiu-Hang Song10Qiu-Hang Song11Yue Zhang12Yue Zhang13Yue Zhang14Ai-Ying Li15Ai-Ying Li16Ai-Ying Li17Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Clinical Foundation of Chinese Medicine, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Medical Laboratory Science, College of Integration of Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaHebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaHebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, ChinaHebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaHebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, ChinaHebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, ChinaHebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, ChinaHebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, ChinaMyocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett (G. acuta) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against myocardial damage. However, the effects and mechanisms of BEL on myocardial fibrosis have not been reported. In vivo, BEL dampened isoprenaline (ISO)-induced cardiac structure disturbance and collagen deposition. In vitro, BEL inhibited transforming growth factor (TGF)-β1-induced cardiac fibroblast (CF) proliferation. In vivo and in vitro, BEL decreased the expression of α-smooth muscle actin (α-SMA), collagen Ⅰ and Ⅲ, and inhibited TGF-β1/Smads signaling. Additionally, BEL impeded p38 activation and NR4A1 (an endogenous inhibitor for pro-fibrogenic activities of TGF-β1) phosphorylation and inactivation in vitro. In CFs, inhibition of p38 by SB203580 inhibited the phosphorylation of NR4A1 and did not limit Smad3 phosphorylation, and blocking TGF-β signaling by LY2157299 and SB203580 could decrease the expression of α-SMA, collagen I and III. Overall, both cell and animal studies provide a potential role for BEL against myocardial fibrosis by inhibiting the proliferation and phenotypic transformation of CFs. These inhibitory effects might be related to regulating TGF-β1/Smads pathway and p38 signaling and preventing NR4A1 cytoplasmic localization.https://www.frontiersin.org/articles/10.3389/fphar.2021.644886/fullbellidifolinGentianella acutamyocardial fibrosisTGF-β1/smads pathwayp38orphan nuclear receptor NR4A1 |