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Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation

Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role i...

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Autores principales: Que, Renye, Shen, Yanting, Ren, Jianlin, Tao, Zhihui, Zhu, Xiaoyan, Li, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819932/
https://www.ncbi.nlm.nih.gov/pubmed/29286085
http://dx.doi.org/10.3892/ijmm.2017.3349
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author Que, Renye
Shen, Yanting
Ren, Jianlin
Tao, Zhihui
Zhu, Xiaoyan
Li, Yong
author_facet Que, Renye
Shen, Yanting
Ren, Jianlin
Tao, Zhihui
Zhu, Xiaoyan
Li, Yong
author_sort Que, Renye
collection PubMed
description Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role in excessive extracellular matrix (ECM) deposition during the pathogenesis of hepatic fibrosis. Our recent study indicated that SSd may be considered a novel type of phytoestrogen with estrogen-like actions. Therefore, the present study aimed to investigate the effects of SSd on the proliferation and activation of HSCs, and the underlying mechanisms associated with estrogen receptors. In the present study, a rat HSC line (HSC-T6) was used and cultured with dimethyl sulfoxide, SSd, or estradiol (E(2); positive control), in the presence or absence of three estrogen receptor (ER) antagonists [ICI-182780, methylpiperidinopyrazole (MPP) or (R,R)-tetrahydrochrysene (THC)], for 24 h as pretreatment. Oxidative stress was induced by exposure to hydrogen peroxide for 4 h. Cell proliferation was assessed by MTT growth assay. Malondialdehyde (MDA), CuZn-superoxide dismutase (CuZn-SOD), tissue inhibitor of metalloproteinases-1 (TIMP- 1), matrix metalloproteinase-1 (MMP-1), transforming growth factor-β1 (TGF-β1), hydroxyproline (Hyp) and collagen-1 (COL1) levels in cell culture supernatants were determined by ELISA. Reactive oxygen species (ROS) was detected by flow cytometry. Total and phosphorylated mitogen-activated protein kinases (MAPKs) and α-smooth muscle actin (α-SMA) were examined by western blot analysis. TGF-β1 mRNA expression was determined by RT-quantitative (q)PCR. SSd and E(2) were able to significantly suppress oxidative stress-induced proliferation and activation of HSC-T6 cells. Furthermore, SSd and E(2) were able to reduce ECM deposition, as demonstrated by the decrease in transforming growth factor-β1, hydroxyproline, collagen-1 and tissue inhibitor of metalloproteinases-1, and by the increase in matrix metalloproteinase-1. These results suggested that the possible molecular mechanism could involve downregulation of the reactive oxygen species/mitogen-activated protein kinases signaling pathway. Finally, the effects of SSd and E(2) could be blocked by co-incubation with ICI-182780 or THC, but not MPP, thus indicating that ERβ may be the potential target of SSd in HSC-T6 cells. In conclusion, these findings suggested that SSd may suppress oxidative stress-induced activation of HSCs, which relied on modulation of ERβ.
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spelling pubmed-58199322018-03-02 Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation Que, Renye Shen, Yanting Ren, Jianlin Tao, Zhihui Zhu, Xiaoyan Li, Yong Int J Mol Med Articles Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role in excessive extracellular matrix (ECM) deposition during the pathogenesis of hepatic fibrosis. Our recent study indicated that SSd may be considered a novel type of phytoestrogen with estrogen-like actions. Therefore, the present study aimed to investigate the effects of SSd on the proliferation and activation of HSCs, and the underlying mechanisms associated with estrogen receptors. In the present study, a rat HSC line (HSC-T6) was used and cultured with dimethyl sulfoxide, SSd, or estradiol (E(2); positive control), in the presence or absence of three estrogen receptor (ER) antagonists [ICI-182780, methylpiperidinopyrazole (MPP) or (R,R)-tetrahydrochrysene (THC)], for 24 h as pretreatment. Oxidative stress was induced by exposure to hydrogen peroxide for 4 h. Cell proliferation was assessed by MTT growth assay. Malondialdehyde (MDA), CuZn-superoxide dismutase (CuZn-SOD), tissue inhibitor of metalloproteinases-1 (TIMP- 1), matrix metalloproteinase-1 (MMP-1), transforming growth factor-β1 (TGF-β1), hydroxyproline (Hyp) and collagen-1 (COL1) levels in cell culture supernatants were determined by ELISA. Reactive oxygen species (ROS) was detected by flow cytometry. Total and phosphorylated mitogen-activated protein kinases (MAPKs) and α-smooth muscle actin (α-SMA) were examined by western blot analysis. TGF-β1 mRNA expression was determined by RT-quantitative (q)PCR. SSd and E(2) were able to significantly suppress oxidative stress-induced proliferation and activation of HSC-T6 cells. Furthermore, SSd and E(2) were able to reduce ECM deposition, as demonstrated by the decrease in transforming growth factor-β1, hydroxyproline, collagen-1 and tissue inhibitor of metalloproteinases-1, and by the increase in matrix metalloproteinase-1. These results suggested that the possible molecular mechanism could involve downregulation of the reactive oxygen species/mitogen-activated protein kinases signaling pathway. Finally, the effects of SSd and E(2) could be blocked by co-incubation with ICI-182780 or THC, but not MPP, thus indicating that ERβ may be the potential target of SSd in HSC-T6 cells. In conclusion, these findings suggested that SSd may suppress oxidative stress-induced activation of HSCs, which relied on modulation of ERβ. D.A. Spandidos 2018-03 2017-12-22 /pmc/articles/PMC5819932/ /pubmed/29286085 http://dx.doi.org/10.3892/ijmm.2017.3349 Text en Copyright: © Que et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Que, Renye
Shen, Yanting
Ren, Jianlin
Tao, Zhihui
Zhu, Xiaoyan
Li, Yong
Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title_full Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title_fullStr Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title_full_unstemmed Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title_short Estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
title_sort estrogen receptor-β-dependent effects of saikosaponin-d on the suppression of oxidative stress-induced rat hepatic stellate cell activation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819932/
https://www.ncbi.nlm.nih.gov/pubmed/29286085
http://dx.doi.org/10.3892/ijmm.2017.3349
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