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Potent effects of dioscin against liver fibrosis.

Zhang X, Han X, Yin L, Xu L, Qi Y, Xu Y, Sun H, Lin Y, Liu K, Peng J - Sci Rep (2015)

Bottom Line: Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes.Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro.Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.

ABSTRACT
We previously reported the promising effects of dioscin against liver injury, but its effect on liver fibrosis remains unknown. The present work investigated the activities of dioscin against liver fibrosis and the underlying molecular mechanisms. Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes. Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro. Notably, dioscin inhibited HSCs activation and induced apoptosis in activated HSCs. In vivo, dioscin significantly improved body weight and hydroxylproline, laminin, α-SMA, TGF-β1, COL1A1 and COL3A1 levels, which were confirmed by histopathological assays. Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs. In conclusion, dioscin exhibited potent effects against liver fibrosis through the modulation of multiple targets and signaling pathways and should be developed as a novel candidate for the treatment of liver fibrosis in the future.

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Dioscin ameliorated liver fibrosis by regulating MMPs/TIMPs, and altering Wnt/β-catenin, TGF-β/Smad and MAPK pathways and oxidative stress.(A) Effects of dioscin on the levels of MMP-1, MMP-2, MMP-9, MMP-13 and TIMP-1 from primay rat HSCs and in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on the levels of p-GSK3β, GSK3β, nuclear and cytosolic β-catenin in primay rat HSCs, and in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of diocsin on expression of TGF-β1 by immunohistochemistry in liver tissue (magnification, 100×), and the levels of p-Smad2/3, Smad2/3 and Smad7 in vivo HSCs isolated from normal, model and dioscin-treated rats. (D) Effects of dioscin on the levels of MAPK phosphorylation in vivo HSCs isolated from normal, model and dioscin-treated rats. (E) Effects of dioscin on the levels of HO-1, Nrf2, keap1 and SOD2 in vivo HSCs isolated from normal, model and dioscin-treated rats. The cropped gels are used and full-length gels are presented in Supplemental Figure S10, S11, S12, S13 and S14. Values are expressed as the means ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.
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f5: Dioscin ameliorated liver fibrosis by regulating MMPs/TIMPs, and altering Wnt/β-catenin, TGF-β/Smad and MAPK pathways and oxidative stress.(A) Effects of dioscin on the levels of MMP-1, MMP-2, MMP-9, MMP-13 and TIMP-1 from primay rat HSCs and in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on the levels of p-GSK3β, GSK3β, nuclear and cytosolic β-catenin in primay rat HSCs, and in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of diocsin on expression of TGF-β1 by immunohistochemistry in liver tissue (magnification, 100×), and the levels of p-Smad2/3, Smad2/3 and Smad7 in vivo HSCs isolated from normal, model and dioscin-treated rats. (D) Effects of dioscin on the levels of MAPK phosphorylation in vivo HSCs isolated from normal, model and dioscin-treated rats. (E) Effects of dioscin on the levels of HO-1, Nrf2, keap1 and SOD2 in vivo HSCs isolated from normal, model and dioscin-treated rats. The cropped gels are used and full-length gels are presented in Supplemental Figure S10, S11, S12, S13 and S14. Values are expressed as the means ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.

Mentions: As shown in Figure 5A, dioscin significantly decreased the levels of MMP-2, MMP-9, TIMP-1, and increased the levels of MMP-1 and MMP-13 in primary rat HSCs and in vivo the isolated HSCs from dioscin-treated rats compared with CCl4-treated animals (the results of statistical analysis are provided in Supplemental Figure 7).


Potent effects of dioscin against liver fibrosis.

Zhang X, Han X, Yin L, Xu L, Qi Y, Xu Y, Sun H, Lin Y, Liu K, Peng J - Sci Rep (2015)

Dioscin ameliorated liver fibrosis by regulating MMPs/TIMPs, and altering Wnt/β-catenin, TGF-β/Smad and MAPK pathways and oxidative stress.(A) Effects of dioscin on the levels of MMP-1, MMP-2, MMP-9, MMP-13 and TIMP-1 from primay rat HSCs and in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on the levels of p-GSK3β, GSK3β, nuclear and cytosolic β-catenin in primay rat HSCs, and in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of diocsin on expression of TGF-β1 by immunohistochemistry in liver tissue (magnification, 100×), and the levels of p-Smad2/3, Smad2/3 and Smad7 in vivo HSCs isolated from normal, model and dioscin-treated rats. (D) Effects of dioscin on the levels of MAPK phosphorylation in vivo HSCs isolated from normal, model and dioscin-treated rats. (E) Effects of dioscin on the levels of HO-1, Nrf2, keap1 and SOD2 in vivo HSCs isolated from normal, model and dioscin-treated rats. The cropped gels are used and full-length gels are presented in Supplemental Figure S10, S11, S12, S13 and S14. Values are expressed as the means ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389718&req=5

f5: Dioscin ameliorated liver fibrosis by regulating MMPs/TIMPs, and altering Wnt/β-catenin, TGF-β/Smad and MAPK pathways and oxidative stress.(A) Effects of dioscin on the levels of MMP-1, MMP-2, MMP-9, MMP-13 and TIMP-1 from primay rat HSCs and in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on the levels of p-GSK3β, GSK3β, nuclear and cytosolic β-catenin in primay rat HSCs, and in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of diocsin on expression of TGF-β1 by immunohistochemistry in liver tissue (magnification, 100×), and the levels of p-Smad2/3, Smad2/3 and Smad7 in vivo HSCs isolated from normal, model and dioscin-treated rats. (D) Effects of dioscin on the levels of MAPK phosphorylation in vivo HSCs isolated from normal, model and dioscin-treated rats. (E) Effects of dioscin on the levels of HO-1, Nrf2, keap1 and SOD2 in vivo HSCs isolated from normal, model and dioscin-treated rats. The cropped gels are used and full-length gels are presented in Supplemental Figure S10, S11, S12, S13 and S14. Values are expressed as the means ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.
Mentions: As shown in Figure 5A, dioscin significantly decreased the levels of MMP-2, MMP-9, TIMP-1, and increased the levels of MMP-1 and MMP-13 in primary rat HSCs and in vivo the isolated HSCs from dioscin-treated rats compared with CCl4-treated animals (the results of statistical analysis are provided in Supplemental Figure 7).

Bottom Line: Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes.Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro.Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.

ABSTRACT
We previously reported the promising effects of dioscin against liver injury, but its effect on liver fibrosis remains unknown. The present work investigated the activities of dioscin against liver fibrosis and the underlying molecular mechanisms. Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes. Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro. Notably, dioscin inhibited HSCs activation and induced apoptosis in activated HSCs. In vivo, dioscin significantly improved body weight and hydroxylproline, laminin, α-SMA, TGF-β1, COL1A1 and COL3A1 levels, which were confirmed by histopathological assays. Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs. In conclusion, dioscin exhibited potent effects against liver fibrosis through the modulation of multiple targets and signaling pathways and should be developed as a novel candidate for the treatment of liver fibrosis in the future.

Show MeSH
Related in: MedlinePlus