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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 induced apoptosis of activated HSCs in vivo.(A) Effects of dioscin on liver tissues from the rats treated with CCl4 and dioscin dual-stained for TUNEL (green) and α-SMA (red) assay (original magnification 200×). (B) Numbers of α-SMA and TUNEL dual-positive cells was counted in five random fields, and the average numbers of dual-positive cells were plotted. (C) Effects of dioscin on cytochrome c release, and the levels of Bcl-2, Bcl-xl, BAX, BAK, caspase 3 and caspase 9 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 S17. Values are expressed as the mean ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.
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f7: Dioscin induced apoptosis of activated HSCs in vivo.(A) Effects of dioscin on liver tissues from the rats treated with CCl4 and dioscin dual-stained for TUNEL (green) and α-SMA (red) assay (original magnification 200×). (B) Numbers of α-SMA and TUNEL dual-positive cells was counted in five random fields, and the average numbers of dual-positive cells were plotted. (C) Effects of dioscin on cytochrome c release, and the levels of Bcl-2, Bcl-xl, BAX, BAK, caspase 3 and caspase 9 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 S17. Values are expressed as the mean ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.

Mentions: Figure 7A demonstrates that the numbers of TUNEL-positive cells were significantly elevated and the α-SMA-positive cells were obviously decreased in the livers of dioscin-treated rats. In fact, the number of dual-positive cells per field in dioscin-treated rats was nearly 2-fold higher than that of in CCl4-treated rats (Figure 7B), which clearly indicated that dioscin induced apoptotic cell death in activated HSCs in vivo. Furthermore, the release of cytochrome c from mitochondria to the cytoplasm was obvious in dioscin- treated groups. In addition, freshly isolated activated HSCs from CCl4-treated rats exhibited an up-regulation of Bcl-2 and Bcl-xl and a down-regulation of BAX, BAK, caspase-3 and caspase-9 relative to cells isolated from control animals, which were significantly restored by dioscin (Figure 7C).


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 induced apoptosis of activated HSCs in vivo.(A) Effects of dioscin on liver tissues from the rats treated with CCl4 and dioscin dual-stained for TUNEL (green) and α-SMA (red) assay (original magnification 200×). (B) Numbers of α-SMA and TUNEL dual-positive cells was counted in five random fields, and the average numbers of dual-positive cells were plotted. (C) Effects of dioscin on cytochrome c release, and the levels of Bcl-2, Bcl-xl, BAX, BAK, caspase 3 and caspase 9 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 S17. Values are expressed as the mean ± 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

f7: Dioscin induced apoptosis of activated HSCs in vivo.(A) Effects of dioscin on liver tissues from the rats treated with CCl4 and dioscin dual-stained for TUNEL (green) and α-SMA (red) assay (original magnification 200×). (B) Numbers of α-SMA and TUNEL dual-positive cells was counted in five random fields, and the average numbers of dual-positive cells were plotted. (C) Effects of dioscin on cytochrome c release, and the levels of Bcl-2, Bcl-xl, BAX, BAK, caspase 3 and caspase 9 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 S17. Values are expressed as the mean ± SD (n = 3). *p < 0.05, **p < 0.01 vs. model group; ##p < 0.01 vs. normal control group.
Mentions: Figure 7A demonstrates that the numbers of TUNEL-positive cells were significantly elevated and the α-SMA-positive cells were obviously decreased in the livers of dioscin-treated rats. In fact, the number of dual-positive cells per field in dioscin-treated rats was nearly 2-fold higher than that of in CCl4-treated rats (Figure 7B), which clearly indicated that dioscin induced apoptotic cell death in activated HSCs in vivo. Furthermore, the release of cytochrome c from mitochondria to the cytoplasm was obvious in dioscin- treated groups. In addition, freshly isolated activated HSCs from CCl4-treated rats exhibited an up-regulation of Bcl-2 and Bcl-xl and a down-regulation of BAX, BAK, caspase-3 and caspase-9 relative to cells isolated from control animals, which were significantly restored by dioscin (Figure 7C).

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