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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 reduced inflammation and induced senescence of activated HSCs.(A) Effects of dioscin on the mRNA levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on expression levels of NF-κB, IκBα, COX2, AP-1, HMGB1 and CYP2E1 in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of dioscin on cell senescence in primary HSCs treated with different concentrations of dioscin (24 14h) for SA-β-Gal staining and dual-staining for p16 or p21 (green) and α-SMA (red) assay (original magnification 200×). (D) Effects of dioscin on cell senescence in live tissues from the rats treated with CCl4 and dioscin for SA-β-Gal staining and double immunostaining of p16/α-SMA and p21/α-SMA (original magnification 200×). The cropped gels are used and full-length gels are presented in Supplemental Figure S15 and S16. 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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f6: Dioscin reduced inflammation and induced senescence of activated HSCs.(A) Effects of dioscin on the mRNA levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on expression levels of NF-κB, IκBα, COX2, AP-1, HMGB1 and CYP2E1 in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of dioscin on cell senescence in primary HSCs treated with different concentrations of dioscin (24 14h) for SA-β-Gal staining and dual-staining for p16 or p21 (green) and α-SMA (red) assay (original magnification 200×). (D) Effects of dioscin on cell senescence in live tissues from the rats treated with CCl4 and dioscin for SA-β-Gal staining and double immunostaining of p16/α-SMA and p21/α-SMA (original magnification 200×). The cropped gels are used and full-length gels are presented in Supplemental Figure S15 and S16. 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: The levels HO-1, Nrf2 and SOD2 were significantly decreased in the isolated activated HSCs from CCl4-treated rats, whereas keap1 level was markedly increased (Figure 5E). However, dioscin treatment significantly elevated HO-1, Nrf2 and SOD2 levels and decreased keap1 level. Additionally, the levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in model groups were significantly increased compared with the HSCs isolated from control animals, and these changes were reversed by dioscin (Figure 6A). Dioscin also markedly reduced the levels of NF-κB, COX2, AP-1, HMGB1 and CYP2E1 and increased IκBα level compared with model groups (Figure 6B).


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 reduced inflammation and induced senescence of activated HSCs.(A) Effects of dioscin on the mRNA levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on expression levels of NF-κB, IκBα, COX2, AP-1, HMGB1 and CYP2E1 in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of dioscin on cell senescence in primary HSCs treated with different concentrations of dioscin (24 14h) for SA-β-Gal staining and dual-staining for p16 or p21 (green) and α-SMA (red) assay (original magnification 200×). (D) Effects of dioscin on cell senescence in live tissues from the rats treated with CCl4 and dioscin for SA-β-Gal staining and double immunostaining of p16/α-SMA and p21/α-SMA (original magnification 200×). The cropped gels are used and full-length gels are presented in Supplemental Figure S15 and S16. 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

f6: Dioscin reduced inflammation and induced senescence of activated HSCs.(A) Effects of dioscin on the mRNA levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in vivo HSCs isolated from normal, model and dioscin-treated rats. (B) Effects of dioscin on expression levels of NF-κB, IκBα, COX2, AP-1, HMGB1 and CYP2E1 in vivo HSCs isolated from normal, model and dioscin-treated rats. (C) Effects of dioscin on cell senescence in primary HSCs treated with different concentrations of dioscin (24 14h) for SA-β-Gal staining and dual-staining for p16 or p21 (green) and α-SMA (red) assay (original magnification 200×). (D) Effects of dioscin on cell senescence in live tissues from the rats treated with CCl4 and dioscin for SA-β-Gal staining and double immunostaining of p16/α-SMA and p21/α-SMA (original magnification 200×). The cropped gels are used and full-length gels are presented in Supplemental Figure S15 and S16. 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: The levels HO-1, Nrf2 and SOD2 were significantly decreased in the isolated activated HSCs from CCl4-treated rats, whereas keap1 level was markedly increased (Figure 5E). However, dioscin treatment significantly elevated HO-1, Nrf2 and SOD2 levels and decreased keap1 level. Additionally, the levels of IL-1β, IL-6, TNF-α, ICAM-1, MIP-1α and MIP-2 in model groups were significantly increased compared with the HSCs isolated from control animals, and these changes were reversed by dioscin (Figure 6A). Dioscin also markedly reduced the levels of NF-κB, COX2, AP-1, HMGB1 and CYP2E1 and increased IκBα level compared with model groups (Figure 6B).

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