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Protective effect of astaxanthin on liver fibrosis through modulation of TGF-β1 expression and autophagy.

Shen M, Chen K, Lu J, Cheng P, Xu L, Dai W, Wang F, He L, Zhang Y, Chengfen W, Li J, Yang J, Zhu R, Zhang H, Zheng Y, Zhou Y, Guo C - Mediators Inflamm. (2014)

Bottom Line: The same results were confirmed in bile duct liagtion, (BDL) model.These results were simultaneously confirmed in vivo and in vitro.In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.

ABSTRACT
Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

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Effects of astaxanthin on expression of TGF-β1, MMP2, TIMP1, and NF-κb. (a) The analysis of western blotting showed that astaxanthin decreased the expression of TGF-β1, TIMP1, and NF-κb and, contrarily, increased the expression of MMP2 compared to CCL4 group. (b) The mRNA level of TGF-β1 was decreased by astaxanthin (40 mg/kg and 80 mg/kg), and the mRNA levels of TIMP1 and NF-κb were decreased with the dose of 80 mg/kg. However, the mRNA levels of MMP2 were increased by astaxanthin (40 mg/kg and 80 mg/kg) compared to CCL4 group. Data are expressed as mean ± SD (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4). (c) The area of positive cells of TGF-β1 was significantly decreased by astaxanthin (40 mg/kg and 80 mg/kg) stained by immunohistochemistry (original magnification: ×200). The expression of NF-κB in nuclei decreased obviously with astaxanthin (40 mg/kg and 80 mg/kg) treatment (original magnification: ×400). (d) The IODs of TGF-β1 and NF-κb were analyzed by Image-pro Plus 6.0. There existed a significant decrease with astaxanthin (40 mg/kg and 80 mg/kg) treatment (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4).
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fig4: Effects of astaxanthin on expression of TGF-β1, MMP2, TIMP1, and NF-κb. (a) The analysis of western blotting showed that astaxanthin decreased the expression of TGF-β1, TIMP1, and NF-κb and, contrarily, increased the expression of MMP2 compared to CCL4 group. (b) The mRNA level of TGF-β1 was decreased by astaxanthin (40 mg/kg and 80 mg/kg), and the mRNA levels of TIMP1 and NF-κb were decreased with the dose of 80 mg/kg. However, the mRNA levels of MMP2 were increased by astaxanthin (40 mg/kg and 80 mg/kg) compared to CCL4 group. Data are expressed as mean ± SD (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4). (c) The area of positive cells of TGF-β1 was significantly decreased by astaxanthin (40 mg/kg and 80 mg/kg) stained by immunohistochemistry (original magnification: ×200). The expression of NF-κB in nuclei decreased obviously with astaxanthin (40 mg/kg and 80 mg/kg) treatment (original magnification: ×400). (d) The IODs of TGF-β1 and NF-κb were analyzed by Image-pro Plus 6.0. There existed a significant decrease with astaxanthin (40 mg/kg and 80 mg/kg) treatment (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4).

Mentions: To explore the potential mechanisms of the protective effect of astaxanthin in liver fibrosis, we firstly determined the expression of TGF-β1 in liver tissue, which is the most important cytokine contributing to the activation of HSCs. Astaxanthin (40 mg/kg and 80 mg/kg) significantly decreased the expression of TGF-β1 at the mRNA and protein levels (Figures 4(a) and 4(b)). In addition, we found smaller areas of TGF-β1 positive cells in the astaxanthin-treated group compared to the CCL4-treated group using immunohistochemical staining (Figure 4(c)), analyzed with Image-Pro Plus 6.0. Secondly, we confirmed that astaxanthin (40 mg/kg and 80 mg/kg) effectively increased the expression of MMP2, which participated in the regression of liver fibrosis through cleavage of the fibrillar ECM. Conversely, TIMP1, the major inhibitor of MMPs, was decreased by astaxanthin (80 mg/kg) (Figures 4(a) and 4(b)). These results showed that astaxanthin ameliorated liver fibrosis through decreased expression of TGF-β1 and a simultaneous stable MMP2/TIMP ratio.


Protective effect of astaxanthin on liver fibrosis through modulation of TGF-β1 expression and autophagy.

Shen M, Chen K, Lu J, Cheng P, Xu L, Dai W, Wang F, He L, Zhang Y, Chengfen W, Li J, Yang J, Zhu R, Zhang H, Zheng Y, Zhou Y, Guo C - Mediators Inflamm. (2014)

Effects of astaxanthin on expression of TGF-β1, MMP2, TIMP1, and NF-κb. (a) The analysis of western blotting showed that astaxanthin decreased the expression of TGF-β1, TIMP1, and NF-κb and, contrarily, increased the expression of MMP2 compared to CCL4 group. (b) The mRNA level of TGF-β1 was decreased by astaxanthin (40 mg/kg and 80 mg/kg), and the mRNA levels of TIMP1 and NF-κb were decreased with the dose of 80 mg/kg. However, the mRNA levels of MMP2 were increased by astaxanthin (40 mg/kg and 80 mg/kg) compared to CCL4 group. Data are expressed as mean ± SD (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4). (c) The area of positive cells of TGF-β1 was significantly decreased by astaxanthin (40 mg/kg and 80 mg/kg) stained by immunohistochemistry (original magnification: ×200). The expression of NF-κB in nuclei decreased obviously with astaxanthin (40 mg/kg and 80 mg/kg) treatment (original magnification: ×400). (d) The IODs of TGF-β1 and NF-κb were analyzed by Image-pro Plus 6.0. There existed a significant decrease with astaxanthin (40 mg/kg and 80 mg/kg) treatment (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4).
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Related In: Results  -  Collection

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fig4: Effects of astaxanthin on expression of TGF-β1, MMP2, TIMP1, and NF-κb. (a) The analysis of western blotting showed that astaxanthin decreased the expression of TGF-β1, TIMP1, and NF-κb and, contrarily, increased the expression of MMP2 compared to CCL4 group. (b) The mRNA level of TGF-β1 was decreased by astaxanthin (40 mg/kg and 80 mg/kg), and the mRNA levels of TIMP1 and NF-κb were decreased with the dose of 80 mg/kg. However, the mRNA levels of MMP2 were increased by astaxanthin (40 mg/kg and 80 mg/kg) compared to CCL4 group. Data are expressed as mean ± SD (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4). (c) The area of positive cells of TGF-β1 was significantly decreased by astaxanthin (40 mg/kg and 80 mg/kg) stained by immunohistochemistry (original magnification: ×200). The expression of NF-κB in nuclei decreased obviously with astaxanthin (40 mg/kg and 80 mg/kg) treatment (original magnification: ×400). (d) The IODs of TGF-β1 and NF-κb were analyzed by Image-pro Plus 6.0. There existed a significant decrease with astaxanthin (40 mg/kg and 80 mg/kg) treatment (n = 7, *P < 0.05 for CCL4 + AST(40) versus CCL4, #P < 0.05 for CCL4 + AST(80) versus CCL4).
Mentions: To explore the potential mechanisms of the protective effect of astaxanthin in liver fibrosis, we firstly determined the expression of TGF-β1 in liver tissue, which is the most important cytokine contributing to the activation of HSCs. Astaxanthin (40 mg/kg and 80 mg/kg) significantly decreased the expression of TGF-β1 at the mRNA and protein levels (Figures 4(a) and 4(b)). In addition, we found smaller areas of TGF-β1 positive cells in the astaxanthin-treated group compared to the CCL4-treated group using immunohistochemical staining (Figure 4(c)), analyzed with Image-Pro Plus 6.0. Secondly, we confirmed that astaxanthin (40 mg/kg and 80 mg/kg) effectively increased the expression of MMP2, which participated in the regression of liver fibrosis through cleavage of the fibrillar ECM. Conversely, TIMP1, the major inhibitor of MMPs, was decreased by astaxanthin (80 mg/kg) (Figures 4(a) and 4(b)). These results showed that astaxanthin ameliorated liver fibrosis through decreased expression of TGF-β1 and a simultaneous stable MMP2/TIMP ratio.

Bottom Line: The same results were confirmed in bile duct liagtion, (BDL) model.These results were simultaneously confirmed in vivo and in vitro.In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.

ABSTRACT
Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

Show MeSH
Related in: MedlinePlus