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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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Effect of astaxanthin on the activation of HSCs. (a) The analysis of western blotting showed that astaxanthin obviously decreased the expression of α-SMA, β-pdfgr, and collagen I with the doses of 40 mg/kg and 80 mg/kg. (b) The mRNA levels of collagen I  α1, collagen I  α2, α-SMA, and β-pdgfr were significantly downregulated by astaxanthin (40 mg/kg and 80 mg/kg). 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 areas of positive cells of α-SMA, β-pdfgr, and collagen I were diminished by astaxanthin (40 mg/kg and 80 mg/kg), showed by immunohistochemistry staining (original magnification: ×200). (d) The IODs of α-SMA, β-pdfgr, and collagen I 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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fig3: Effect of astaxanthin on the activation of HSCs. (a) The analysis of western blotting showed that astaxanthin obviously decreased the expression of α-SMA, β-pdfgr, and collagen I with the doses of 40 mg/kg and 80 mg/kg. (b) The mRNA levels of collagen I  α1, collagen I  α2, α-SMA, and β-pdgfr were significantly downregulated by astaxanthin (40 mg/kg and 80 mg/kg). 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 areas of positive cells of α-SMA, β-pdfgr, and collagen I were diminished by astaxanthin (40 mg/kg and 80 mg/kg), showed by immunohistochemistry staining (original magnification: ×200). (d) The IODs of α-SMA, β-pdfgr, and collagen I 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: Evidence indicates that HSCs play a pivotal role in liver fibrosis, because they are the main matrix-producing cells. Hence, quantitative analysis of HSC activation could predict the progression of liver fibrosis. Following transdifferentiation from quiescent cells to myofibroblast-like cells, α-SMA is selectively expressed in HSCs and is the most frequently used marker to indicate HSCs activation. In addition, platelet-derived growth factor (PDGF) is one of the most important cytokines in HSCs activation. Accordingly, β-PDFGR would be expressed in HSCs when transformed and may be a marker of HSCs activation. In the present study, we determined the expression of α-SMA, β-PDFGR, and collagen I to assess the activation status of HSCs in the liver. The results showed that astaxanthin (40 mg/kg and 80 mg/kg) significantly reduced the expression of mRNA encoding collagen I α1, collagen I α2, α-SMA, and β-PDGFR and their corresponding proteins (Figures 3(a) and 3(b)). Furthermore, we observed the expression of α-SMA, collagen I, and β-PDGFR by immunohistochemical staining. Similar to MT and SR staining, the α-SMA, collagen I, and β-PDGFR positive areas were visibly reduced after astaxanthin administration (40 mg/kg and 80 mg/kg) (Figure 3(c)), analyzed with Image-Pro Plus 6.0. In addition, results showed that astaxanthin (80 mg/kg) could also inhibit the activation of HSCs in BDL model (Figure 2). These results showed that astaxanthin inhibited the activation of HSCs through unknown mechanisms.


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)

Effect of astaxanthin on the activation of HSCs. (a) The analysis of western blotting showed that astaxanthin obviously decreased the expression of α-SMA, β-pdfgr, and collagen I with the doses of 40 mg/kg and 80 mg/kg. (b) The mRNA levels of collagen I  α1, collagen I  α2, α-SMA, and β-pdgfr were significantly downregulated by astaxanthin (40 mg/kg and 80 mg/kg). 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 areas of positive cells of α-SMA, β-pdfgr, and collagen I were diminished by astaxanthin (40 mg/kg and 80 mg/kg), showed by immunohistochemistry staining (original magnification: ×200). (d) The IODs of α-SMA, β-pdfgr, and collagen I 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).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: Effect of astaxanthin on the activation of HSCs. (a) The analysis of western blotting showed that astaxanthin obviously decreased the expression of α-SMA, β-pdfgr, and collagen I with the doses of 40 mg/kg and 80 mg/kg. (b) The mRNA levels of collagen I  α1, collagen I  α2, α-SMA, and β-pdgfr were significantly downregulated by astaxanthin (40 mg/kg and 80 mg/kg). 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 areas of positive cells of α-SMA, β-pdfgr, and collagen I were diminished by astaxanthin (40 mg/kg and 80 mg/kg), showed by immunohistochemistry staining (original magnification: ×200). (d) The IODs of α-SMA, β-pdfgr, and collagen I 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: Evidence indicates that HSCs play a pivotal role in liver fibrosis, because they are the main matrix-producing cells. Hence, quantitative analysis of HSC activation could predict the progression of liver fibrosis. Following transdifferentiation from quiescent cells to myofibroblast-like cells, α-SMA is selectively expressed in HSCs and is the most frequently used marker to indicate HSCs activation. In addition, platelet-derived growth factor (PDGF) is one of the most important cytokines in HSCs activation. Accordingly, β-PDFGR would be expressed in HSCs when transformed and may be a marker of HSCs activation. In the present study, we determined the expression of α-SMA, β-PDFGR, and collagen I to assess the activation status of HSCs in the liver. The results showed that astaxanthin (40 mg/kg and 80 mg/kg) significantly reduced the expression of mRNA encoding collagen I α1, collagen I α2, α-SMA, and β-PDGFR and their corresponding proteins (Figures 3(a) and 3(b)). Furthermore, we observed the expression of α-SMA, collagen I, and β-PDGFR by immunohistochemical staining. Similar to MT and SR staining, the α-SMA, collagen I, and β-PDGFR positive areas were visibly reduced after astaxanthin administration (40 mg/kg and 80 mg/kg) (Figure 3(c)), analyzed with Image-Pro Plus 6.0. In addition, results showed that astaxanthin (80 mg/kg) could also inhibit the activation of HSCs in BDL model (Figure 2). These results showed that astaxanthin inhibited the activation of HSCs through unknown mechanisms.

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