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New insight into the antifibrotic effects of praziquantel on mice in infection with Schistosoma japonicum.

Liang YJ, Luo J, Yuan Q, Zheng D, Liu YP, Shi L, Zhou Y, Chen AL, Ren YY, Sun KY, Sun Y, Wang Y, Zhang ZS - PLoS ONE (2011)

Bottom Line: The antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica.The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension.Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT

Background: Schistosomiasis is a parasitic disease infecting more than 200 million people in the world. Although chemotherapy targeting on killing schistosomes is one of the main strategies in the disease control, there are few effective ways of dealing with liver fibrosis caused by the parasite infection in the chronic and advanced stages of schistosomiasis. For this reason, new strategies and prospective drugs, which exert antifibrotic effects, are urgently required.

Methods and findings: The antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica. Murine fibrosis models were established by cutaneous infection with 14 ± 2 Schistosoma japonicum cercariae. Then, the mice of both chronic (8 weeks post-infection) and advanced (15 weeks post-infection) schistosomiasis were treated by gavage of praziquantel (250 mg/kg, once daily for 3 days) to eliminate worms, and followed by praziquantel anti-fibrosis treatment (300 mg/kg, twice daily for 30 days). The fibrosis-related parameters assessed were areas of collagen deposition, content of hydroxyproline and mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9, TIMP1, IL-4, IL-10, IL-13 and IFN-γ of liver. Spleen weight index, alanine aminotransferase activity and liver portal venous pressure were also measured. The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension. In order to confirm the anti-fibrotic properties of praziquantel, we established a CCL(4)-induced model and revealed that CCL(4)-induced liver fibrosis was inhibited by PZQ treatment for 30 days. Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs). It is indicated that mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9 and TIMP1 of HSCs were all inhibited after praziquantel anti-parasite treatments.

Conclusions: The significant amelioration of hepatic fibrosis by praziquantel treatment validates it as a promising drug of anti-fibrosis and offers potential of a new chemotherapy for hepatic fibrosis resulting from schistosomiasis.

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Related in: MedlinePlus

Anti-fibrosis treatment with prizaquantel inhibited expressions of profibrotic genes and α-SMA protein expression in liver, but increased MMP9 mRNA expressions of mice 15 weeks post infection with Schistosoma japonicum.(A)α-SMA; (B)Col1α1; (C)Col3α1; (D)TGF-β were reduced by anti-fibrosis treatment with high dose prizaquantel. (E)MMP9 levels in high dose group were increased about 10 fold compared with uninfected group, whereas (F) TIMP1 levels were decreased nearly to uninfected level. α-SMA protein expressions was assessed by immunohistochemistry. (G) Representative images of immunohistochemistry by light microscope (×100). Gi, uninfected; Gii, infected; Giii, anti-parasite; Giv, low dose; Gv, high dose. Arrows showed the positive staining. (H) α-SMA positive areas were measured by software IPP6.0. Expression of IL-4 (I), IL-10 (J), IL-13(K) and IFN-γ (L) were significantly reduced in high dose group compared respectively with infected, anti-parasite or low dose group. (* p<0.05, ** p<0.01, *** p<0.001).
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pone-0020247-g009: Anti-fibrosis treatment with prizaquantel inhibited expressions of profibrotic genes and α-SMA protein expression in liver, but increased MMP9 mRNA expressions of mice 15 weeks post infection with Schistosoma japonicum.(A)α-SMA; (B)Col1α1; (C)Col3α1; (D)TGF-β were reduced by anti-fibrosis treatment with high dose prizaquantel. (E)MMP9 levels in high dose group were increased about 10 fold compared with uninfected group, whereas (F) TIMP1 levels were decreased nearly to uninfected level. α-SMA protein expressions was assessed by immunohistochemistry. (G) Representative images of immunohistochemistry by light microscope (×100). Gi, uninfected; Gii, infected; Giii, anti-parasite; Giv, low dose; Gv, high dose. Arrows showed the positive staining. (H) α-SMA positive areas were measured by software IPP6.0. Expression of IL-4 (I), IL-10 (J), IL-13(K) and IFN-γ (L) were significantly reduced in high dose group compared respectively with infected, anti-parasite or low dose group. (* p<0.05, ** p<0.01, *** p<0.001).

Mentions: We also detected the expressions of fibrosis-related genes. Col1α1, Col3α1, α-SMA and TGF-β mRNAs of liver were all markedly decreased in high dose group in comparison to both infected group and anti-parasite group (Figure 9A–D), which were similar to those changes in the mice with chronic schistosomiasis. Liver TIMP1 mRNA was reduced in low dose group, but more significantly decreased in high dose group in comparison to anti-parasite group. However, the expression of liver MMP9 mRNA was increased nearly five-fold in high dose group in comparison to both anti-parasite group and low dose group (Figure 10E–F). Hence, PZQ did not inhibit all kinds of fibrosis-related genes in liver. The immunohistochemistry change of liver α-SMA in each group was accordant with its α-SMA mRNA expression (Figure 9G–H). Gene Expressions of Th1/Th2 cytokines of IL4, IL10, IL13 and IFN-γ were all reduced in high dose group in comparison to infected, anti-parasite and low dose group, respectively (Figure 9I–L). Normal mice treated with high dose PZQ for 30 days (Text S2) showed reduced mRNA expression of Col1α1, TGF-β and TIMP1 in liver in comparison to untreated control mice (Figure S2A, D and F). Col3α1 and α-SMA (Figure S2B and C) showed a tendency to decrease, while MMP9 (Figure S2E) showed a tendency to increase, but the changes were not significant statistically. We also demonstrated that PZQ did not inhibit the proliferation of splenic mononuclear cells stimulated by schistosomal egg antigens detected by incorporation of 3H-thymidine (TDR) (Text S3 and Figure S3).


New insight into the antifibrotic effects of praziquantel on mice in infection with Schistosoma japonicum.

Liang YJ, Luo J, Yuan Q, Zheng D, Liu YP, Shi L, Zhou Y, Chen AL, Ren YY, Sun KY, Sun Y, Wang Y, Zhang ZS - PLoS ONE (2011)

Anti-fibrosis treatment with prizaquantel inhibited expressions of profibrotic genes and α-SMA protein expression in liver, but increased MMP9 mRNA expressions of mice 15 weeks post infection with Schistosoma japonicum.(A)α-SMA; (B)Col1α1; (C)Col3α1; (D)TGF-β were reduced by anti-fibrosis treatment with high dose prizaquantel. (E)MMP9 levels in high dose group were increased about 10 fold compared with uninfected group, whereas (F) TIMP1 levels were decreased nearly to uninfected level. α-SMA protein expressions was assessed by immunohistochemistry. (G) Representative images of immunohistochemistry by light microscope (×100). Gi, uninfected; Gii, infected; Giii, anti-parasite; Giv, low dose; Gv, high dose. Arrows showed the positive staining. (H) α-SMA positive areas were measured by software IPP6.0. Expression of IL-4 (I), IL-10 (J), IL-13(K) and IFN-γ (L) were significantly reduced in high dose group compared respectively with infected, anti-parasite or low dose group. (* p<0.05, ** p<0.01, *** p<0.001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101229&req=5

pone-0020247-g009: Anti-fibrosis treatment with prizaquantel inhibited expressions of profibrotic genes and α-SMA protein expression in liver, but increased MMP9 mRNA expressions of mice 15 weeks post infection with Schistosoma japonicum.(A)α-SMA; (B)Col1α1; (C)Col3α1; (D)TGF-β were reduced by anti-fibrosis treatment with high dose prizaquantel. (E)MMP9 levels in high dose group were increased about 10 fold compared with uninfected group, whereas (F) TIMP1 levels were decreased nearly to uninfected level. α-SMA protein expressions was assessed by immunohistochemistry. (G) Representative images of immunohistochemistry by light microscope (×100). Gi, uninfected; Gii, infected; Giii, anti-parasite; Giv, low dose; Gv, high dose. Arrows showed the positive staining. (H) α-SMA positive areas were measured by software IPP6.0. Expression of IL-4 (I), IL-10 (J), IL-13(K) and IFN-γ (L) were significantly reduced in high dose group compared respectively with infected, anti-parasite or low dose group. (* p<0.05, ** p<0.01, *** p<0.001).
Mentions: We also detected the expressions of fibrosis-related genes. Col1α1, Col3α1, α-SMA and TGF-β mRNAs of liver were all markedly decreased in high dose group in comparison to both infected group and anti-parasite group (Figure 9A–D), which were similar to those changes in the mice with chronic schistosomiasis. Liver TIMP1 mRNA was reduced in low dose group, but more significantly decreased in high dose group in comparison to anti-parasite group. However, the expression of liver MMP9 mRNA was increased nearly five-fold in high dose group in comparison to both anti-parasite group and low dose group (Figure 10E–F). Hence, PZQ did not inhibit all kinds of fibrosis-related genes in liver. The immunohistochemistry change of liver α-SMA in each group was accordant with its α-SMA mRNA expression (Figure 9G–H). Gene Expressions of Th1/Th2 cytokines of IL4, IL10, IL13 and IFN-γ were all reduced in high dose group in comparison to infected, anti-parasite and low dose group, respectively (Figure 9I–L). Normal mice treated with high dose PZQ for 30 days (Text S2) showed reduced mRNA expression of Col1α1, TGF-β and TIMP1 in liver in comparison to untreated control mice (Figure S2A, D and F). Col3α1 and α-SMA (Figure S2B and C) showed a tendency to decrease, while MMP9 (Figure S2E) showed a tendency to increase, but the changes were not significant statistically. We also demonstrated that PZQ did not inhibit the proliferation of splenic mononuclear cells stimulated by schistosomal egg antigens detected by incorporation of 3H-thymidine (TDR) (Text S3 and Figure S3).

Bottom Line: The antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica.The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension.Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT

Background: Schistosomiasis is a parasitic disease infecting more than 200 million people in the world. Although chemotherapy targeting on killing schistosomes is one of the main strategies in the disease control, there are few effective ways of dealing with liver fibrosis caused by the parasite infection in the chronic and advanced stages of schistosomiasis. For this reason, new strategies and prospective drugs, which exert antifibrotic effects, are urgently required.

Methods and findings: The antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica. Murine fibrosis models were established by cutaneous infection with 14 ± 2 Schistosoma japonicum cercariae. Then, the mice of both chronic (8 weeks post-infection) and advanced (15 weeks post-infection) schistosomiasis were treated by gavage of praziquantel (250 mg/kg, once daily for 3 days) to eliminate worms, and followed by praziquantel anti-fibrosis treatment (300 mg/kg, twice daily for 30 days). The fibrosis-related parameters assessed were areas of collagen deposition, content of hydroxyproline and mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9, TIMP1, IL-4, IL-10, IL-13 and IFN-γ of liver. Spleen weight index, alanine aminotransferase activity and liver portal venous pressure were also measured. The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension. In order to confirm the anti-fibrotic properties of praziquantel, we established a CCL(4)-induced model and revealed that CCL(4)-induced liver fibrosis was inhibited by PZQ treatment for 30 days. Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs). It is indicated that mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9 and TIMP1 of HSCs were all inhibited after praziquantel anti-parasite treatments.

Conclusions: The significant amelioration of hepatic fibrosis by praziquantel treatment validates it as a promising drug of anti-fibrosis and offers potential of a new chemotherapy for hepatic fibrosis resulting from schistosomiasis.

Show MeSH
Related in: MedlinePlus