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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 reduced spleen weights in mice 8 weeks post infection with Schistosoma japonicum.(A) images of representative spleens in different groups. The bar is 1 cm. (B) Statistical analysis of spleen weights. (C) Spleen weight index (spleen weight/body weight). (* p<0.05, ** p<0.01, *** p<0.001).
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pone-0020247-g002: Anti-fibrosis treatment with prizaquantel reduced spleen weights in mice 8 weeks post infection with Schistosoma japonicum.(A) images of representative spleens in different groups. The bar is 1 cm. (B) Statistical analysis of spleen weights. (C) Spleen weight index (spleen weight/body weight). (* p<0.05, ** p<0.01, *** p<0.001).

Mentions: PZQ was administrated to the mice infected with S. japonicum at week 8 post-infection for either 3 days (anti-parasite group, 250 mg/kg/day) or 30 days (anti-fibrosis group,300 mg/kg/12 hours). Homochronous normal mice (uninfected group) and untreated mice (infected group) were also used in the experiments. The perfusion of hepatic portal system showed that no adult worm was detected in anti-parasite group at the end of the treatment (data not shown), which demonstrated that the administration of PZQ for anti-parasite treatment resulted in parasitologic cure. As shown in figures 1A and 1B, the areas of Sirius Red- stained liver were significantly decreased in anti-fibrosis group in comparison to both infected group and anti-parasite group. The accordant results were observed in measurement of liver hydroxyproline contents (Figure 1C). In addition, the spleen weight and the spleen index (spleen weight/body weight) of the mice were also reduced in anti-fibrosis group in comparison to both infected group and anti-parasite group (Figure 2). Serum ALT which was dramatically increased after the infection was decreased by anti-fibrosis therapy of PZQ (Figure 3).


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 reduced spleen weights in mice 8 weeks post infection with Schistosoma japonicum.(A) images of representative spleens in different groups. The bar is 1 cm. (B) Statistical analysis of spleen weights. (C) Spleen weight index (spleen weight/body weight). (* 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-g002: Anti-fibrosis treatment with prizaquantel reduced spleen weights in mice 8 weeks post infection with Schistosoma japonicum.(A) images of representative spleens in different groups. The bar is 1 cm. (B) Statistical analysis of spleen weights. (C) Spleen weight index (spleen weight/body weight). (* p<0.05, ** p<0.01, *** p<0.001).
Mentions: PZQ was administrated to the mice infected with S. japonicum at week 8 post-infection for either 3 days (anti-parasite group, 250 mg/kg/day) or 30 days (anti-fibrosis group,300 mg/kg/12 hours). Homochronous normal mice (uninfected group) and untreated mice (infected group) were also used in the experiments. The perfusion of hepatic portal system showed that no adult worm was detected in anti-parasite group at the end of the treatment (data not shown), which demonstrated that the administration of PZQ for anti-parasite treatment resulted in parasitologic cure. As shown in figures 1A and 1B, the areas of Sirius Red- stained liver were significantly decreased in anti-fibrosis group in comparison to both infected group and anti-parasite group. The accordant results were observed in measurement of liver hydroxyproline contents (Figure 1C). In addition, the spleen weight and the spleen index (spleen weight/body weight) of the mice were also reduced in anti-fibrosis group in comparison to both infected group and anti-parasite group (Figure 2). Serum ALT which was dramatically increased after the infection was decreased by anti-fibrosis therapy of PZQ (Figure 3).

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