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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

Spleen weights were not changed after Anti-fibrosis treatment with low dose or high dose prizaquantel compared with anti-parasite treatment in mice 15 weeks post infection with Schistosoma japonicum.Spleen weights were reduced in anti-parasite, anti-fibrosis low dose and high dose groups compared with infected group, but no significant changes were found between treated groups. (** p<0.01).
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pone-0020247-g006: Spleen weights were not changed after Anti-fibrosis treatment with low dose or high dose prizaquantel compared with anti-parasite treatment in mice 15 weeks post infection with Schistosoma japonicum.Spleen weights were reduced in anti-parasite, anti-fibrosis low dose and high dose groups compared with infected group, but no significant changes were found between treated groups. (** p<0.01).

Mentions: In this study, PZQ was administrated to the mice infected with S.japonicum at week 15 post-infection for either 3 days (anti-parasite group, 250 mg/kg/day) or 30 days (anti-fibrosis low dose group, 75 mg/kg/12 hours; anti-fibrosis high dose group, 300 mg/kg/12 hours). Homochronous normal mice (uninfected group) and untreated infected mice (infected group) were also used in the experiments. As expected, the areas of Sirius Red staining on the liver sections were significantly decreased in high dose group in comparison to both infected group and anti-parasite group. In low dose group, the Sirius Red stained-areas decreased without statistical significance in comparison to anti-parasite group. Also, the change profiles of the liver hydroxyproline contents were in accordance with those of Sirius Red staining (Figure 5). The spleen weights of mice in anti-parasite group and anti-fibrosis groups (both low dose and high dose) were decreased in comparison to infected group, but no significant differences between them (Figure 6). Portal hypertension is a characteristic manifestation of advanced schistosomiasis japonica and resulted mainly from severe hepatic fibrosis. To evaluate the anti-fibrosis effects of PZQ on the mice with advanced schistosomiasis, we measured liver portal venous pressure. The results showed that the pressure of the mice were significantly decreased after anti-parasite treatment and further decreased to nearly normal levels after both low dose and high dose treatment of PZQ (Figure 7). Serum ALT levels were significantly decreased only in high dose group, which were nearly back to normal baselines (Figure 8).


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)

Spleen weights were not changed after Anti-fibrosis treatment with low dose or high dose prizaquantel compared with anti-parasite treatment in mice 15 weeks post infection with Schistosoma japonicum.Spleen weights were reduced in anti-parasite, anti-fibrosis low dose and high dose groups compared with infected group, but no significant changes were found between treated groups. (** p<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020247-g006: Spleen weights were not changed after Anti-fibrosis treatment with low dose or high dose prizaquantel compared with anti-parasite treatment in mice 15 weeks post infection with Schistosoma japonicum.Spleen weights were reduced in anti-parasite, anti-fibrosis low dose and high dose groups compared with infected group, but no significant changes were found between treated groups. (** p<0.01).
Mentions: In this study, PZQ was administrated to the mice infected with S.japonicum at week 15 post-infection for either 3 days (anti-parasite group, 250 mg/kg/day) or 30 days (anti-fibrosis low dose group, 75 mg/kg/12 hours; anti-fibrosis high dose group, 300 mg/kg/12 hours). Homochronous normal mice (uninfected group) and untreated infected mice (infected group) were also used in the experiments. As expected, the areas of Sirius Red staining on the liver sections were significantly decreased in high dose group in comparison to both infected group and anti-parasite group. In low dose group, the Sirius Red stained-areas decreased without statistical significance in comparison to anti-parasite group. Also, the change profiles of the liver hydroxyproline contents were in accordance with those of Sirius Red staining (Figure 5). The spleen weights of mice in anti-parasite group and anti-fibrosis groups (both low dose and high dose) were decreased in comparison to infected group, but no significant differences between them (Figure 6). Portal hypertension is a characteristic manifestation of advanced schistosomiasis japonica and resulted mainly from severe hepatic fibrosis. To evaluate the anti-fibrosis effects of PZQ on the mice with advanced schistosomiasis, we measured liver portal venous pressure. The results showed that the pressure of the mice were significantly decreased after anti-parasite treatment and further decreased to nearly normal levels after both low dose and high dose treatment of PZQ (Figure 7). Serum ALT levels were significantly decreased only in high dose group, which were nearly back to normal baselines (Figure 8).

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