RESUMEN
The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-ß was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-ß compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.
Asunto(s)
Glucósidos/farmacología , Taninos Hidrolizables/farmacología , Subunidad alfa1 del Receptor de Interleucina-13/antagonistas & inhibidores , Cirrosis Hepática Experimental/tratamiento farmacológico , Cirrosis Hepática Experimental/parasitología , Macrófagos/efectos de los fármacos , Schistosoma/patogenicidad , Esquistosomiasis/tratamiento farmacológico , Animales , Antihelmínticos/uso terapéutico , Biomarcadores/análisis , Línea Celular , Glucósidos/uso terapéutico , Taninos Hidrolizables/uso terapéutico , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Factor 4 Similar a Kruppel , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Praziquantel/uso terapéutico , ARN Interferente Pequeño/genéticaRESUMEN
This study tried to find the mechanism of Corilagin interference with interleukin (IL)-13/signal transducer and activator of transcription (STAT) 6 signaling pathways in IL-13-activated liver alternative activation macrophages in schistosomiasis-induced liver fibrosis in Balb/c mice. As a result, IL-13 in serum and the mRNA expression of IL-13 Receptor α1, IL-4 Receptor α and downstream mediators supressor of cytokine signaling (SOCS) 1, Kruppel-like factor (KLF) 4, peroxisome proliferator-activated receptor (PPAR) δ in the liver tissue were significantly inhibited by Corilagin (P<0.05 or 0.01). The protein expression of IL-13 Receptor α1, IL-4 Receptor α, SOCS1, KLF4, PPARγ, PPARδ and Phospho-STAT6 (P-STAT6) in Corilagin group were also markedly suppressed when compared with the model group (P<0.05 or 0.01). Furthermore, the inhibitory effect was enhanced when the concentration of Corilagin increased (P<0.05). By hematoxylin and eosin (HE) staining, when compared with the model group, the Corilagin group showed smaller granulomas (P<0.05 or 0.01). The area of positive cells and integrated optical density (IOD) of CD68, CD206 and KLF4 was significantly decreased by Corilagin stained by IHC (P<0.05 or 0.01). In conclusion, Corilagin had potential to relieve hepatic fibrosis caused by egg granuloma in Schistosoma japonicum infection by decreasing the expression of molecules associated with IL-13/STAT6 signaling pathway in liver alternative activation macrophages.
Asunto(s)
Glucósidos/farmacología , Taninos Hidrolizables/farmacología , Interleucina-13/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Hígado/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Factor de Transcripción STAT6/metabolismo , Esquistosomiasis/complicaciones , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Glucósidos/uso terapéutico , Taninos Hidrolizables/uso terapéutico , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
This study sought to investigate the anti-fibrotic effect of Corilagin via interference with the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model. Mice were infected with Schistosoma japonicum cercaria to establish the mouse model of schistosomiasis-induced hepatic fibrosis. At four weeks after infection, the groups were given different medications. The living conditions were observed. Real-time PCR was employed to detect the mRNA levels of miR-21, smad7 and connective tissue growth factor (CTGF), and western blotting was used to examine the protein levels of smad7, CTGF, smad1, p-smad1, smad2, p-smad2, ERK1/2, p-ERK1/2 and TGF-ß receptor I. Immunohistochemistry was used to examine the expression of CTGF. Compared with the model group, increasing concentrations of Corilagin improved the quality of life, inhibited the mRNA expression of miR-21, promoted smad7 protein expression, and inhibited CTGF protein expression (p<0.05 or 0.01). Moreover, Corilagin significantly reduced the protein levels of p-smad1, p-smad2, p-ERK1/2, and TGF-ß receptor I (p<0.05 or 0.01). CTGF staining in the cytoplasm was markedly decreased by Corilagin (p<0.05 or 0.01). In conclusion, Corilagin inhibited schistosomiasis-induced hepatic fibrosis via the miR21/smad7/ERK pathway in this animal model.
Asunto(s)
Glucósidos/farmacología , Taninos Hidrolizables/farmacología , Cirrosis Hepática/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/genética , Schistosoma japonicum/efectos de los fármacos , Esquistosomiasis Japónica/tratamiento farmacológico , Animales , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Cirrosis Hepática/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Calidad de Vida , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Schistosoma japonicum/genética , Schistosoma japonicum/fisiología , Esquistosomiasis Japónica/parasitología , Proteína smad7/genética , Proteína smad7/metabolismoRESUMEN
OBJECTIVE: To observe the effect of Rougan Huaqian granules combined with human mesenchymal stem cell (hMSC) transplantation on the liver fibrosis in carbon tetrachloride-induced cirrhosis rats. METHODS: Sixty SD rats were randomly divided into five groups. The rats in control group received intraperitoneal injection of saline, while those in model control group, treatment group A, group B and group C received intraperitoneal injection of carbon tetrachloride oily solution to induce liver cirrhosis within 8 weeks. Then, the rats in the model control group, treatment group A, treatment group B, treatment group C received vein tail injection of saline, Rougan Huaqian granules, hMSC suspension and Rougan Huaqian granules combined with hMSC suspension. RESULTS: The treatment groups had significantly different liver function (AST levels), liver fibrosis index (laminin and HA), hepatic sinusoidal wallsα-smooth muscle actin, IV collagen and laminin protein expression and I, III collagen from the model group (P<0.05). The transplanted cells showed human hepatocyte-like cells differentiation trend in the liver. CONCLUSIONS: The Rougan Huaqian granules combined with hMSC transplantation can alleviate liver fibrosis in cirrhosis rats.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Cirrosis Hepática/terapia , Trasplante de Células Madre Mesenquimatosas , Animales , Peso Corporal/efectos de los fármacos , Colágeno/análisis , Colágeno/genética , Colágeno/metabolismo , Femenino , Humanos , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Metaloproteinasa 13 de la Matriz/análisis , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To investigate the impact of bone marrow mesenchymal stem cells on Smad expression of hepatic fibrosis rats. METHODS: A total of 48 adult female SD rats were randomly divided into three groups, normal control group (n=10), observation group (n=19) with liver fibrosis model rats injected with BMSCs cells; model group (n=19), with liver fibrosis model rats injected with physiological saline. Serum index, TGF-ß1 and Smad expression were detected. RESULTS: Type III procollagen, IV collagen, hyaluronic acid, laminin levels of observation group were significantly lower than those of model group (P<0.05). The content and expression of TGF-ß1 in serum and liver tissue of observation group were significantly lower than those of model group(P<0.05). Compared with normal control group, the Smad3, Smad4 mRNA and protein expression of model group were significantly increased, the Smad7 mRNA and protein expression were significantly reduced (P<0.05). Compared with model group, Smad3, Smad4 mRNA and protein expression of observation group were significantly reduced, and Smad7 mRNA expression were significantly increased (P<0.05). CONCLUSIONS: BMSCs can regulate Smad expression to some extent, and reduce the degree of liver fibrosis.