RESUMO
Liver fibrosis is an important process that occurs in most types of chronic liver diseases and often results in the end stage of liver diseases, such as cirrhosis, portal hypertension, and hepatocellular carcinoma. Sorafenib, a multiple tyrosine kinase inhibitor, has been shown to inhibit liver fibrosis in multiple experimental fibrosis mouse and rat models. The aim of this study was to test the therapeutic effect of sorafenib on liver fibrosis induced by infection with a parasite, Schistosoma japonicum, in mice. Mice were percutaneously infected through the abdomen with Schistosoma cercariae to develop a schistosomula liver fibrosis model. Eight weeks after infection, infected mice were treated with the anti-parasitic agent praziquantel for 2 days and sorafenib for 2 weeks. Hepatic histopathological changes were assessed using hematoxylin and eosin (HE) and Masson's trichome staining. The hepatic expression levels of collagen I, collagen III, alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and PDGF receptor-beta (PDGFR-ß) were analyzed by immunohistochemistry and western blot. Praziquantel administration alone but not sorafenib reduced liver fibrosis, and the combination of praziquantel and sorafenib significantly attenuated liver fibrosis in S. japonicum-infected mice. Moreover, sorafenib plus praziquantel markedly decreased the hepatic deposition of collagen and expression of fibrogenic genes in these mice. In conclusion, the use of sorafenib following praziquantel treatment may represent a potential therapeutic strategy for liver fibrosis induced by S. japonicum in patients.
Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Praziquantel/uso terapêutico , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/tratamento farmacológico , Actinas/análise , Actinas/metabolismo , Animais , Colágeno Tipo I/análise , Colágeno Tipo I/metabolismo , Colágeno Tipo III/análise , Colágeno Tipo III/metabolismo , Feminino , Fígado/parasitologia , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos BALB C , Niacinamida/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/análise , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/análise , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Schistosoma japonicum/metabolismo , Esquistossomose Japônica/parasitologia , SorafenibeRESUMO
In recent years, along with rapid development of targeted therapy in non-small cell lung cancer, traditional chemotherapy get less and less attention. Yet it still can not be ignored in the current that how to locate and use traditional chemotherapy so patients could derive maximum benefit. For this purpose, through the literature review and analysis, we point out there are still many traditional chemotherapy irreplaceable places whatever patients' driver gene status. And there are some new treatment modalities of traditional chemotherapy which have been developed to further improve patients' survival. At the same time, through exposition of predictive bio-markers development in chemotherapy, we pointed out that the future of traditional chemotherapy must be part of "targeted therapy".
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismoRESUMO
BACKGROUND: Japanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk' regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model. METHODS: JEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated. FINDINGS: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 µg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 µg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV. CONCLUSIONS: Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Encefalite Japonesa/tratamento farmacológico , Encefalite Japonesa/virologia , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Animais , Linhagem Celular , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrocompostos , Análise de Sobrevida , Resultado do Tratamento , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
Glycyrrhetinic acid (GA) is an active component of licorice root that has long been used as a herbal medicine for the treatment of peptic ulcer, hepatitis, and pulmonary and skin diseases in Asia and Europe. In this study, we analyzed the effect of GA extracted from Glycyrrhiza uralensis Fisch. on the expression of Toll-like receptors (TLRs) that play key roles in regulating the innate immune response against invading pathogens. Stimulation of Ana-1 murine macrophages with GA induced a significant dose-dependent expression of TLR-4, and its mRNA expression that increased from 3-h post-treatment was approximately fivefold over the level in the mock-treated cells. No endotoxin contamination contributed to the GA-induced TLR-4 expression, because polymyxin B treatment did not alter the upregulated expression of TLR-4 in GA-treated cells. Several molecules, such as myeloid differentiation factor 88, interferon-ß, and interleukin-6, which are involved in the TLR-4 downstream signaling pathway, were upregulated significantly in response to GA stimulation. Our findings demonstrate that GA is able to induce the expression of TLR-4 and activate its downstream signaling pathway.
Assuntos
Ácido Glicirretínico/isolamento & purificação , Glycyrrhiza uralensis/química , Macrófagos/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Ácido Glicirretínico/química , Ácido Glicirretínico/imunologia , Humanos , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genéticaRESUMO
Icariin is the major pharmacologically active compound of Herba epimedii which has been used as a tonic, aphrodisiac and an antirheumatic in traditional Chinese medicine. This study analysed the effect of icariin on the expression of Toll-like receptor 9 (TLR9) which plays an important role in regulation of the innate immune response. Stimulation of Ana-1 murine macrophages with icariin induced a significant dose-dependent expression of TLR9, and its mRNA expression which increased from 3 h post-treatment was approximately five-fold that of DMSO-treated cells. Several molecules, such as myeloid differentiation factor 88, tumor necrosis factor-α and interleukin 6, which are involved in the TLR9 downstream signaling pathway, were also significantly up-regulated in response to icariin stimulation. Our findings demonstrated that icariin is able to induce the expression of TLR9.