RESUMO
Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient's quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
Assuntos
NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Qualidade de Vida , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/metabolismo , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/metabolismoRESUMO
Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-ß1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.
Assuntos
Extratos Vegetais/farmacologia , Pneumonite por Radiação/patologia , Animais , Biópsia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos da radiação , Camundongos , Pneumonite por Radiação/diagnóstico por imagem , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/genética , Microtomografia por Raio-XRESUMO
The green tea component (-)-epigallocatechin-3-gallate (EGCG) has been shown to sensitize many different types of cancer cells to anticancer drug-induced apoptosis, although it protects against non-cancerous primary cells against toxicity from certain conditions such as exposure to arsenic (As) or ultraviolet irradiation. Here, we found that EGCG promotes As-induced toxicity of primary-cultured bovine aortic endothelial cells (BAEC) at doses in which treatment with each chemical alone had no such effect. Increased cell toxicity was accompanied by an increased condensed chromatin pattern and fragmented nuclei, cleaved poly(ADP-ribose) polymerase (PARP), activity of the pro-apoptotic enzymes caspases 3, 8 and 9, and Bax translocation into mitochondria, suggesting the involvement of an apoptotic signaling pathway. Fluorescence activated cell sorting analysis revealed that compared with EGCG or As alone, combined EGCG and As (EGCG/As) treatment significantly induced production of reactive oxygen species (ROS), which was accompanied by decreased catalase activity and increased lipid peroxidation. Pretreatment with N-acetyl-L-cysteine or catalase reversed EGCG/As-induced caspase activation and EC toxicity. EGCG/As also increased the phosphorylation of c-Jun N-terminal kinase (JNK), which was not reversed by catalase. However, pretreatment with the JNK inhibitor SP600125 reversed all of the observed effects of EGCG/As, suggesting that JNK may be the most upstream protein examined in this study. Finally, we also found that all the observed effects by EGCG/As are true for other types of EC tested. In conclusion, this is firstly to show that EGCG sensitizes non-cancerous EC to As-induced toxicity through ROS-mediated apoptosis, which was attributed at least in part to a JNK-activated decrease in catalase activity.
Assuntos
Aorta/patologia , Arsenitos/farmacologia , Catalase/metabolismo , Catequina/análogos & derivados , Endotélio Vascular/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Chá/química , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/enzimologia , Western Blotting , Catequina/farmacologia , Bovinos , Células Cultivadas , Resistência a Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Humanos , Técnicas Imunoenzimáticas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Oxirredução , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Teratogênicos/farmacologiaRESUMO
Effusanin C, a constituent of Isodon japonicus, has been used in oriental countries as a traditional folk medicine to treat inflammatory diseases, but its mechanism of action remains unknown. Here, we investigate the inhibitory activity of effusanin C in inflammatory monocytes. Effusanin C markedly inhibited the production of inflammatory mediators including nitric oxide, IL-1ß, and TNF-α in macrophages and dendritic cells. Furthermore, molecular studies showed that effusanin C inhibited phosphorylation of p38, JNK, and ERK, degradation of IκBß, and nuclear translocation of NF-κB p50/p65 in these cells. Taken together, these data show that effusanin C inhibits inflammatory responses by blocking NF-κB and MAPK signalings in monocytes.
Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Interleucina-1beta/genética , Isodon , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Componentes Aéreos da Planta , Fator de Necrose Tumoral alfa/genéticaRESUMO
Paecilomyces cicadae Miquel Samson is the anamorph of Cordyceps cicadae Shing and is used in functional foods for the prevention and treatment of various diseases. In the present study, we examined the effects of P. cicadae polysaccharide (PCP) on dendritic cell (DC) maturation. Phenotypic maturation of DCs by PCP was confirmed by the elevated expressions of CD80, CD86, major histocompatibility complex (MHC)-I, and MHC-II molecules and functional maturation by increased expression of interleukin-12, interleukin-1ß, and tumor necrosis factor-α, enhanced allogenic T cell stimulation, and decreased endocytosis. PCP induced the maturation of DCs from C3H/HeN and C57BL/6 mice but not from Toll-like receptor (tlr) 4â»/â» knockout mice and TLR4-mutated C3H/HeJ mice, which suggests that TLR4 is the membrane receptor for PCP. PCP increased the degradation of inhibitor of nuclear factor-κB (NF-κB) α/ß, which enhanced the nuclear translocation of NF-κB p50/p65 and induced the phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases, which are signaling molecules downstream of TLR4. These results indicate that PCP induces DC maturation through TLR4 signaling.
Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Paecilomyces/química , Polissacarídeos/farmacologia , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Polissacarídeos/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologiaRESUMO
Polysaccharide (PLP) isolated from Phellinus linteus inhibits tumor growth and metastasis by enhancing immune functions of macrophages, dendritic cells, NK cells, T cells, and B cells. Here, we report that PLP can inhibit the development of autoimmune diabetes in non-obese diabetic (NOD) mice. Although 80% of the NOD mice had developed diabetes by 24 weeks of age, none of the PLP-treated NOD mice developed diabetes. The mean blood glucose levels were 110mg/dl in PLP-treated mice and 499mg/dl in control NOD mice. Histological examination of the pancreatic islets revealed that most of the islets isolated from PLP-treated mice were less infiltrated with lymphocytes compared with those of control mice. Spleen cells from diabetic NOD mice could adaptively transfer diabetes into NOD/SCID mice, but those from PLP-treated NOD mice showed delayed transfer of diabetes. PLP inhibited the expression of inflammatory cytokines, including IFN-gamma, IL-2, and TNF-alpha by Th1 cells and macrophages, but up-regulated IL-4 expression by Th2 cells in NOD mice. PLP did not prevent streptozotocin-induced diabetic development in ICR mice. Taken together, these results suggest that PLP inhibits the development of autoimmune diabetes by regulating cytokine expression.