RESUMO
Retinopathy of prematurity, a leading cause of visual impairment in low birth-weight infants, remains a crucial therapeutic challenge. Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that promotes rod and cone photoreceptor survival and cone outer segment regeneration in the degenerating retina. Ciliary neurotrophic factor expression is regulated by many factors such as all-trans retinoic acid (ATRA). In this study, we found that ATRA increased CNTF expression in mouse retinal pigment epithelial (RPE) cells in a dose- and time-dependent manner, and PKA signaling pathway is necessary for ATRA-induced CNTF upregulation. Furthermore, we showed that ATRA promoted CNTF expression through CREB binding to its promoter region. In addition, CNTF levels were decreased in serum of retinopathy of prematurity children and in retinal tissue of oxygen-induced retinopathy mice. In mouse RPE cells cultured with high oxygen, CNTF expression and secretion were decreased, but could be recovered after treatment with ATRA. In conclusion, our data suggest that ATRA administration upregulates CNTF expression in RPE cells.
Assuntos
Fator Neurotrófico Ciliar/biossíntese , Células Epiteliais/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Tretinoína/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Epiteliais/patologia , Humanos , Camundongos , Regiões Promotoras Genéticas , Epitélio Pigmentado da Retina/patologia , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologiaRESUMO
Our previous study suggests that heme oxygenase-1 (HO-1) may play an important role in the metastasis of gastric cancer. Zinc protoporphyrin IX (ZnPPIX) is a special HO-1 inhibitor that inhibits the angiogenesis of pancreatic and lung cancer. In this study, we employed ZnPPIX to investigate the role of HO-1 in peritoneal metastasis of gastric cancer (PMGC) and explored the potential mechanism. We established animal model of PMGC by orthotopic implantation into nude mice of human gastric cancer cell line GC9811-P with high peritoneal metastasis potential. The mice were injected intraperitoneally with saline, CTX or ZnPPIX. Tumor microvessel density (MVD) in peritoneal metastatic nodules was determined by immunohistochemistry, and vascular endothelial growth factor (VEGF) level was determined by ELISA. We found that the number, volume, weight of peritoneal metastatic nodules and volume of seroperitoneum in ZnPPIX (4 mg/kg) group decreased remarkably compared with control group. MVD value and VEGF level of peritoneal metastatic tumor in ZnPPIX (4 mg/kg) group also decreased significantly, while the survival rate and survival time of the mice were higher than control group. ZnPPIX dose-dependently suppressed VEGF and GC9811-P induced angiogenesis. Furthermore, ZnPPIX suppressed VEGF induced reactive oxygen species production and ERK phosphorylation in human umbilical vein endothelial cells. In conclusion, our results suggest that HO-1 plays an important role in PMGC and ZnPPIX is an effective antitumor and antiangiogenic agent for PMGC.