RESUMEN
Purpose: To investigate whether reduced Sox9 function exerts neuroprotection in light-induced retinal damage in rats and to explore the potential mechanism behind it. Methods: Retinal light damage was used as a model for retinal degeneration. Two weeks before light damage in adult Sprague Dawley (SD) rats, the Sox9-shRNA lentiviral vector was intravitreally injected. On days 3, 7, and 14, retinal function was assessed using electroretinography (ERG), and the thickness of the outer nuclear layer (ONL) was measured in hematoxylin and eosin (HE) stained sections. The protein levels of glial fibrillary acidic protein (GFAP), vimentin, nestin, and chondroitin sulfate proteoglycans (Cspgs), which are related to gliosis and extracellular matrix (ECM) remodeling, were observed using western blot analysis. The expression of GFAP was further evaluated by immunohistochemistry. Results: On days 3, 7, and 14 after light damage, the thickness of the ONL and the amplitudes of the ERG waves were significantly better preserved in the Sox9-shRNA group when compared with the control group. The protein levels of GFAP, vimentin, nestin, and Cspgs were significantly downregulated in the Sox9-shRNA group. Furthermore, the staining intensity and the spatial distribution of GFAP in the retinas were also obviously attenuated at every studied time point. Conclusions: Intravitreal injection of the Sox9-shRNA lentiviral vector preserved rat retinal morphology and function after light damage and downregulated GFAP, vimentin, nestin, and Cspgs, which are related to Müller cell gliosis and ECM remodeling. The results indicate that Sox9 might be a potential therapeutic target for retinal degenerative diseases.
Asunto(s)
Técnicas de Silenciamiento del Gen , Vectores Genéticos/metabolismo , Lentivirus/genética , Luz , Fármacos Neuroprotectores/metabolismo , Retina/patología , Retina/efectos de la radiación , Factor de Transcripción SOX9/metabolismo , Animales , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Electrorretinografía , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Nestina/metabolismo , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Retina/metabolismo , Vimentina/metabolismoRESUMEN
BACKGROUND: Previous studies have investigated the relationship between CYP2C19 polymorphism and clinical prognosis in coronary artery disease patients treated with clopidogrel, but the results were inconsistent. AIMS: To assess the impact of CYP2C19 polymorphism on the risk of adverse clinical events by performing a meta-analysis of relevant studies in the last few years. METHODS: Prospective cohort studies or post-hoc analyses of randomized controlled trials were identified from the databases of PubMed/Medline, EMBASE and the Cochrane Library. Endpoints were fatal or non-fatal myocardial infarction, cardiovascular or all-cause death, definite or probable stent thrombosis, target vessel revascularization, target lesion revascularization, urgent revascularization, ischaemic stroke and bleeding. Pooled effects were measured by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 21 studies involving 23,035 patients were included. Compared with non-carriers of the CYP2C19 variant allele, the carriers were found to have an increased risk of adverse clinical events (OR 1.50, 95% CI 1.21-1.87; P=0.0003), myocardial infarction (OR 1.62, 95% CI 1.35-1.95; P<0.00001), stent thrombosis (OR 2.08, 95% CI 1.67-2.60; P<0.00001), ischaemic stroke (OR 2.14, 95% CI 1.36-3.38; P=0.001) and repeat revascularization (OR 1.35, 95% CI 1.10-1.66; P=0.004), but not of mortality (P=0.500) and bleeding events (P=0.930). CONCLUSION: CYP2C19 polymorphism is significantly associated with risk of adverse clinical events in clopidogrel-treated patients.