Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator–activated receptor α (PPARα) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and determined if the effect is PPARα dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPARα agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-κB in the retinas of OIR and diabetic models. Fenofibrate’s beneficial effects were blocked by a specific PPARα antagonist. Furthermore, Pparα knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPARα-dependent mechanism.

IntroductionCOPD is rapidly becoming one of the most challenging health problems worldwide, which is characterized by not fully reversible airflow limitation. Although a lot of treatment medications have been delivered, the treatment goals of COPD are often not achieved. Furthermore, few well-designed randomized controlled trials in the People’s Republic of China have been reported to evaluate the impact of pharmacist-managed clinic (PMC) on medication adherence and health-related quality of life in patients with COPD.MethodsA prospective randomized controlled study (on a PMC group and a control group) was conducted between January 2015 and December 2015. A structured education about COPD was provided by a clinical pharmacist to the PMC group. Primary outcomes were medication adherence (assessed by medication refill adherence scores) and health-related quality of life (assessed by St George’s Respiratory Questionnaire). Secondary outcomes were exacerbation rate, hospitalization rate, and smoking behavior.ResultsA total of 244 patients were enrolled for our study. The PMC group showed a significantly greater improvement in medication adherence compared with the baseline (93.1±14.2 vs 78.8±12.3, P<0.01). When compared with the control group, there were more patients whose medication refill adherence score was ≥80 in the PMC group (83.3% vs 51.3%, P<0.01). The total St George’s Respiratory Questionnaire scores was found to be improved significantly in the PMC group (42.7±3.2 vs 52.4±5.2, P<0.05). There was a lower hospitalization rate in the PMC group, and more patients in the PMC group quit smoking (71.0% vs 52.2%, P<0.05).ConclusionThe PMC may result in improvement of medication adherence and the health-related quality of life in patients with COPD. In the PMC group, a significant reduction in exacerbation rate, hospitalization rate, and smoking behavior was observed; therefore, our study provides support for a greater involvement of PMC in the care of patients with COPD.

PURPOSE. Choroidal neovascularization (CNV) is a severe complication of AMD. The Wnt signaling pathway has been shown to mediate angiogenesis. The purpose of this study was to investigate the pathogenic role of the Wnt pathway in CNV and explore the therapeutic potential of a novel Wnt signaling inhibitor in CNV.METHODS. Adult rats and mice were photocoagulated using diode laser to induce CNV. On the same day, the animals were intravitreally injected with a monoclonal antibody (Mab2F1) blocking LRP6 or nonspecific mouse IgG. The Wnt signaling activation and target gene expression in the eyecup were determined by Western blot analysis. Fundus angiography was used to examine leakage from the laser lesion. CNV areas were measured on choroidal flatmount using FITC-dextran. The canonical wingless-type MMTV integration site (Wnt) signaling pathway plays a critical role in the regulation of inflammation and angiogenesis. 5,6 Wnt ligands are secreted, cysteine-rich glycosylated proteins, 3 which bind to frizzled (Fz) receptors or to the coreceptor complex of Fz and low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6). RESULTS. Levels of 4-6Binding of Wnt ligands results in LRP6 phosphorylation and activation, 7,8 leading to dissociation of the kinase complex containing glycogen synthase kinase-3b (GSK3b), 9 axin and adenomatous polyposis.3 The GSK3b complex dissociation prevents transcription factor b-catenin from phosphorylation and degradation.10 Consequently, b-catenin is accumulated in the cytoplasm and translocated into the nucleus, complexes with TCF/LEF family transcription factors, 11 regulating expression of Wnt target genes including VEGF, which is the key pathogenic factor in CNV. [12][13][14][15] Although studies of the pathogenesis and treatment of AMD have been delayed by lacking of ideal animal models, 16 laserinduced CNV rodent models are commonly used to study CNV in wet AMD. [17][18][19][20] Moreover, our previous study has shown that the Wnt signaling pathway is activated in very low-density lipoprotein receptor (VLDLR) knockout (KO) mice, a genetic animal model of subretinal neovascularization (NV). 21 The present study investigated the role of the Wnt signaling pathway in laser-induced CNV and explored therapeutic potential of a blocker of Wnt signaling in laser-induced CNV and VLDLR KO models. METHODS AnimalsCare, use, and treatment of experimental animals were in strict agreement with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male C57BL/6J mice and VLDLR KO mice (10 weeks old; The Jackson Laboratory, Bar Harbor, ME) and male Brown Norway rats (8-10 weeks old; Charles River, Wilmington, MA) were used in this study. In all procedures, animals were anesthetized by intramuscular injection of 50 mg/kg ketamine hydrochloride (Vedco, St. Joseph, MO) and 10 mg/kg xylazine (Vedco), and pupils were dilated with topical administration of 1% cyclopentolate (Wilson, Mustang, OK). CNV InductionLaser photocoagulation (532 nm, 150-250 mW, 0.01 second, 50 lm; model di...

Aims/hypothesis Retinal Müller cells are known to produce inflammatory and angiogenic cytokines, which play important roles in diabetic retinopathy. Hypoxia-inducible factor (HIF)-1 has been shown to play a crucial role in retinal inflammation and neovascularisation. We sought to determine the role of Müller cell-derived HIF-1 in oxygeninduced retinopathy (OIR) and diabetic retinopathy using conditional Hif-1α (also known as Hif1a) knockout (KO) mice. Methods Conditional Hif-1α KO mice were generated by crossing mice expressing cyclisation recombinase (cre, also known as P1_gp003) in Müller cells with floxed Hif-1α mice and used for OIR and streptozotocin-induced diabetes to induce retinal neovascularisation and inflammation, respectively. Abundance of HIF-1α and pro-angiogenic and pro-inflammatory factors was measured by immunoblotting and immunohistochemistry. Retinal neovascularisation was visualised by angiography and quantified by counting pre-retinal nuclei. Retinal inflammation was evaluated by leucostasis and vascular leakage. Results While the Hif-1α KO mice showed significantly decreased HIF-1α levels in the retina, they exhibited no apparent histological or visual functional abnormalities (2011( ) 54:1554( -1566( DOI 10.1007( /s00125-011-2081 under normal conditions. Compared with wild-type counterparts, Hif-1α KO mice with OIR demonstrated attenuated overproduction of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1, reduced vascular leakage and alleviated neovascularisation in the retina. Under diabetes conditions, disruption of Hif-1α in Müller cells attenuated the increases of retinal vascular leakage and adherent leucocytes, as well as the overproduction of VEGF and ICAM-1. Conclusions/interpretation Müller cell-derived HIF-1α is a key mediator of retinal neovascularisation, vascular leakage and inflammation, the major pathological changes in diabetic retinopathy. Müller cell-derived HIF-1α is therefore a promising therapeutic target for diabetic retinopathy.