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Yang Y.,Yunnan Province 2nd Hospital | Yang Y.,University of Missouri | Yang Y.,Yunnan University | Yang K.,Shanghai JiaoTong University | And 7 more authors.
Molecular and Cellular Endocrinology

Diabetes induces pathologic proliferation and angiogenesis in the retina that leads to catastrophic loss of vision. Decursin is a novel therapeutic that targets the vascular endothelial growth factor (VEGF) receptor (VEGFR) with putative anti-proliferative and anti-angiogenic activities. Thereby we utilized human retinal microvascular endothelial cells (HRMEC) and human umbilical vein endothelial cells (HUVEC) under conditions of excess glucose to explore dose-dependent responses of decursin on markers of migration, angiogenesis, and proliferation. Decursin dose-dependently inhibited tube formation, VEGFR-2 expression, along with relative metabolic activity and 5-bromo-2'-deoxy-uridine (BrdU) activity in both cell lines. We then correlated our findings to the streptozotocin-induced rat model of diabetes. Following three months of decursin treatment VEGFR-2 expression was significantly inhibited. Our data would suggest that decursin may be a potent anti-angiogenic and anti-proliferative agent targeting the VEGFR-2 signaling pathway, which significantly inhibits diabetic retinal neovascularization. © 2013 Elsevier Ireland Ltd. Source

Yang Y.,Yunnan Province 2nd Hospital | Yang Y.,Harry uman Va Medical Center | Hayden M.R.,University of Missouri | Sowers S.,Diabetes | And 4 more authors.
Oxidative Medicine and Cellular Longevity

Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20-74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase Cisoforms and hexosamine pathway flux. These pathways individually and synergisticallycontribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/ fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative - redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling mayprovide both the clinician and researcher a new concept of approaching this complicated disease process. © 2010 Landes Bioscience. Source

Yang Y.,Yunnan Province 2nd Hospital | Yang Y.,University of Missouri | Andresen B.T.,University of Missouri | Andresen B.T.,Harry uman Medical Center | And 3 more authors.
Experimental Biology and Medicine

Genetic factors are important in the pathogenesis of diabetic retinopathy (DR); there is a clear association of increased expression of vascular endothelial growth factor (VEGF) with DR as well as numerous VEGF polymorphisms that are linked to increased VEGF levels and DR. In this study, the relationships between the VEGF promoter polymorphism -634C/G, plasma VEGF levels and DR were examined in the Han Chinese. Ninety-six healthy subjects and 285 subjects with type 2 diabetes were enrolled in this study. The diabetic subjects were divided into three groups depending on the degree of DR as determined by fundus photography and fluorescent angiography. Along with standard clinical characteristics, the -634C/G polymorphism was examined using TaqMan allelic discrimination, and plasma VEGF levels were analyzed by enzyme-linked immunosorbent assay. The distribution of the polymorphism differed significantly between patients with and without retinopathy; this was most pronounced between the no DR and proliferative DR groups. Significantly greater plasma VEGF levels were present in those with the -634CC genotype, and only the proliferative DR group had elevated plasma VEGF levels. Logistic regression revealed that the -634C/G polymorphism is strongly associated with DR. This study suggests that diabetic Han Chinese carrying the -634CC VEGF promoter polymorphism have a genetic risk of DR, and this polymorphism may be a major factor influencing plasma VEGF levels. Therefore, this polymorphism may be used as a biomarker at the onset of diabetes in the Han Chinese to predict the risk of DR, allowing for clinicians to treat these patients more aggressively. Copyright © 2010 by the Society for Experimental Biology and Medicine. Source

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