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Dysregulation of Wnt/β-catenin signaling contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization. Here, we evaluated the inhibitory effect of a monoclonal antibody (Mab) specific for the E1E2 domain of Wnt coreceptor low-density lipoprotein receptor–related protein 6, Mab2F1, on canonical Wnt signaling and its therapeutic potential for diabetic retinopathy. Mab2F1 displayed robust inhibition on Wnt signaling with a half-maximal inhibitory concentration (IC50) of 20 μg/mL in retinal pigment epithelial cells. In addition, Mab2F1 also attenuated the accumulation of β-catenin and overexpression of vascular endothelial growth factor, intercellular adhesion molecule-1, and tumor necrosis factor-α induced by high-glucose medium in retinal endothelial cells. In vivo, an intravitreal injection of Mab2F1 significantly reduced retinal vascular leakage and decreased preretinal vascular cells in oxygen-induced retinopathy (OIR) rats, demonstrating its inhibitory effects on ischemia-induced retinal neovascularization. Moreover, Mab2F1 blocked the overexpression of the inflammatory/angiogenic factors, attenuated leukostasis, and reduced retinal vascular leakage in both early and late stages of streptozotocin-induced diabetes. In conclusion, Mab2F1 inhibits canonical Wnt signaling, vascular leakage, and inflammation in the retina of diabetic retinopathy models, suggesting its potential to be used as a therapeutic agent in combination with other antiangiogenic compounds.

Decreased Expression of Pigment Epithelium-Derived Factor Is Involved in the Pathogenesis of Diabetic Nephropathy Joshua J. Wang , Sarah X. Zhang , Kangmo Lu , Ying Chen , Robert Mott , Sanai Sato and Jian-xing Ma From the Department of Medicine, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Address correspondence and reprint requests to Jian-xing Ma, MD, PhD, 941 Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK 73104. E-mail: jian-xing-ma{at}ouhsc.edu Abstract Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-β (TGF-β) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the high-glucose-induced overexpression of TGF-β, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-β expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy. ECM, extracellular matrix ELISA, enzyme-linked immunosorbent assay FBS, fetal bovine serum HMC, human glomerular mesangial cell PEDF, pigment epithelium-derived factor STZ, streptozotocin TGF-β, transforming growth factor-β VEGF, vascular endothelial growth factor Footnotes J.J.W. and S.X.Z. contributed equally to this work. Accepted October 12, 2004. Received June 8, 2004. DIABETES

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.

The \"Four Pillars of Manufacturing Knowledge\" essentially differentiates the unique character of manufacturing, manufacturing engineering, and manufacturing engineering technology; defines the standard for advanced manufacturing topics; and provides a body of knowledge with which all those engaged in advanced manufacturing education can align. Developed by the Society of Manufacturing Engineers (SME) through its Center for Education, the four pillars are derived from the ABET accreditation criteria for manufacturing engineering programs and build on the topics in the SME-defined \"Body of Knowledge for the Certification of Manufacturing Engineers and Manufacturing Technologists.\" The four pillars term encompasses 1) materials and manufacturing processes; 2) product, tooling, and assembly engineering; 3) manufacturing systems and operations; and 4) manufacturing competitiveness. The Four Pillars of Manufacturing Knowledge model is a tool for promoting greater understanding of the breadth and depth of the field of manufacturing engineering. Initiatives are underway, led by the SME Center for Education, to build on this foundation, to promulgate the model broadly within SME, and to engage in dialogue with other professional societies that represent engineering, engineering technology, industrial technology, and related educational programs whose graduates enter manufacturing-related career paths. This article outlines how this tool applies to engineering technology programs. [PUBLICATION ABSTRACT]

Salutary Effect of Pigment Epithelium–Derived Factor in Diabetic Nephropathy Evidence for Antifibrogenic Activities Joshua J. Wang 1 , Sarah X. Zhang 1 , Robert Mott 1 , Ryan R. Knapp 2 , Wei Cao 2 , Kai Lau 3 and Jian-xing Ma 1 1 Departments of Medicine Endocrinology and Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 2 Department of Ophthalmology, Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 3 Department of Medicine Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Address correspondence and reprint requests to Jian-xing Ma, MD, PhD, 941 Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK 73104. E-mail: jian-xing-ma{at}ouhsc.edu Abstract Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium–derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-β (TGF-β)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-β1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-β1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti–TGF-β and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-β, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection. Ad-GFP, adenovirus expressing green fluorescent protein Ad-PEDF, adenovirus expressing pigment epithelium–derived factor CTGF, connective tissue growth factor ECM, extracellular matrix ELISA, enzyme-linked immunosorbent assay GFP, green fluorescent protein HMC, human mesangial cell MMP-2, matrix metalloproteinase-2 PEDF, pigment epithelium–derived factor STZ, streptozotocin TGF-β, transforming growth factor-β UAE, urine albumin excretion Footnotes J.J.W. and S.X.Z. contributed equally to this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted March 13, 2006. Received November 4, 2005. DIABETES

Remains of freshwater midges are abundant in lake sediments, and their species distributions are closely related to the surface-water temperature of lakes; their distributions thus provide a powerful tool for paleoclimatology. The distribution of species in a core from Splan Pond in Atlantic Canada indicates that there were abrupt transitions in late-glacial temperatures between warm and cold states. The transitions are correlative with the well-known warm Alleøod and cold Younger Dryas events in Europe. These data thus confirm the inference from palynological data that these events affected regions on both sides of the Atlantic.

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-beta (TGF-beta)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-beta1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-beta1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti-TGF-beta and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-beta, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection.

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 down-regulation 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. Diabetes 62:261-272, 2013

Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator--activated receptor ([alpha] (PPAR[alpha]) 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 PPAR[alpha] 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 PPAR[alpha] 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-[kappa]B in the retinas of OIR and diabetic models. Fenofibrate's beneficial effects were blocked by a specific PPAR[alpha] antagonist. Furthermore, Ppar[alpha] knockout abolished the fenofibrate-induced down-regulation 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 PPAR[alpha]-dependent mechanism. Diabetes 62:261-272, 2013

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.