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OBJECTIVE--In diabetes, retinal vascular basement membrane (BM) undergoes significant thickening and compromises vessel function including increased vascular PERMEABILITY, a prominent lesion of early diabetic retinopathy. In this study we determined whether altered expression and activity of lysyl oxidase (LOX), a cross-linking enzyme, may compromise vascular basement membrane functional integrity under high-glucose (HG) conditions. RESEARCH DESIGN AND METHODS--Rat retinal endothelial cells (RRECs) grown in normal (5 mmol/l) or HG (30 mmol/l glucose) medium for 7 days were assessed for expression of LOX and proLOX by Western blot analysis and LOX enzyme activity. To determine whether HG alters cellular distribution patterns of LOX and proLOX, immunostaining with respective antibodies was performed. Similarly, cells grown in normal or HG medium were subjected to both LOX inhibition with β-aminopropionitrile (BAPN) and by small interfering RNA knockdown, and respectively examined for cell monolayer permeability. Additionally, retinas of streptozotocin (STZ)-induced diabetic rats were analyzed to determine if diabetes altered LOX expression. RESULTS--Western blot analysis revealed significantly increased LOX and proLOX expression in cells grown in HG medium compared with those grown in normal medium. The increased LOX level was strikingly similar to LOX upegulation in the diabetic retinas. In cells grown in HG medium, LOX activity and cell monolayer permeability was significantly increased, as were LOX and proLOX immunostaining. Small interfering RNA- or BAPN-induced-specific blockage of LOX expression or activity, respectively, reduced cell monolayer permeability. CONCLUSIONS--HG-induced increased LOX expression and activity compromises barrier functional integrity, a prominent lesion of diabetic retinopathy. Diabetes 59:3159-3166, 2010, The pathogenesis of diabetic microangiopathy is influenced by qualitative and quantitative changes of the capillary basement membrane. Although histologic and functional changes that accompany diabetic microangiopathy have been well documented [...]

Background: Single-agent doxorubicin has been widely used to treat unresectable hepatocellular carcinoma (HCC), but the response rate is low (

Background: Mesolimbic dopamine is thought to play a role in the reinforcing properties of ethanol, but ethanol‐induced changes in extracellular dopamine in the ventral striatum have not been well characterized in mouse models.