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PURPOSE. The purpose of the study was to investigate the effects of hyperglycemia on EGFR (epidermal growth factor receptor)-mediated wound response and signal transduction in the corneal epithelium of rats with type I diabetes mellitus (DM). METHODS. Corneal epithelia were removed from streptozotocin (STZ)- and weight-matched normal rats. Wound healing was monitored by fluorescein staining at 24 or 48 hours after epithelial debridement. Phosphorylation of EGFR, AKT, ERK, and BAD was determined by Western blot analysis. The distribution of phospho-AKT and proliferating cell nuclear antigen (PCNA) in rat corneas was examined by immunohistochemistry. Cell death was evaluated by TUNEL staining. RESULTS. A significant delay in corneal epithelial wound healing was observed 48 hours after wounding in the diabetic rats compared with the weight-matched control rats. In the DM rat corneas, epithelial cells demonstrated diminished responses to wounding, as assessed by the phosphorylation of EGFR and its downstream signaling molecules, AKT and ERK. Furthermore, although the distribution pattern of phospho-AKT suggested a role for AKT in epithelial migration and proliferation in the normoglycemic rat corneas, it was abrogated in the healing epithelia of the DM rats. Consistent with impaired AKT activity, the number of PCNA-stained cells was also greatly reduced in the healing corneas of the diabetic rats. Finally, decreases in pBAD (Ser(136) and Ser(112)) and increases in TUNEL-positive cells were observed in both the uninjured and healing corneal epithelia of the DM rats, but not of the control rats. CONCLUSIONS. In the corneas of SZT rats, EGFR-PI3K-AKT and ERK, as well as their downstream BAD signaling pathways in migratory epithelium, were altered, resulting in increased apoptosis, decreased cell proliferation, and delayed wound closure.

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PURPOSE. This study seeks to characterize corneal functions and complications in a streptozocin (STZ)-induced rat model of type I diabetes mellitus (DM) and to understand the pathogenesis of diabetic keratopathy. METHODS. DM was induced via STZ injection in Sprague-Dawley rats. Body weight, length, and corneal size were measured and compared with the age-matched normal controls. Corneal morphology and histology were evaluated with slit lamp, digital confocal microscopy and hematoxylin and eosin staining. Tear secretion was measured with cotton threads, and corneal sensitivity was determined with an esthesiometer. Protein expression and distribution were assessed with Western blotting and immunohistochemistry. Wound healing was determined using an in vivo corneal epithelial debridement model. RESULTS. Compared with the normal control rats, STZ rats had reduced body weight, and body length, but minimally affected corneal size. No significant changes in ocular surface regularity, corneal thickness, and morphology were noted in diabetic corneas. STZ rats showed stronger Rose Bengal staining, decreased tear secretion, slightly attenuated sensitivity, less innervation, delayed epithelial wound healing, and impaired epidermal growth factor receptor signaling in their corneas. While the expression of adherens junction protein β-catenin, and tight junction proteins occludin and ZO-1 was unchanged, the formation of these junctions after wound closure was delayed. CONCLUSIONS. Pathogenesis of diabetic keratopathy involves multiple tissues and/or cell types and several events including reduced tear secretion, impaired innervation, weakened cell junction, and altered wound responses. These insights may prove useful for the clinical translation of evolving strategies for the management and treatment of diabetic corneal complications.

Background Activation of innate immunity plays a key role in determining the outcome of an infection. Here, we investigated whether Toll-like receptors (TLRs) are involved in retinal innate response and explored the prophylactic use of TLR2 ligand in preventing bacterial endophthalmitis. Methods C57BL/6 (B6) mice were given intravitreal injections of Pam3Cys, a synthetic ligand of TLR2, or vehicle (PBS) 24 h prior to S. aureus (SA) inoculation. The severity of endophthalmitis was graded by slit lamp, electroretinography (ERG), histological examinations and determination of bacterial load in the retina. The expression of cytokines/chemokines and cathelicidin-related antimicrobial peptide (CRAMP) was assessed by ELISA and Western blot respectively. Results Intravitreal injections of Pam3Cys up-regulated TLR2 expression in the B6 retina and Pam3Cys pretreatment significantly improved the outcome of SA endophthalmitis, preserved retinal structural integrity and maintained visual function assessed with ERG in B6 mice. Furthermore, Pam3Cys pretreatment activated retinal microglia cells, induced the expression of CRAMP, and remarkably reduced the bacterial load. Conclusions This is the first report that highlights the existence and role of TLR2 in retinal innate immune response to SA infection and suggests that modulation of TLR activation provides a novel prophylactic approach to prevent bacterial endophthalmitis.

Plasmonic color filtering and color printing have attracted considerable attention in recent years due to their supreme performance in display and imaging technologies. Although various color‐related devices are designed, so far very few studies have touched the topic of dynamic color generation. In this article, dynamic color generation is demonstrated by integrating plasmonic nanostructures with vanadium dioxide based on its tunable optical properties through insulator–metal transition. Periodic arrays of silver nanodisks on a vanadium dioxide film are fabricated to realize different colors, relying on the excitation of localized and propagating surface plasmons, and Wood's anomaly. By tuning spatial periodicity of the arrays and diameter of the silver nanodisks, various colors can be achieved across the entire visible spectrum. Further, using insulator–metal transition of vanadium dioxide, the colors can be actively tuned by varying temperature. The approach of dynamic color generation based on the phase transition of vanadium dioxide can easily realize diverse color patterns, which makes it beneficial for display and imaging technology with distinct advantages of multifunctionality, flexibility, and high efficiency.

The oral anti-diabetic drug metformin has been found to reduce cardiovascular complications independent of glycemic control in diabetic patients. However, its role in diabetic retinal microvascular complications is not clear. This study is to investigate the effects of metformin on retinal vascular endothelium and its possible mechanisms, regarding two major pathogenic features of diabetic retinopathy: angiogenesis and inflammation. In human retinal vascular endothelial cell culture, metformin inhibited various steps of angiogenesis including endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. Its anti-angiogenic activity was confirmed in vivo that metformin significantly reduced spontaneous intraretinal neovascularization in a very-low-density lipoprotein receptor knockout mutant mouse (p<0.05). Several inflammatory molecules upregulated by tumor necrosis factor-α in human retinal vascular endothelial cells were markedly reduced by metformin, including nuclear factor kappa B p65 (NFκB p65), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). Further, metformin significantly decreased retinal leukocyte adhesion (p<0.05) in streptozotocin-induced diabetic mice. Activation of AMP-activated protein kinase was found to play a partial role in the suppression of ICAM-1 and MCP-1 by metformin, but not in those of NFκB p65 and IL-8. Our findings support the notion that metformin has considerable anti-angiogenic and anti-inflammatory effects on retinal vasculature. Metformin could be potentially used for the purpose of treating diabetic retinopathy in addition to blood glucose control in diabetic patients.

EGFR modulates HGF/c-Met activity by inducing c-Met ectodomain shedding, and HGF/c-Met transactivates EGFR, leading to an enhanced activation of downstream signaling pathways. Cross talk between EGFR and c-Met may play a key role in regulating RPE cell migration, proliferation, and wound healing.