0.005% latanoprost induced dry eye-like ocular surface damage via promotion of inflammation in mice.

Pathological neovascularization and fibrosis are common pathological changes of many retinal diseases, such as proliferative retinopathy (PR) and age-related macular degeneration (AMD). Treatment modalities for these pathological changes are limited. The purpose of the present study was to test the effects of palmitoylethanolamide (PEA), an endocannabinoid mimetic amide, on retinal neovascularization and fibrosis and to determine its molecular mechanism of action. METHODS. A rat Müller cell line (rMC-1), a mouse model of oxygen-induced retinopathy (OIR), and the very-low-density lipoprotein receptor (VLDLR) knockout mouse model were used. PEA was intraperitoneally injected or orally administrated in animal models. Inflammation and profibrotic changes were evaluated by western blot analysis. Glial fibrillary acidic protein (GFAP) and peroxisome proliferator-activated receptor alpha (PPARα) were measured by RT-PCR and western blot analysis. RESULTS. Profibrotic changes were present in OIR and Vldlr −/− retinas. PEA significantly alleviated inflammation and inhibited neovascularization in OIR and Vldlr −/− retinas and suppressed profibrotic changes in OIR and Vldlr −/− retinas. Moreover, PEA potently suppressed Müller gliosis in these retinas. In rMC-1 cells, PEA suppressed Müller gliosis, reduced inflammatory cytokines, and attenuated profibrotic changes. Further, both mRNA and protein levels of PPARα were elevated in the retina under PEA treatment, and the effects of PEA were abolished in Pparα −/− OIR mice. CONCLUSIONS. PEA reduced retinal neovascularization and fibrotic changes and suppressed Müller gliosis in experimental PR and neovascular AMD by activating PPARα. PEA may be a potential treatment for retinopathies with pathological neovascularization and fibrosis.

Energy band diagrams are widely utilized to explain the switching mechanism of resistance random access memory (RRAM). However, a precise and quantitative band theory is still lacking in this field. Although HfS2 has good applications in many fields because of its good electrical and optical properties, its applications in RRAM have seldom been reported. In this work, the exfoliated nanosheets of HfS2 were utilized to fabricate memory devices with a structure of Pt/Al/HfS2/p+-Si, which show typical bipolar resistive switching behavior with high switching voltage and a small ratio of high and low resistive states (R-ratio). According to the density functional theory (DFT) calculation results of energy band diagrams, instead of conductive filament formation in other resistive switching materials, the doping of sulfur vacancy (VS) of 3.8% is already enough to change the whole HfS2 layer from the semiconductor to the metal. The transition is caused by the change in the VS doping concentration from low to high, which is the result of the generation and movement of VS under an electric field. The DFT also calculated that HfS2 devices utilizing Indium Tin Oxide as the bottom electrode can show bipolar resistive switching behavior with lower switching voltage and a higher R-ratio than those utilizing p+-Si, which is confirmed by the experimental results. The DFT calculation can be utilized for both explaining the switching mechanism and designing the device structure to optimize the switching characteristics.

Subretinal fibrosis is a common pathological change that causes vision loss in neovascular age-related macular degeneration (nAMD). Treatment modalities for subretinal fibrosis are limited. In the present study, the effects of fenofibrate, a specific peroxisome proliferator-activated receptor alpha agonist, on subretinal fibrosis of nAMD were tested, and its molecular mechanisms of action were delineated. Collagen deposition and protein expression of fibrotic markers, such as vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin, were increased in very low-density lipoprotein receptor (VLDLR) knockout mouse, indicating Vldlr −/− mice can be used as a model for subretinal fibrosis. Fenofibrate suppressed subretinal fibrosis of Vldlr −/− mice by reducing collagen deposition and protein expression of fibrotic markers. Two fibrotic pathways, TGF-β-Smad2/3 signaling and Wnt signaling, were significantly up-regulated, while inhibited by fenofibrate in Vldlr −/− retinas. Moreover, fenofibrate significantly reduced the downstream connective tissue growth factor (CTGF) expression of these two pathways. Müller cells were a major source of CTGF in Vldlr −/− retinas. Fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr −/− retinas. In cultured Müller cells, fenofibrate reversed TGF-β2-induced up-regulation of Wnt signaling and CTGF expression. These findings suggested that fenofibrate inhibits subretinal fibrosis by suppressing TGF-β-Smad2/3 signaling and Wnt signaling and reducing CTGF expression, and thus, fenofibrate could be a potential treatment for nAMD with subretinal fibrosis.

Diabetic retinopathy (DR) is a microvascular complication of diabetes. Aberrant Wnt signaling activation plays a pathological role in DR. However, the underlying mechanisms of aberrant Wnt signaling in DR remain unknown. Autophagy has been reported to be involved in the pathophysiology of DR. The present study aimed therefore to investigate the regulatory effects of autophagy on Wnt signaling in DR. Wnt signaling was activated in the retina of db/db mice combined with an increase in the expression of the autophagic proteins microtubule-associated protein 1A/1B-light chain 3 and beclin-1 and a decrease in the expression of the autophagic protein P62. Inhibition of autophagy by 3-methyladenin decreased Wnt signaling in diabetic retinas, indicating a potential association between Wnt signaling and autophagy. Rapamycin, an autophagy inducer, upregulated Wnt signaling in the retina of normal C57BL/6J mice. In cultured Müller cells, rapamycin induced autophagy and activated Wnt signaling, while chloroquine, an autophagy inhibitor, inhibited autophagy and downregulated Wnt signaling, suggesting that autophagy could regulate Wnt signaling in mice retina and retinal cells. In summary, this study demonstrated that autophagy may positively regulate Wnt signaling in diabetic retinas, indicating a potential mechanism of Wnt signaling upregulation in DR and a possible novel therapeutic target of DR.