RO4929097, a Selective γ-Secretase Inhibitor, Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model.

Purpose: This study aimed to explore whether RO4929097 (RO), a specific γ-secretase inhibitor, could inhibit the subretinal fibrosis in laser-induced mouse model and the relevant molecular mechanisms. Methods: Male C57BL/6J mice were used to produce choroidal neovascularization (CNV) and subretinal fibrosis by laser photocoagulation, and RO was administered intravitreally 1 day after laser induction. The sizes of CNV and subretinal fibrosis were measured and quantified in both 2D and 3D constructions. The ARPE-19 cell line and primary human RPE (phRPE) cells were treated with TGFß1, in combination with or without RO, to examine Notch related molecules, epithelial mesenchymal transition (EMT), cell viability, migration, and contractile function, as well as the crosstalk between Notch and other EMT relevant signaling pathways. Results: Intravitreal injection of RO reduced the sizes of both CNV and subretinal fibrosis in laser-induced young and old mice at day 7 and day 14 after laser induction. Moreover, EMT and Notch activation in RPE-choroid complexes from laser-induced mice were significantly attenuated by RO. In vitro, TGFß1 activated Notch signaling and induced EMT in ARPE-19 cells, accompanied by enhanced EMT-related function, which were inhibited by RO. The inhibition of RO on EMT was further confirmed in TGFß1-treated phRPE cells. Blockage of Notch signaling by RO could inhibit ERK1/2 signaling; whereas ERK1/2 inhibition had no effect on Notch. The action of RO was independent of Smad2/3 or p38, and co-inhibition of Notch and Smad2/3 showed synergistic effect on EMT inhibition. Conclusions: RO exerts its antifibrotic effect by directly inhibiting Notch signaling and indirectly suppressing ERK1/2 signaling. Targeting Notch signaling might provide a therapeutic strategy in prevention and treatment of subretinal fibrosis in neovascular age-related macular degeneration (nAMD).

Anti-VEGF reduces inflammatory features in macular edema secondary to retinal vein occlusion.

AIM: To investigate the anti-inflammatory effect of intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) in patients with macular edema secondary to retinal vein occlusion (RVO-ME). METHODS: Twenty-eight eyes from twenty-eight treatment-naïve patients (14 males and 14 females) with RVO-ME were included in this retrospective study. The retinal vein occlusion (RVO) was comprised of both central retinal vein occlusion (CRVO, n=14) and branch retinal vein occlusion (BRVO, n=14). Intravitreal injection of anti-VEGF reagents were administered monthly for three consecutive months, in which 18 patients were injected with ranibizumab and 10 patients were injected with conbercept. All eyes were imaged with optical coherence tomography angiography (OCTA) at baseline and 1wk after monthly intravitreal anti-VEGF injection. The visual acuity (VA), central macular thickness (CMT), the number of hyperreflective foci (HRF) recognized as an inflammatory sign in OCT images, and non-perfusion area (NPA), were compared before and after anti-VEGF treatments. RESULTS: The mean interval between baseline and follow-up was 29.4±0.79 (range, 27-48)d. Compared with the baseline, the VA improved (logMAR 1.5±0.1 vs 0.8±0.1, P<0.05) and CMT decreased (460±34.0 µm vs 268.8±12.0 µm, P<0.05), significantly, after anti-VEGF treatment. The number of HRF was decreased significantly (76.5±4.8 vs 47.8±4.3, P<0.05) after anti-VEGF treatment. CONCLUSION: Anti-VEGF therapy is effective in treating RVO-ME. The mechanisms for the decreased HRF and the reduction of NPA by anti-VEGF therapy merits further exploration.

Hyperreflective Foci and Subretinal Fluid Are Potential Imaging Biomarkers to Evaluate Anti-VEGF Effect in Diabetic Macular Edema.

Purpose: The aim was to investigate the effect and underlying mechanism of anti-vascular endothelial growth factor (anti-VEGF) in diabetic macular edema (DME) by optical coherence tomography angiography (OCTA). Methods: Twenty-five eyes in 18 treatment-naïve patients with DME were included. All eyes were imaged by OCTA at baseline and 1 week after monthly intravitreal aflibercept injection (IAI). Visual acuity was measured as best corrected visual acuity (BCVA). Additional parameters were evaluated by OCTA, including central macular thickness (CMT), the number of hyperreflective foci (HRF), foveal avascular zone (FAZ), vessel density (VD) in the deep capillary plexus (DCP), the en-face area of cystoid edema in DCP segmentation, and subretinal fluid (SRF) height. Results: The mean time between baseline and final follow-up by OCTA was 79.24 ± 38.15 (range, 28-163) days. Compared with baseline, BCVA was increased significantly after the 3rd IAI, while CMT was decreased significantly from the 1st IAI. SRF height and the area of cystoid edema in DCP segmentation were decreased significantly after the 2nd IAI compared with baseline. The number of HRF was decreased significantly after the 1st IAI (8.87 ± 9.38) compared with baseline (11.22 ± 10.63). However, FAZ's area and perimeter as well as VD in DCP showed no significant changes post-treatment. Conclusion: Anti-VEGF is effective in treating DME, improving visual acuity and decreasing macular edema. The decreased HRF indicates anti-inflammatory effects of aflibercept to deactivate retinal microglia/macrophages. The decreased cystoid edema and SRF height indicated improved drainage function of Müller glial cells and retinal pigment epithelium after IAI.

Shape-controlled solvothermal synthesis of Bi2S3 for photocatalytic reduction of CO2 to methyl formate in methanol.

Different shape of bismuth sulfide (Bi2S3), including nanoparticles, and urchin-like, microspheres hierarchical nanostructures, have been successfully fabricated using a facile and template-free solvothermal method. Their crystal and porous structures, morphologies, as well as the optical absorption were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), UV-vis diffuse reflection spectroscopy (DRS) and nitrogen sorption. The electron microscopy observations showed that both the sulfur sources and solvents greatly affected the morphologies of the as-prepared Bi2S3. Compared with Bi2S3 nanoparticles, the hierarchical architectures exhibited higher activity for photocatalytic reduction of CO2 to methyl formate (MF) in methanol, and Bi2S3 microspheres showed the highest activity. This was attributed to their special hierarchical structure, good permeability and high light-harvesting capacity.

Photocatalytic reduction of CO2 in methanol to methyl formate over CuO-TiO2 composite catalysts.

Photocatalytic reduction of CO(2) on CuO-TiO(2) composite catalysts in the presence of methanol to prepare methyl formate had been investigated. Methanol was used as sacrificial reagent to react with the photo-generated holes in the valence band, and CO(2) was reduced by the electrons in the conduction band. CuO-TiO(2) was optimized for CuO loading, preparation method and calcination temperature. The catalyst of 1.0CuO-TiO(2), calcined at 450°C and CTAB as a dispersant showed the highest overall activity. The heterojunction between CuO and TiO(2) demonstrated with HRTEM played an important role in enhancing the photocatalytic activity.