NLRP3 and autophagy in retinal ganglion cell inflammation in age-related macular degeneration: potential therapeutic implications.

Retinal degenerative diseases were a large group of diseases characterized by the primary death of retinal ganglion cells (RGCs). Recent studies had shown an interaction between autophagy and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes, which may affect RGCs in retinal degenerative diseases. The NLRP3 inflammasome was a protein complex that, upon activation, produces caspase-1, mediating the apoptosis of retinal cells and promoting the occurrence and development of retinal degenerative diseases. Upregulated autophagy could inhibit NLRP3 inflammasome activation, while inhibited autophagy can promote NLRP3 inflammasome activation, which leaded to the accelerated emergence of drusen and lipofuscin deposition under the neurosensory retina. The activated NLRP3 inflammasome could further inhibit autophagy, thus forming a vicious cycle that accelerated the damage and death of RGCs. This review discussed the relationship between NLRP3 inflammasome and autophagy and its effects on RGCs in age-related macular degeneration, providing a new perspective and direction for the treatment of retinal diseases.

Protective effects of CY-09 and astaxanthin on NaIO3-induced photoreceptor inflammation via the NLRP3/autophagy pathway.

AIM: To study the effect of the NLRP3/autophagy pathway on the photoreceptor inflammatory response and the protective mechanism of CY-09 and astaxanthin (AST). METHODS: ICR mice were intraperitoneally injected NaIO3, CY-09, AST successively and divided into 5 groups, including the control, NaIO3, NaIO3+CY-09, NaIO3+AST, and NaIO3+CY-09+AST groups. Spectral domain optical coherence tomography and flash electroretinogram were examined and the retina tissues were harvested for immunohistochemistry, enzyme linked immunosorbent assay (ELISA), and Western blotting. Retinal pigment epithelium cell line (ARPE-19 cells) and mouse photoreceptor cells line (661W cells) were also treated with NaIO3, CY-09, and AST successively. Cell proliferation was assessed by cell counting kit-8 (CCK-8) assay. Apoptosis was analyzed by flow cytometry. Changes in autophagosome morphology were observed by transmission electron microscopy. Quantitative polymerase chain reaction (qPCR) was used to detect NLRP3 and caspase-1. NLRP3, caspase-1, cleaved caspase-1, p62, Beclin-1, and LC3 protein levels were measured by Western blotting. IL-1ß and IL-18 were measured by ELISA. RESULTS: Compared with the control group, the activity of NaIO3-treated 661W cells decreased within 24 and 48h, apoptosis increased, NLRP3, caspase-1, IL-1ß and IL-18 levels increased, and autophagy-related protein levels increased (P<0.05). Compared with NaIO3 group, CY-09 and AST inhibited apoptosis (P<0.05), reduced NLRP3, caspase-1, IL-1ß and IL-18 expression (P<0.05), and inhibited autophagy. Compared with the other groups, CY-09 combined with AST significantly decreased NLRP3 expression and inhibited the expression of the autophagy-related proteins p62, Beclin-1, and LC3 in vitro and in vivo (P<0.05). CONCLUSION: CY-09 and AST inhibit NaIO3-induced inflammatory damage through the NLRP3/autophagy pathway in vitro and in vivo. CY-09 and AST may protect retina from inflammatory injury.

Intelligent Diagnosis of Multiple Peripheral Retinal Lesions in Ultra-widefield Fundus Images Based on Deep Learning.

INTRODUCTION: Compared with traditional fundus examination techniques, ultra-widefield fundus (UWF) images provide 200° panoramic images of the retina, which allows better detection of peripheral retinal lesions. The advent of UWF provides effective solutions only for detection but still lacks efficient diagnostic capabilities. This study proposed a retinal lesion detection model to automatically locate and identify six relatively typical and high-incidence peripheral retinal lesions from UWF images which will enable early screening and rapid diagnosis. METHODS: A total of 24,602 augmented ultra-widefield fundus images with labels corresponding to 6 peripheral retinal lesions and normal manifestation labelled by 5 ophthalmologists were included in this study. An object detection model named You Only Look Once X (YOLOX) was modified and trained to locate and classify the six peripheral retinal lesions including rhegmatogenous retinal detachment (RRD), retinal breaks (RB), white without pressure (WWOP), cystic retinal tuft (CRT), lattice degeneration (LD), and paving-stone degeneration (PSD). We applied coordinate attention block and generalized intersection over union (GIOU) loss to YOLOX and evaluated it for accuracy, sensitivity, specificity, precision, F1 score, and average precision (AP). This model was able to show the exact location and saliency map of the retinal lesions detected by the model thus contributing to efficient screening and diagnosis. RESULTS: The model reached an average accuracy of 96.64%, sensitivity of 87.97%, specificity of 98.04%, precision of 87.01%, F1 score of 87.39%, and mAP of 86.03% on test dataset 1 including 248 UWF images and reached an average accuracy of 95.04%, sensitivity of 83.90%, specificity of 96.70%, precision of 78.73%, F1 score of 81.96%, and mAP of 80.59% on external test dataset 2 including 586 UWF images, showing this system performs well in distinguishing the six peripheral retinal lesions. CONCLUSION: Focusing on peripheral retinal lesions, this work proposed a deep learning model, which automatically recognized multiple peripheral retinal lesions from UWF images and localized exact positions of lesions. Therefore, it has certain potential for early screening and intelligent diagnosis of peripheral retinal lesions.

Efficacy and safety of the dexamethasone implant in vitrectomized and nonvitrectomized eyes with diabetic macular edema: A systematic review and meta-analysis.

Purpose: To compare the efficacy and safety of the intravitreal dexamethasone (DEX) implant for the treatment of diabetic macular edema (DME) in vitrectomized and nonvitrectomized eyes. Methods: We performed a literature search in four electronic databases (PubMed, EMBASE, MEDLINE, and Cochrane Library) from inception to 22 May 2022. Studies comparing the efficacy of the DEX implant in vitrectomized and nonvitrectomized eyes with DME with at least 3 months of follow-up were included. The main outcomes included comparison of the mean change in the best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline to different follow-up endpoints between the vitrectomized and nonvitrectomized groups. The secondary outcomes were the mean duration of action for the first DEX implantation and the number of required injections throughout the follow-up period. Safety data were collected and compared. Results: The final analysis included 7 studies involving 582 eyes, 208 vitrectomized eyes and 374 nonvitrectomized eyes. The mean between-group differences in BCVA improvement were not significant at any endpoint, with averages difference of -0.07 logarithm of the minimum angle of resolution (logMAR) (p = 0.088) at 1 month, -0.03 logMAR (p = 0.472) 3 months, -0.07 logMAR (p = 0.066) 6 months, and -0.04 logMAR (p = 0.486) 12 months. The mean between-group differences in CMT reduction were not statistically significant, with mean differences of 7.17 µm (p = 0.685) at 1 month, 20.03 µm (p = 0.632) 3 months, -1.80 µm (p = 0.935) 6 months, and -25.65 µm (p = 0.542) 12 months. However, the vitrectomized group had a significantly shorter duration of action during the first DEX implantation than the nonvitrectomized group, with a mean difference of 0.8 months (p = 0.005). No significant between-group differences were detected for the number of required injections or safety profile. Conclusion: This meta-analysis showed similar efficacy and safety of the sustained-release DEX intravitreal implant for vitrectomized and nonvitrectomized eyes with DME. The intravitreal DEX implant could be considered an effective choice for DME treatment in eyes with prior vitrectomy.

Efficacy of single-dose intravitreal dexamethasone implantation for retinal vein occlusion patients with refractory macular edema: A systematic review and meta-analysis.

Purpose: To assess the functional and anatomical consequences of single-dose dexamethasone (DEX) implants for the treatment of refractory macular edema (ME) secondary to retinal vein occlusion (RVO) after anti-vascular endothelial growth factor agents. Methods: A literature search of studies on switching therapy to DEX implants from anti-VEGF agents in refractory RVO patients was performed with five electronic databases (PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library) prior to January 2022. The main outcomes included best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes at different follow-up endpoints from baseline. All analyses were performed using Stata version 15.0. Results: The final analysis included four eligible studies with a total of 99 patients. After single-dose DEX implant application, BCVA improved significantly at 2, 3, and 6 months with an average gain of -0.23 logarithm of the minimum angle of resolution (logMAR) (p = 0.004), -0.20 logMAR (p = 0.027), and -0.09 logMAR (p = 0.021), respectively. Mean CMT reduction was also significant from baseline to 2 months (-241.89 µm, p < 0.001), 3 months (-222.61 µm, p < 0.001), and 6 months (-90.49 µm, p < 0.001). No serious adverse events were observed in any of the included studies. Conclusion: This meta-analysis showed that RVO patients with refractory ME could benefit significantly from switching therapy to DEX implantation, with efficacy lasting 6 months after a single-dose application. Intravitreal DEX implantation is a safe and effective option for refractory cases.

Efficacy and safety of single-dose dexamethasone implantation for patients with persistent diabetic macular edema: a systematic review and meta-analysis.

PURPOSE: This meta-analysis was conducted to evaluate the efficacy and safety of single-dose dexamethasone implantation for treating persistent DME (diabetic macular edema) refractory to anti-VEGF (anti-vascular endothelial growth factor) drugs over a period of 6 months. METHODS: All related clinical trials were reviewed by searching electronic databases of PubMed, Medline, Web of Science, Cochrane Library, and EMBASE. The primary outcome parameters were best-corrected visual acuity (BCVA) and central macular thickness (CMT). We performed this meta-analysis by using Stata15.0. RESULTS: Ten clinical trials involving 362 eyes from 328 patients were eligible in the final analysis. After single-dose dexamethasone implantation, there was a significant improvement in BCVA from baseline to 1, 3, and 6 months with an average increase of - 0.15 logMAR (p < 0.001), - 0.14 logMAR (p < 0.001), and - 0.07 logMAR (p = 0.004), respectively. Further, mean CMT decreased significantly with an average reduction of 249.18 µm (p < 0.001), 217.66 µm (p < 0.001), and 91.56 µm (p < 0.001) at months 1, 3, and 6, respectively. CONCLUSIONS: Our results indicate that switching to a dexamethasone implant could achieve significant anatomical and functional improvement among patients with refractory DME. Clinicians should be aware of this treatment option in refractory DME.