Targeting cGAS-STING signaling protects retinal ganglion cells from DNA damage-induced cell loss and promotes visual recovery in glaucoma.

BACKGROUND: Glaucoma is an optic neurodegenerative disease. Retinal ganglion cells (RGCs) are the fundamental neurons in the trabecular meshwork, and their loss is the main pathological reason for glaucoma. The present study was to investigate mechanisms that regulate RGCs survival. METHODS: A mouse model of glaucoma was established by injecting hypertonic saline into the limbal veins. RGCs apoptosis was detected by using flow cytometry. Protein expressions in RGCs in response to DNA damage inducer cisplatin treatment were detected by immunofluorescence and western blot. The expressions of inflammatory cytokines were determined using ELISA and real-time PCR. RESULTS: In the hypertonic saline-injected mice, we found visual function was impaired followed by the increased expression of γH2AX and activation of cGAS-STING signaling. We found that DNA damage inducer cisplatin treatment incurred significant DNA damage, cell apoptosis, and inflammatory response. Mechanistically, cisplatin treatment triggered activation of the cGAS-STING signaling by disrupting mitochondrial function. Suppression of cGAS-STING ameliorated inflammation and protected visual function in glaucoma mice. CONCLUSIONS: The data demonstrated that cGAS-STING signaling is activated in the damaged retinal ganglion cells, which is associated with increased inflammatory responses, DNA damage, and mitochondrial dysfunction. Targeting the cGAS-STING signaling pathway represents a potential way to alleviate glaucoma-related visual function.

Diagnostic value of 3D Optical Coherence Tomography Multimode Images in the Diagnosis of Acute Central Serous Chorioretinopathy.

BACKGROUND: Spectral-Domain Optical Coherence Tomography (SD-OCT) provides non-invasive, high-speed, high-resolution, three-dimensional cross-section imaging of the macula. OBJECTIVES: This study aimed to investigate the diagnostic value of the multimodal imaging technique of three-dimension (3D) optical coherence tomography (OCT) (3D-OCT) for the diagnosis and characterization of acute central serous chorioretinopathy (CSC). METHODS: In this prospective clinical study 3D-OCT examinations of 82 cases with acute CSC were performed on the macular area, and the image characteristics were analyzed. Our study included a total of 87 eyes from 82 cases of CSC patients, 67 males and 15 females (mean age ± standard deviation (SD): 42.89 ±7.80 years old; age range: 27 to 56 years old. The 3D-OCT images were evaluated for the presence of subretinal fluid, subretinal space, fluctuation of the internal limiting membrane (ILM), folds of retinal pigment epithelial (RPE), retinal pigment epithelium detachment (PED), and flat irregular PED. The foveal thickness was measured using the manual caliper of OCT software. RESULTS: The OCT B-scan images showed 87 (100%) eyes had exudative retinal detachment (ERD), 38 (44%) had flat irregular PED, 36 (41%) had PED, 8 (9%) had subretinal turbidity structure, 2 (2%) had subretinal dot-like precipitates, 1 (1%) had focal choroidal excavation (FCE), and 1 (1%) eye had fluctuation of internal limiting membrane (FI). In the ILM-RPE thickness map, all eyes had a round or round like regular uniform domes. Fifty-seven (66%) domes were limited in the examination area and 30 (44%) domes were beyond the scope of this examination and only a partial section of the dome could be observed. In the en-face image, all eyes had a round or round-like black figure that corresponded with domes in the ILM-RPE thickness map. In RPE surface, 76 (87%) eyes had a shallow plate depression, 71(82%) had small focal uplift, and 1 (1%) eye had a focal concave feature. CONCLUSIONS: In the OCT ILM-RPE thickness, en-face image, and RPE surface maps, acute CSC exhibited specific imaging characteristics that can be helpful for reliable diagnosis and differential diagnosis of CSC.

The protein tyrosine kinase inhibitor genistein suppresses hypoxia-induced atrial natriuretic peptide secretion mediated by the PI3K/Akt-HIF-1α pathway in isolated beating rat atria.

Genistein, an isoflavonoid that can inhibit protein tyrosine kinase (PTK) phosphorylation, has been shown to play pivotal roles in the signal transduction pathways of hypoxic disorders. In this study, we established a rat model of isolated beating atrium and investigated the regulator role of genistein and its downstream signaling pathways in acute hypoxia-induced atrial natriuretic peptide (ANP) secretion. Radioimmunoassay was used to detect the ANP content in the atrial perfusates. Western blot analysis was used to determine the protein level of hypoxia-inducible factor 1α (HIF-1α), and GATA4 in the atrial tissue. The results showed that acute hypoxia substantially promoted ANP secretion, whereas this effect was partly attenuated by the PTKs inhibitor genistein (3 µM). By Western blotting analysis, we found that hypoxia-induced increase in phosphorylation of Akt and transcriptional factors, including HIF-1α, were also reversed by genistein. The perfused HIF-1α inhibitors rotenone (0.5 µM) or CAY10585 (10 µM) plus genistein significantly abolished the enhanced ANP section induced by hypoxia. Additionally, the perfused PI3K/Akt agonist insulin-like growth factor 1 (30 µM) also abolished ANP secretion induced by genistein and inhibited expression of HIF-1α. In summary, our data suggested that acute hypoxia markedly increased ANP secretion by PTKs through the phosphoinositide-3 kinase (PI3K)/HIF-1α dependent pathway.

miR-708 and miR-335-3p Inhibit the Apoptosis of Retinal Ganglion Cells Through Suppressing Autophagy.

This study aimed to clarify the regulation role of miR-708 and miR-335-3p in retinal ganglion cell (RGC) autophagy and apoptosis in glaucoma. Chronic glaucoma mice were established by laser photocoagulation. RGCs were isolated and transfected with a series of plasmids and the cultured in 60 mmHg pressure. miR-335-3p, miR-708, and ATG3 mRNA expressions were detected by qRT-PCR. Protein levels of ATG3, autophagy-related protein LC3, and p62 were detected by Western blot. The apoptosis of RGCs was detected by flow cytometry. The regulation role of miR-335-3p/miR-708 in ATG3 was confirmed by the dual-luciferase reporter gene. The expressions of several miRNAs were measured in retinal tissues from chronic glaucoma mice and RGCs under pressure conditions, and results showed that both miR-335-3p and miR-708 were down-regulated. Besides, the inhibition of miR-708 and miR-335-3p induced the apoptosis of RGCs through promoting autophagy. Also, miR-708 and miR-335-3p could bind to ATG3 and targeted regulated ATG3. Furthermore, the interference with miR-708/miR-335-3p induced RGC apoptosis by up-regulating ATG3 to promote autophagy. In general, the down-regulation of miR-708 and miR-335-3p contributed to the apoptosis of RGCs through promoting autophagy in glaucoma.

Diagnostic Function of 3D Optical Coherence Tomography Images in Diagnosis of Vogt-Koyanagi-Harada Disease at Acute Uveitis Stage.

BACKGROUND This study analyzed the macular 3D-OCT images of Vogt-Koyanagi-Harada disease (VKH) in uveitis, explored the characteristics of 3D-OCT images of the macular region of VKH, and assessed which characteristics contribute most to VKH diagnosis. MATERIAL AND METHODS The 3D-OCT examination of 25 cases of VKH was performed on the macular area, and the image characteristics were analyzed. RESULTS Our study included a total of 50 eyes from 25 cases of VKH patients, 10 males and 15 females, aged 17 to 64 years, mean (39.44±11.60) years old. According to OCT B-scan images, 49 (98%) eyes had ERD, 49 (98%) eyes had nerve retinal edema, 36 (72%) eyes had endometrium-like structure (including cysts), 5 (10%) eyes had RPE folds, 35 (70%) eyes had changes in the internal septum, 49 (98%) eyes had RPE monolayer structure outside the ERD region. In ILM-RPE thickness, 49 (98%) eyes had retinal irregular thickening and 31 (62%) eyes had radial stripe changes. In ILM contour figure, 50 eyes (100%) showed exceptional uplift, 5 (10%) eyes had small focal uplift for PED on the RPE surface, and 48 (96%) eyes had wavy ups and downs. CONCLUSIONS In OCT B-scan imaging, the ERT, retinal edema of the retina, and the RPE monolayer structure outside the range are most likely to occur in VKH. The ILM-RPE thickness chart in 3D reconstruction showed irregular thickening of the retina. The ILM contour graph showed abnormal uplift, and RPE surface wavy ups and downs in VKH most likely to occur.