Management after cataract surgery for patients with diabetic retinopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and effectiveness of various treatment modalities in patients with diabetic retinopathy (DR) who underwent cataract surgery. METHODS: A comprehensive search for randomized controlled trials (RCTs) was conducted using the PubMed, Embase, Cochrane Library, and CNKI databases up to December 22, 2021. The safety and efficacy of treatment modalities were assessed using the risk ratio (RR) to compare the progression of DR and the mean difference to evaluate the best corrected visual acuity (BCVA) and macular thickness (MT). RESULTS: The meta-analysis of the RCTs revealed that anti-VEGF (anti-vascular endothelial growth factor) drugs significantly reduced the progression of DR [RR: 0.37 (95%CI 0.19, 0.70), P = 0.002] and improved BCVA [mean difference = - 0.06 (- 0.12, - 0.01), P = 0.03] in patients with pre-existing DR who underwent cataract surgery. Steroid drugs also showed a significant reduction in macular thickness [mean difference = - 55.63 (- 90.73, - 20.53), I2 = 56%, P = 0.002] in DR patients two weeks after cataract surgery compared to the control group. The safety profiles of different management options did not differ significantly. CONCLUSION: The present meta-analysis suggests that anti-VEGF drugs can effectively slow down the progression of diabetic retinopathy, improve BCVA, and reduce MT in DR patients who underwent cataract surgery. Steroid drugs also show promise in reducing MT. However, further studies with larger sample sizes are required to compare the efficacy and safety of different management options in a multi-center clinical setting.

Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome.

Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.

Leukemia Inhibitory Factor Protects against Degeneration of Cone Photoreceptors Caused by RPE65 Deficiency.

BACKGROUND: Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber's congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65. METHODS: LIF was administrated to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting. RESULTS: Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection. CONCLUSION: LIF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.

Rhodopsin-associated retinal dystrophy: Disease mechanisms and therapeutic strategies.

Rhodopsin is a light-sensitive G protein-coupled receptor that initiates the phototransduction cascade in rod photoreceptors. Mutations in the rhodopsin-encoding gene RHO are the leading cause of autosomal dominant retinitis pigmentosa (ADRP). To date, more than 200 mutations have been identified in RHO. The high allelic heterogeneity of RHO mutations suggests complicated pathogenic mechanisms. Here, we discuss representative RHO mutations as examples to briefly summarize the mechanisms underlying rhodopsin-related retinal dystrophy, which include but are not limited to endoplasmic reticulum stress and calcium ion dysregulation resulting from protein misfolding, mistrafficking, and malfunction. Based on recent advances in our understanding of disease mechanisms, various treatment methods, including adaptation, whole-eye electrical stimulation, and small molecular compounds, have been developed. Additionally, innovative therapeutic treatment strategies, such as antisense oligonucleotide therapy, gene therapy, optogenetic therapy, and stem cell therapy, have achieved promising outcomes in preclinical disease models of rhodopsin mutations. Successful translation of these treatment strategies may effectively ameliorate, prevent or rescue vision loss related to rhodopsin mutations.

The effect of interlayer water of metal-modified montmorillonite for catalytic ozonation.

The catalytic ozonation-based advanced oxidation process (AOP) is applied to remove nondegradable chemical oxygen demand (COD), while the application in industry is limited by the economics and activity of catalysts. In this study, we demonstrate that by taking atrazine (ATZ) as a model pollutant, the removal rates of catalytic ozonation were negatively correlated with the interlayer water content of metal-modified montmorillonite (Mx@MMT), instead of the loadings metals. Among the modified MMT, Zn0.1@MMT achieved 83.2% degradation of ATZ within 15 min, and corresponding removal rates of COD and total organic carbon (TOC) reached 40.3% and 46.5%, respectively. Detailed EPR and quenching experiments identified that hydroxyl radicals (HO•) were the main reactive oxygen species and QTOF/MS/MS analysis helped to propose a possible degradation pathway of ATZ. Moreover, the catalytic performance of Zn0.1@MMT under different conditions was also systematically evaluated.

Identification of a novel compound heterozygous CYP4V2 variant in a patient with autosomal recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) belongs to a family of retinal disorders that is characterized by the progressive degeneration of rod and cone photoreceptors. The aim of the present study was to screen for possible disease-causing genetic variants in a non-consanguineous Chinese family with non-syndromic autosomal recessive RP. Whole-exome sequencing (WES) was performed in samples from the affected individual (the proband) and those from the two children of the proband. A novel compound heterozygous variant of c.C958T (p.R320X) and c.G1355A (p.R452H) in the Cytochrome P450 family 4 subfamily V member 2 (CYP4V2) gene was identified through WES. Subsequently, this variant was validated by direct Sanger sequencing. This compound heterozygous variant was found to be absent from other unaffected family members and 400 ethnically-matched healthy control individuals. In addition, this compound variant was co-segregated with the RP phenotype in an autosomal recessive manner. In silico analysis revealed that both c.C958T (p.R320X) and c.G1355A (p.R452H) could compromise the protein function of CYP4V2. These results strongly suggest this compound variant to be a disease-causing variant, which expands upon the spectrum of currently known CYP4V2 genetic variants associated with retinal diseases.

Exogenous PDE5 Expression Rescues Photoreceptors in RD1 Mice.

BACKGROUND: Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is critical in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The RD1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The RD1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca2+ influx. In this study, we aim to test whether the PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the RD1 retina. METHODS: Electroporation used the PDE5 expression plasmid to transfect neonatal RD1 mice. The mouse retina degeneration was assessed by retinal sections' stains with DAPI. The expression and localization of phototransduction proteins in photoreceptors were analysed by immunostaining. The expression of proteins in cultured cells was analysed by immunoblotting. RESULTS: The exogenous PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in RD1 mice. Unlike endogenous photoreceptor-specific PDE6 localised in the outer segments of photoreceptors, ectopically- expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in RD1 mice. PDE5 co-expression with rhodopsin in cultured cells showed enhanced rhodopsin expression. CONCLUSION: Lowering the cGMP level in photoreceptors by PDE5 is sufficient to rescue photoreceptors in RD1 retinas. cGMP may also play a role in rhodopsin expression regulation in photoreceptors.

Leukemia inhibitory factor protects photoreceptor cone cells against oxidative damage through activating JAK/STAT3 signaling.

BACKGROUND: The present study aimed to investigate the protective role of leukemia inhibitory factor (LIF) against oxidative damage in photoreceptor cone cells. METHODS: In vivo, dark-adapted mice were injected with LIF or phosphate-buffered saline (PBS) intravitreously prior to being exposed to 5,000 lux bright light to determine the protective effect of LIF against light damage in cone cells. Oxidative damage to cone cells was analyzed using electroretinograms, immunostaining, Western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In vitro, 661W cells were pretreated with 5 ng/mL of LIF with or without 50 µM of signal transducer and activator of transcription 3 (STAT3) inhibitor S3I201 for 1 h prior to treatment with 1 mM H2O2; cell survival, apoptosis, the oxidative stress index, and the activation of STAT3, extracellular signal-regulated kinase (ERK1/2), and AKT were subsequently determined. RESULTS: In vivo, light induction damaged the function and morphology of cone cells, and LIF was observed to protect cone cells from this light damage. Moreover, the activation of the Janus tyrosine kinase (JAK)/STAT3 signaling pathway and the subsequent changes in apoptosis and proliferation-related genes were found to be involved in the protective effect of LIF against light-induced retinal damage. In the H2O2-induced 661W cell model, H2O2 increased cellular apoptosis rates, the expression levels of Bcl-2-associated X-protein (BAX) and cleaved caspase 3, reactive oxygen species (ROS) production, and malondialdehyde content, while decreasing the cell viability, and Bcl-2, superoxide dismutase, catalase, and glutathione peroxidase activity. LIF was observed to block these events; however, the administration of the STAT3 inhibitor S3I201 reversed the beneficial effects of LIF on H2O2-triggered apoptosis and ROS production. CONCLUSIONS: In conclusion, the present study suggested that LIF may relieve oxidative damage in cone cells through suppressing apoptosis and oxidative stress by targeting the STAT3 signaling pathway.

VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases.

Age-related macular degeneration (AMD) and diabetic retinopathy (DR), leading causes of blindness, share a common retinal environment: hypoxia which is a major stimulator for the upregulation of vascular endothelial growth factor (VEGF), a cardinal pathogenic factor for the breakdown of blood-retina barrier (BRB). As a result of intensive studies on VEGF pathobiology, anti-VEGF strategy has become a major therapeutics for wet AMD and DR. To investigate the potential impact of anti-VEGF strategy on major retinal supporting cells, Müller glia (MG), we disrupted VEGF receptor-2 (VEGFR2) in MG with conditional knockout (CKO) and examined the effect of VEGFR2-null on MG viability and neuronal integrity in mice. VEGFR2 CKO mice demonstrated a significant loss of MG density in diabetes/hypoxia, which in turn resulted in accelerated retinal degeneration. These defects appear similar to the clinical characteristics in a significant portion of wet-AMD patients with long-term anti-VEGF therapies. In this article, we will discuss the potential relevance of these clinical characteristics to the critical role of VEGF signaling in MG viability and neuronal integrity in hypoxia.

Ahmed Valves vs Trabeculectomy Combined with Pans Plana Vitrectomy for Neovascular Glaucoma with Vitreous Hemorrhage.

PURPOSE: Vitreous hemorrhage is common in advanced neovascular glaucoma (NVG), which has poor visual prognosis. This study aimed to compare the efficacy of 23-G pars planar vitrectomy (PPV) combined with either Ahmed glaucoma valve (AGV) implantation or trabeculectomy after intravitreal ranibizumab (IVR) treatment for NVG with vitreous hemorrhage. METHODS: This retrospective, nonrandomized study included 33 eyes of 33 patients with NVG with vitreous hemorrhage. After IVR treatment for 3-7 days, 18 eyes underwent PPV + AGV (AGV group) and 15 underwent PPV + trabeculectomy (trabeculectomy group). The success criterion was a postoperative intraocular pressure (IOP) of 6-21 mm Hg, with or without antiglaucoma medication. RESULTS: Postoperative IOP decreased significantly in both groups, but the mean IOP after 12 months was significantly lower in the AGV group (16.92 ± 2.75 mm Hg) than the trabeculectomy group (21.50 ± 5.79 mm Hg; p = 0.018). The AGV group required fewer glaucoma medications than the trabeculectomy group. The cumulative probabilities of surgical success rates for the AGV and trabeculectomy groups at 12 months were 71.3% and 46.7%, respectively. No significant differences in postoperative complications were observed between the groups. CONCLUSIONS: For NVG with vitreous hemorrhage, PPV with AGV implantation may reduce IOP more effectively than PPV with trabeculectomy.

Müller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes.

To dissect the role of vascular endothelial growth factor receptor-2 (VEGFR2) in Müller cells and its effect on neuroprotection in diabetic retinopathy (DR), we disrupted VEGFR2 in mouse Müller glia and determined its effect on Müller cell survival, neuronal integrity, and trophic factor production in diabetic retinas. Diabetes was induced with streptozotocin. Retinal function was measured with electroretinography. Müller cell and neuronal densities were assessed with morphometric and immunohistochemical analyses. Loss of VEGFR2 caused a gradual reduction in Müller glial density, which reached to a significant level 10 months after the onset of diabetes. This observation was accompanied by an age-dependent decrease of scotopic and photopic electroretinography amplitudes and accelerated loss of rod and cone photoreceptors, ganglion cell layer cells, and inner nuclear layer neurons and by a significant reduction of retinal glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Our results suggest that VEGFR2-mediated Müller cell survival is required for the viability of retinal neurons in diabetes. The genetically altered mice established in this study can be used as a diabetic animal model of nontoxin-induced Müller cell ablation, which will be useful for exploring the cellular mechanisms of neuronal alteration in DR.

Simplified system to investigate alteration of retinal neurons in diabetes.

Diabetic retinopathy (DR) is traditionally considered as a microvascular complication in diabetic retinas. Emerging evidences suggest that the alteration of neuronal function and the death of retinal neurons are part of DR pathology. However, surprisingly little is known about how retinal neurons behave in DR. As diabetic animals are chronicle models that are difficult and expensive to maintain, we used a chemical hypoxia model that mimics the later stage of diabetes and investigated its potential in predicting retinal cell behaviors in diabetes in an efficient manner. In this chapter, we discuss the similarities and differences between diabetic and hypoxic models and the usefulness and limitation of the cobalt-chloride-generated hypoxia system in mice for studying retinal neurobiology in diabetes.

Cumulative association between age-related macular degeneration and less studied genetic variants in PLEKHA1/ARMS2/HTRA1: a meta and gene-cluster analysis.

The objective of this study is to examine the cumulative effect of the less studied genetic variants in PLEKHA1/ARMS2/HTRA1 on age-related macular degeneration (AMD). We performed an extensive literature search for studies on the association between AMD and the less studied genetic variants in PLEKHA1/ARMS2/HTRA1. Multiple meta-analyses were performed to evaluate the association between individual genetic variants and AMD. A gene-cluster analysis was used to investigate the cumulative effect of these less studied genetic variants on AMD. A total of 23 studies from 20 published papers met the eligibility criteria and were included in our analyses. Several genetic variants in the gene cluster are significantly associated with AMD in our meta-analyses or in individual studies. Gene-cluster analysis reveals a strong cumulative association between these genetic variants in this gene cluster and AMD (p < 10(-5)). However, two previously suspected SNPs in ARMS2, including rs2736911, the SNP having the largest number of studies in our meta-analyses; and rs3793917, the SNP with the largest sample size, were not significantly associated with AMD (both p's > 0.12). Sensitivity analyses reveal significant association of AMD with rs2736911 in Chinese but not in Caucasian, with c.372_815del443ins54 in Caucasian but not in Chinese, and with rs1049331 in both ethnic groups. These less studied genetic variants have a significant cumulative effect on wet AMD. Our study provides evidence of the joint contribution of genetic variants in PLEKHA1/ARMS2/HTRA1 to AMD risk, in addition to the two widely studied genetic variants whose association with AMD was well established.

No association of genetic variants in BDNF with major depression: a meta- and gene-based analysis.

Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random-effects meta-analysis to evaluate genetic variants in BDNF with MDD. A gene-based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta-analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89-1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67-1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74-1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18-5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85-1.14; P = 0.831) for rs988748. The gene-based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta- and novel gene-based analyses provide no evidence of the association of BDNF with major depression.

Activation of the ERK 1/2 and STAT3 signaling pathways is required for 661W cell survival following oxidant injury.

AIM: To evaluate the influence of hydrogen peroxide (H(2)O(2)) on mouse photoreceptor-derived 661W cell survival and to determine the effect of PD98059, an inhibitor for MEK1 (the direct upstream activator of ERK1/2), and S3I201, a STAT3- specific inhibitor on 661W cell survival after H(2)O(2) exposure. METHODS: The mouse photoreceptor-derived 661W cells were cultured. 661W cells were treated for 12 hours with different concentrations (0, 0.25, 0.50, 0.75, 1mmol/L) of H(2)O(2) and cell viability was determined by 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide ) (MTT) assay. 661W cells were treated with different concentrations H(2)O(2) (0, 5, 10, 50, 500, 1000 µmol/L) for 15 minutes or 1mmol/L H(2)O(2) for different time points (0,5,10,15,30 minutes), and p-Tyr705-STAT3, STAT3, Phospho-p44/42 MAPK (Thr202/Tyr204), ERK1/2 were surveyed by immunoblot analysis. After treatment with 50µmol/L PD98059, or S3I201 for 1 hour, the inhibition efficiency of cell signal pathways was analyzed by immunoblot analysis and the effects of inhibitors on cell viability were determined by MTT. RESULTS: After treating with different concentrations of H(2)O(2) for 12 hours, the cell viability of 661W cells decreased in concentration-dependent manner (P<0.05). Moreover, H(2)O(2) induced phosphorylation of ERK1/2 and STAT3 in 661W cells (P<0.05). After pretreatment with 50µmol/L PD98059 or S3I201 for 1 hour, H(2)O(2)-induced phosphorylation of ERK1/2 or STAT3 was suppressed separately (P<0.05). Using PD98059 or S3I201 to inhibit ERK1/2 or STAT3 signal pathway, the cell viability of 661W cells decreased significantly (P<0.05). CONCLUSION: We demonstrated that the exposure of 661W cells to H(2)O(2) increased the activation of ERK1/2 and STAT3 signal pathways. Activation of these pathways is required for 661W cell survival following oxidant injury.

No association of genetic polymorphisms in CYP1B1 with primary open-angle glaucoma: a meta- and gene-based analysis.

PURPOSE: To examine the effects of genetic polymorphisms in cytochrome P450, subfamily 1, polypeptide 1 (C1P1B1) on primary open-angle glaucoma (POAG). METHODS: A systematic literature search was performed, and random-effects meta-analyses were used to evaluate genetic polymorphisms in CYP1B1 with POAG. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in CYP1B1. RESULTS: A total of six studies from published papers were included in our analysis. Random-effects meta-analyses failed to detect any significant association of POAG with genetic polymorphisms in CYP1B1, including rs180040, rs1056836, rs10012, rs1056827, rs1056837, and rs2567206. The gene-based analysis indicated that the cumulative effect of genetic polymorphisms in CYP1B1 is not associated with POAG (p>0.50). CONCLUSIONS: We did not find any evidence of strong association of POAG with CYP1B1 genetic polymorphisms and their cumulative effect.

Genetic variants in FTO associated with metabolic syndrome: a meta- and gene-based analysis.

The objective of this study was to examine the effect of genetic variants in fat mass and obesity associated (FTO) gene on metabolic syndrome (MetS). A systematic literature search was performed and random-effects meta-analysis was used to evaluate genetic variants in FTO with MetS. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in FTO. A total of 18 studies from 13 published papers were included in our analysis. Random-effects meta-analysis yielded an estimated odds ratio of 1.19 (95% CI 1.12-1.27; P = 1.38 × 10(-7)) for rs9939609, 1.19 (95% CI 1.05-1.35; P = 0.008) for rs8050136, and 1.89 (95% CI 1.20-2.96; P = 0.006) for rs1421085. The gene-based analysis indicated that FTO is strongly associated with MetS (P < 10(-5)). This association remains after excluding rs9939609, a SNP that was frequently reported to have strong association with obesity and MetS. In this study, we concluded that the FTO gene may play a critical role in leading to MetS. Targeting this gene may provide novel therapeutic strategies for the prevention and treatment of metabolic syndrome.