Dongqing Yuan

Suppression of experimental choroidal neovascularization by curcumin in mice.

Purpose To investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms. Methods C57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting. Results Curcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05). Conclusion Curcumin treatment led to the suppression of CNV development together with inflammatory and angiogenic processes including NF-κB and HIF−1α activation, the up-regulation of inflammatory and angiogenic cytokines, and infiltrating macrophages and granulocytes. This provides molecular and cellular evidence of the validity of curcumin supplementation as a therapeutic strategy for the suppression of age-related macular degeneration (AMD)-associated CNV.

Association between variants A69S in ARMS2 gene and response to treatment of exudative AMD: a meta-analysis

A study was undertaken to investigate the association between A69S in age-related maculopathy susceptibility 2 (ARMS2) and the response to anti-angiogenesis treatment in exudative age-related macular degeneration (AMD). A literature-based meta-analysis was performed of studies relevant to A69S and the response to anti-angiogenesis treatment. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI) and Sinomed databases were used to retrieve articles up to July 2014. Pooled ORs and 95% CIs were estimated using fixed and random effects models in Stata V.9.0. Q-statistic testing was used to assess heterogeneity. Twelve articles comprising 2389 cases were included in the final meta-analysis. The analysis of the overall population indicated a statistically significant association between A69S and the response to anti-angiogenesis treatment in exudative AMD (GG vs TT: OR 1.34 (95% CI 1.01 to 1.77), p=0.039; GT vs TT: OR 1.58 (95% CI 1.08 to 2.31), p=0.018; GG+GT vs TT: OR 1.74 (95% CI 1.19 to 2.52), p=0.004). In subgroup analysis, A69S appeared more likely to be a predictor for anti-angiogenic response in the East Asian population (GG vs TT: OR 1.65 (95% CI 1.02 to 2.68), p=0.042; GT vs TT: OR 1.66 (95% CI 1.17 to 2.37), p=0.005; GG+GT vs TT: OR 1.82 (95% CI 1.07 to 3.10), p=0.027; G vs T: OR 1.56 (95% CI 1.01 to 2.41)). However, no statistical significance was found in the Caucasian subgroup analysis. This study shows an association between A69S polymorphism in the ARMS2 gene and the anti-angiogenesis treatment response. A69S could be considered predictive of the anti-angiogenic effects, especially in Asian populations.

The Age-related Maculopathy Susceptibility 2 Polymorphism and Polypoidal Choroidal Vasculopathy in Asian Populations: A Meta-Analysis

OBJECTIVE To assess the role of the age-related maculopathy susceptibility 2 (ARMS2) A69S polymorphism as a risk factor for polypoidal choroidal vasculopathy (PCV) in Asian populations. METHODS We performed a meta-analysis of the association of the A69S variant with PCV in Asian populations using data available from 14 case-control studies involving 6552 subjects. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Sensitivity analysis also was performed. MAIN OUTCOME MEASURES Understanding the relationship between the A69S variant and PCV is essential to provide new insights into pathophysiology and potential targets for intervention of PCV. RESULTS The pooled OR in random-effects models for genotype TG+TT versus wild homozygous genotype GG is 2.39 (95% CI, 1.98-2.89), the OR of heterozygous genotype TG versus GG is 1.66 (95% CI, 1.37-2.00), the OR of homozygous genotype TT versus GG is 4.74 (95% CI, 3.94-5.70), and the OR of allele T versus G is 2.14 (95% CI, 1.79-2.56). A sensitivity analysis indicated the robustness of our findings. CONCLUSIONS Our analysis provides evidence that the A69S variant is associated with an increased risk of PCV in Asian populations. The variant of A69S could be a promising genetic biomarker of PCV. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Face-down or no face-down posturing following macular hole surgery: a meta-analysis.

To evaluate the impact of postoperative posturing with or without face‐down on the anatomical and functional outcomes of macular hole surgery.

Protective Effects of Astragaloside IV on db/db Mice with Diabetic Retinopathy

Objectives Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the potential biological functions of astragaloside IV (AS IV) have long been described in traditional system of medicine, its protective effect on DR remains unclear. This study aims to investigate the function and mechanism of AS IV on type 2 diabetic db/db mice. Methods Db/db mice were treated with AS IV (4.5 mg/kg or 9 mg/kg) or physiological saline by oral gavage for 20 weeks along with db/m mice. In each group, retinal ganglion cell (RGC) function was measured by pattern electroretinogram (ERG) and apoptosis was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Blood and retina aldose reductase (AR) activity were quantified by chemiluminescence analysis. The expressions of phosporylated-ERK1/2, NF-κB were determined by Western blot analysis. Furthermore, the expression of related downstream proteins were quantified by Label-based Mouse Antibody Array. Results Administration of AS IV significantly improved the amplitude in pattern ERG and reduced the apoptosis of RGCs.in db/db mice. Furthermore, downregulation of AR activity, ERK1/2 phosphorylation, NF-κB and related cytokine were observed in AS IV treatment group. Conclusions Our study indicated that AS IV, as an inhibitor of AR, could prevent the activation of ERK1/2 phosporylation and NF-kB and further relieve the RGCs disfunction in db/db mice with DR. It has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing DR.

Edaravone Protect against Retinal Damage in Streptozotocin-Induced Diabetic Mice

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.

Association of the Receptor for Advanced Glycation End Products Gene Polymorphisms with Diabetic Retinopathy in Type 2 Diabetes: A Meta-Analysis

Aims: To investigate the association between diabetic retinopathy (DR) in type 2 diabetes mellitus and three polymorphisms of the receptor for advanced glycation end products (RAGE) gene, –429T/C, –374T/A and Gly82Ser. Methods: A literature search was conducted through PubMed and Web of Science (up to August 31, 2011). Pooled odds ratios (ORs) were estimated using fixed-effects (FE) and random-effects (RE) models in co-dominant, recessive and dominant models. A sensitivity analysis was performed by excluding invalid studies. Results: Six articles investigated the –429T/C polymorphism, 7 publications were associated with the –374T/A polymorphism and 5 studies were associated with Gly82Ser in DR. For the –429T/C variant, we found no significant difference between DR patients and those with diabetes without retinopathy. A significant association of allele A with DR was found in the recessive model for the –374T/A variant (RE OR = 0.64, 95% CI = 0.42–0.99, p = 0.05, p heterogeneity = 0.55). In the recessive and co-dominant models for the Gly82Ser polymorphism, the pooled ORs were positive in the fixed-effects model (FE OR = 2.89, 95% CI = 1.49–5.60, p = 0.002, p heterogeneity = 0.20; and FE OR = 3.45, 95% CI = 1.76–6.67, p = 0.0003, p heterogeneity = 0.07, respectively), but in the random-effects model the results were negative. Conclusions: Our research confirmed an association between the RAGE –374T/A polymorphism and retinopathy in subjects with type 2 diabetes and the –374AA allele was found to be a protective factor for type 2 diabetes. Otherwise, the RAGE Gly82Ser polymorphism might be considered a significant risk for DR in Asian populations.

Application of 3-dimensional printing technology to construct an eye model for fundus viewing study.

Objective To construct a life-sized eye model using the three-dimensional (3D) printing technology for fundus viewing study of the viewing system. Methods We devised our schematic model eye based on Navarros eye and redesigned some parameters because of the change of the corneal material and the implantation of intraocular lenses (IOLs). Optical performance of our schematic model eye was compared with Navarros schematic eye and other two reported physical model eyes using the ZEMAX optical design software. With computer aided design (CAD) software, we designed the 3D digital model of the main structure of the physical model eye, which was used for three-dimensional (3D) printing. Together with the main printed structure, polymethyl methacrylate(PMMA) aspherical cornea, variable iris, and IOLs were assembled to a physical eye model. Angle scale bars were glued from posterior to periphery of the retina. Then we fabricated other three physical models with different states of ammetropia. Optical parameters of these physical eye models were measured to verify the 3D printing accuracy. Results In on-axis calculations, our schematic model eye possessed similar size of spot diagram compared with Navarros and Bakarajus model eye, much smaller than Arianpours model eye. Moreover, the spherical aberration of our schematic eye was much less than other three model eyes. While in off- axis simulation, it possessed a bit higher coma and similar astigmatism, field curvature and distortion. The MTF curves showed that all the model eyes diminished in resolution with increasing field of view, and the diminished tendency of resolution of our physical eye model was similar to the Navarros eye. The measured parameters of our eye models with different status of ametropia were in line with the theoretical value. Conclusions The schematic eye model we designed can well simulate the optical performance of the human eye, and the fabricated physical one can be used as a tool in fundus range viewing research.

Genetic Association with Response to Intravitreal Ranibizumab for Neovascular Age-Related Macular Degeneration in the Han Chinese Population

Purpose: To investigate a possible association between gene variants and patient response to treatment with intravitreal ranibizumab for neovascular age-related macular degeneration (AMD). Methods: Visual acuity score (VAS) was recorded at baseline and a subsequent visit at 6 months. Genotypes of 3 polymorphisms in known AMD susceptibility loci (rs1061170 in complement factor H (CFH), rs11200638 in HTRA1 and rs1413711 in VEGF) were determined. Central retinal thickness and maximum thickness of the lesion were also measured. Results: A total of 168 neovascular AMD patients treated with intravitreal ranibizumab were included in our study. For HTRA1 rs11200638, mean VAS changes were 3.5, 9.4 and 10.6 letters for the AA, AG and GG genotypes, respectively (p = 0.022). In contrast, for CFH rs1061170 and VEGF rs1413711, mean VAS changes were not significant. However, there was no significant difference in the changes in central retinal thickness and maximum lesion thickness among the genotypes of the tested single-nucleotide polymorphisms. Conclusions: HTRA1 gene polymorphism may influence patient response to treatment with intravitreal ranibizumab for neovascular AMD.

Pharmacokinetics of HM-3 After Intravitreal Administration in Mice

Abstract Purpose: HM-3, an RGD-modified endostatin-derived polypeptide, is a potent angiogenesis inhibitor synthesized in our laboratory. This study investigated the HM-3 pharmacokinetics of intravitreally administered in mice eyes as an anti-angiogenesis drug for age-related macular degeneration. Materials and methods: A total of 288 C57BL/6J mice were evaluated and divided into four groups. Each mouse in different groups received single bilateral intravitreal injection with HM-3. The concentrations of HM-3 in choroid/sclera, retina and serum were determined by indirect competitive enzyme-linked immunosorbent assay. Results: After intravitreal administration of doses of 0, 10, 20 and 40 μg/eye HM-3, the observed maximum concentration (Cmax) was 12.98 ± 1.42, 27.87 ± 3.64 and 55.96 ± 11.94 ng/mg, respectively; and the total area under the curve (AUCtot) was 739.23 ± 190.32, 1171.74 ± 528.75 and 1777.71 ± 511.64 h ng/mg; the elimination half-life (T1/2) in retina was 104.85 ± 36.90, 107.42 ± 35.25 and 101.12 ± 15.82 h; the mean residence time (MRT) was 172.46 ± 63.80, 164.70 ± 52.72 and 181.32 ± 26.01 h, respectively. In choroid/sclera, the Cmax was 5.29 ± 0.34, 6.29 ± 1.87 and 8.14 ± 0.71 ng/mg, respectively; AUCtot was 579.03 ± 56.50, 762.20 ± 201.09 and 720.91 ±243.87 h ng/mg; T1/2 was 54.04 ± 25.99, 59.33 ± 24.46 and 47.10 ± 10.00 h, respectively; MRT was 139.98 ± 23.93, 155.43 ± 17.81 and 136.45 ± 18.17 h, respectively. But in serum, the Cmax was 482.00 ± 38.97, 493.94 ± 97.64 and 1033.10 ± 276.33 ng/ml, respectively; AUCtot was 21128.55 ± 4683.68, 53444.57 ± 16963.99 and 53164.84 ±1535.06 h ng/ml; T1/2 was 48.39 ± 14.89, 47.96 ± 12.97 and 49.98 ± 30.07 h, respectively; MRT was 108.6 ± 47.17, 159.76 ± 18.82 and 125.33 ± 21.41 h, respectively. Conclusions: The pharmacokinetic profiles of intravitreal administration HM-3 provide the basis for the development of reasonable dosing regimens of clinical choroidal neovascularization (CNV) treatment. However, the vitreous and blood retinal barrier might be barriers to drug distribution and diffusion. In addition, fluid flow for the anterior transport and choroidal blood circulation might play important roles for multiple peaking. Carrying out the research into pharmacokinetics of HM-3 provides the information for laying down drug delivery scheme in mice model of CNV.