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Chen C.,Shanghai JiaoTong University | Chen C.,Shanghai Key Laboratory of Fundus Disease | Sun Q.,Shanghai JiaoTong University | Sun Q.,Shanghai Key Laboratory of Fundus Disease | And 7 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2015

Background: To unravel the molecular genetic background responsible for autosomal dominant congenital pulverulent nuclear cataracts in a four-generation Chinese family. Methods: Family history data were collected, ophthalmological examinations were performed, and genomic DNA was extracted from peripheral blood of the family members. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. The structure modelling of the protein was displayed based on Swiss-Model Server, and its possible changes in the secondary structure were predicted using Antheprot 2000 software. The chemical dissimilarity and possible functional impact of an amino acid substitution were performed with Grantham score, PolyPhen-2, and SIFT predictions. Protein distributions were assessed by confocal microscopy. Results: A novel heterozygous c.829C > T transition that led to the substitution of a highly conserved histidine by tyrosine at codon 277 (p.H277Y) in the coding region of connexin50 (Cx50, GJA8) was identified. Bioinformatics analysis showed that the mutation likely altered the secondary structure of the protein by replacing the helix of the COOH-terminal portion with a turn. The mutation was predicted to be moderately conservative by Grantham score and to be deleterious by both PolyPhen-2 and SIFT with consistent results. In addition, when expressed in COS1 cells, the mutation led to protein accumulation and caused changes in Cx 50 protein localization pattern. Conclusions: This is a novel missense mutation [c.829C > T, (p.H277Y)] identified in exon 2 of Cx50. Our findings expand the spectrum of Cx50 mutations that are associated with autosomal dominant congenital pulverulent nuclear cataract. © 2015, Springer-Verlag Berlin Heidelberg.


Xu Y.,Shanghai JiaoTong University | Xu Y.,Shanghai Key Laboratory of Fundus Disease | Jin H.,Shanghai JiaoTong University | Jin H.,Shanghai Key Laboratory of Fundus Disease | And 12 more authors.
FEBS Letters | Year: 2014

Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation for the study of human endogenous anterior uveitis. The mechanisms accounting for the development of ocular inflammation remain hazy. MicroRNAs (mi-RNAs) have been proposed as novel regulators of inflammation. It remains unclear whether a microRNA-mediated regulatory mechanism is involved in LPS-induced EIU. In this study, we report that miR-93 expression in the eyes of EIU rats and LPS-stimulated macrophages is significantly decreased. We also show that miR-93 inhibits NF-κB activation and pro-inflammatory cytokines by targeting IRAK4 expression. We further demonstrate that miR-93 inhibits IRAK4 expression by binding directly to the 3′-UTR of IRAK4. Our findings suggest that miR-93 is a negative regulator of the immune response in EIU. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Lu X.,Shanghai JiaoTong University | Sun X.,Shanghai JiaoTong University | Sun X.,Shanghai Key Laboratory of Fundus Disease
Drug Design, Development and Therapy | Year: 2015

In developed countries, age-related macular degeneration (AMD) is the leading cause of irreversible blindness in individuals over the age of 65 years. Vascular endothelial growth factor (VEGF) plays a vital role in the formation of neovascular AMD. VEGF regulates angiogenesis, enhances vascular permeability, and drives the formation of choroidal neovascularization. As a result of the introduction of anti-VEGF drugs, the incidence of blindness from neovascular AMD has greatly reduced. Anti-VEGF drugs are used as a first-line treatment for neovascular AMD. The most recent anti-VEGF drug is conbercept, also named KH902, which was approved for the treatment of neovascular AMD by the China Food and Drug Administration in December 2013. In this review, recent clinical information regarding the use of conbercept to treat neovascular AMD is summarized. Conbercept is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF, which has a high binding affinity to VEGF and a long half-life in vitreous. Preclinical studies have demonstrated its anti-angiogenesis activity in both ocular neovascular disease models and tumor models. Clinical trials of conbercept have shown its superior efficacy and safety. Patients respond well even with 3-month treatment intervals following loading doses once a month for 3 months. The potential therapeutic effect of conbercept on the treatment of polypoidal choroidal vasculopathy, a special type of neovascular AMD, is also promising. In summary, conbercept is a new treatment option for ophthalmologists and their patients and may help address the limitations of current anti-VEGF drugs. © 2015 Lu and Sun.


Dong K.,Shanghai JiaoTong University | Zhu H.,Shanghai JiaoTong University | Song Z.,Shanghai JiaoTong University | Gong Y.,Shanghai JiaoTong University | And 8 more authors.
American Journal of Pathology | Year: 2012

Necroptosis is a recently discovered programmed necrosis. Evidence demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. In this study, we investigated the role of necrostatin-1 on photoreceptor survival and functional protection after experimental retinal detachment (RD) in rats. Necrostatin-1/inactive analogue of necrostatin-1 was introduced into the subretinal space at RD induction and 6 hours afterward, respectively. We found that necrostatin-1 attenuated retinal histopathological damage and reduced plasma membrane breakdown (a morphological hallmark of necroptosis) in outer retinal layers. Transmission electron microscopy showed that necrostatin-1 directly protected neurons by inhibiting necroptotic, not apoptotic, cell death. Treatment with necrostatin-1 inhibited the induction of receptor-interacting protein kinase phosphorylation after RD (a biomarker of necroptosis). Finally, electroretinographic recording proved that necrostatin-1 contributed to objective functional improvement after RD. These findings indicate that necrostatin-1 is a promising therapeutic agent that protects photoreceptors from necroptosis and improves functional outcome. © 2012 American Society for Investigative Pathology.


Wang L.,Shanghai JiaoTong University | Wang L.,Shanghai Key Laboratory of Fundus Disease | Xu Y.,Shanghai JiaoTong University | Xu Y.,Shanghai Key Laboratory of Fundus Disease | And 8 more authors.
Biochemical Pharmacology | Year: 2014

H-RN, a novel antiangiogenic peptide derived from the kringle 1 domain of hepatocyte growth factor (HGF), consists of the sequence RNPRGEEGGPW (molecular weight: 1254.34 Da). Emerging evidence indicates that HGF and the kringle domain exhibit anti-inflammatory effects in inflammatory diseases. In the present study, we assessed the anti-inflammatory effect of H-RN in models of experimental ocular inflammation, including endotoxin-induced uveitis (EIU) and experimental autoimmune uveitis (EAU). The results demonstrated that intravitreal treatment of H-RN concentration-dependently suppressed clinical manifestation, inhibited ocular inflammatory cytokine production and improved histopathologic scores. Moreover, H-RN attenuated the LPS-induced mRNA and protein expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW 264.7 cells and inhibited cell chemotactic migration toward LPS. We also demonstrated that H-RN suppressed TNF-α-induced adhesion molecule expression in HUVECs, including ICAM-1, VCAM-1 and E-selectin, which contributed to its suppressive effect on adherence of U937 cells to endothelial cells. We also demonstrated the possible anti-inflammation mechanism of H-RN. Western blot and immunofluorescence staining analyses revealed that H-RN significantly suppressed LPS-induced phosphorylation of nuclear factor (NF)-κB-p65 at Ser276. Based on examination of upstream pathways, we found that H-RN inhibited PI3K-p85 and AKTSer473 phosphorylation, which may result in the attenuation of LPS-induced IKK complex activation and IκB degradation. Thus, our studies suggest that the 11-amino-acid peptide H-RN exhibits anti-inflammatory effects in vitro and in vivo and may represent a promising candidate for ocular inflammatory diseases. © 2014 Elsevier Inc.


Yang X.,Shanghai JiaoTong University | Yang X.,Shanghai Key Laboratory of Fundus Disease | Jin H.,Shanghai JiaoTong University | Jin H.,Shanghai Key Laboratory of Fundus Disease | And 6 more authors.
PLoS ONE | Year: 2011

Background: Pancreatitis-associated protein (PAP) is a pancreatic secretory protein belongs to the group VII of C-type lectin family. Emerging evidence suggests that PAP plays a protective effect in inflammatory diseases. In the present study, we newly identified a 16-amino-acid peptide (named PAPep) derived from C-type lectin-like domain (CTLD) of human PAP with potent anti-inflammatory activity using both in vivo and in vitro assays. Methodology/Principal Findings: We assessed the anti-inflammatory effect of PAPep on endotoxin-induced uveitis (EIU) in rats and demonstrated that intravitreal pretreatment of PAPep concentration-dependently attenuated clinical manifestation of EIU rats, reduced protein leakage and cell infiltration into the aqueous humor (AqH), suppressed tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein (MCP)-1 production in ocular tissues, and improved histopathologic manifestation of EIU. Furthermore, PAPep suppressed the LPS-induced mRNA expression of TNF-α and IL-6 in RAW 264.7 cells, inhibited protein expression of ICAM-1 in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) as well as U937 cells adhesion to HUVECs. Western blot analysis in ocular tissues and different cell lines revealed that the possible mechanism for this anti-inflammatory effect of PAPep may depend on its ability to inhibit the activation of NF-kB signaling pathway. Conclusions/Significance: Our studies provide the first evidence that the sequence of PAPep is within the critically active region for the anti-inflammatory function of PAP and the peptide may be a promising candidate for the management of ocular inflammatory diseases. © 2011 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Feng J.,Shanghai JiaoTong University | Chen X.,Shanghai JiaoTong University | Sun X.,Shanghai JiaoTong University | Wang F.,Shanghai JiaoTong University | And 2 more authors.
Ophthalmic Research | Year: 2014

Aims: Age-related lipofuscin N-retinylidene-N-retinylethanolamine (A2E) accumulated in human retinal pigment epithelium (RPE) cells confers susceptibility to blue light-mediated damage, which represents one pathogenesis of age-related macular degeneration. This study investigated the expression of 2 best-characterized endoplasmic reticulum (ER) stress markers, glucose-related protein 78 (GRP78) and C/EBP homologous protein (CHOP), as well as their regulation by oxidative stress after blue light-mediated damage of A2E-containing RPE cells. Methods: ARPE-19 cells were incubated with A2E (10, 25, 50 μM) for 2 h and exposed to blue light for 20 min. A2E distributions in RPE cells were assessed via laser scanning confocal microscope and liquid chromatography-mass spectrometry. Cell viability was measured by a Cell Titer 96 Aqueous One Solution cell proliferation assay. The quantity of intracellular reactive oxygen species (ROS) was detected by dihydroethidium fluorescence using flow cytometry. Expressions of GRP78 and CHOP were measured at both mRNA and protein levels. To examine the role of oxidative stress in regulating GRP78 and CHOP expression, RPE cells were pretreated with the antioxidant N-acetylcysteine (NAC) for 2 h. RNA interference of GRP78 performed by short hairpin RNA was used to evaluate the effect of GRP78 in blue light-mediated damage of RPE cells. Results: After blue light exposure, A2E-treated RPE cells showed a gradual decrease in cell viability and a particular increase in ROS levels. Meanwhile, the expressions of GRP78 and CHOP in A2E-treated RPE cells were significantly increased at different time points after illumination. Pretreatment with NAC attenuated the expression of 2 ER stress markers, especially CHOP in A2E and blue light-treated RPE cells. Silencing of GRP78 by RNA interference upregulated CHOP and caspase-12 expression as well as aggravated the blue light-mediated damage of A2E-laden RPE cells. Conclusion: RPE cells exhibited ROS accumulation and subsequent elevation of GRP78 and CHOP expression after A2E and blue light-induced damage. The ROS scavenger NAC diminished ER stress protein expression, suggesting a connection between ER and oxidative stress in blue light-mediated damage of A2E-containing RPE cells. Besides, GRP78 may play a protective role in it. © 2014 S. Karger AG, Basel.


Zhou M.,Shanghai JiaoTong University | Zhou M.,Shanghai Key Laboratory of Fundus Disease | Wang W.,Sun Yat Sen University | Huang W.,Sun Yat Sen University | Zhang X.,Sun Yat Sen University
BMC Ophthalmology | Year: 2014

Background: To evaluate the surgical outcome of Ahmed glaucoma valve (AGV) implantation with a new technique of mitomycin C (MMC) application. Methods: This is a retrospective study. All patients with refractory glaucoma underwent FP-7 AGV implantation. Two methods of MMC application were used. In the traditional technique, 6 x 4 mm cotton soaked with MMC (0.25-0.33 mg/ml) was placed in the implantation area for 2-5mins; in the new technique, the valve plate first was encompassed with a thin layer of cotton soaked with MMC, then inserted into the same area. A 200 ml balanced salt solution was applied for irrigation of MMC. The surgical success rate, intraocular pressure (IOP), number of anti-glaucoma medications used, and postoperative complications were analyzed between the groups. Results: The surgical outcomes of two MMC applied techniques were compared. The new technique group had only one case (2.6%) of encapsulated cyst formation out of 38 eyes, while there were eight (19.5%) cases out of 41 eyes the in traditional group. The difference was statistically significant (P = 0.030). According to the definition of success rate, there was 89.5% in the new technique group and 70.7% in the traditional group at the follow-up end point. There was a significant difference between the two groups (P = 0.035). Mean IOP in the new technique group were significantly lower than those of the traditional group at 3 and 6 months (P < 0.05). Conclusions: By using a thin layer of cotton soaked with MMC to encompass the valve plate, the new MMC application technique could greatly decrease the incidence of encapsulated cyst and increase the success rate following AGV implantation. © 2014 Zhou et al.; licensee BioMed Central Ltd.


Sun Q.,Shanghai JiaoTong University | Sun Q.,Shanghai Key Laboratory of Fundus Disease | Xu X.,Shanghai JiaoTong University | Xu X.,Shanghai Key Laboratory of Fundus Disease
Current Medicinal Chemistry | Year: 2015

Despite progress in pharmacological modalities, treatments for ocular diseases are inconvenient, traumatic, costly and often end in poor final visual results. Peptides, considered as protein fragments, can adequately mimic protein binding and thus are used as therapeutic agents. Chemical modifications and bioengineering techniques are being frequently introduced to improve efficacy and stability of peptides, thereby improving their druggability. Cell-penetrating peptides (CPPs), peptides characterized by penetrating plasma membrane, are famous barrier- passers. They are good candidates for carrying drugs through ocular barriers. Therapeutic peptide and CPP perfectly complement each other. Once united, they may form an optimal formula for ocular topical administration, which can work both effectively and smartly. The consequent noninvasive delivery and economical cost would actualize prophylactic intervention, early treatment and long-term therapy to avoid chronic irreversible vision loss. The aim of the current review is a) to summarize recent therapeutic peptides, both anti-angiogenic and anti-inflammation, evidenced by animal experiments in vivo; b) to discuss the discovery strategies for therapeutic peptide; c) to present current delivery strategies for ophthalmic therapeutic peptide; and d) to introduce CPPs which are capable to deliver cargos to intraocular space via ocular surface administration. © 2015 Bentham Science Publishers.


Zhou M.,Shanghai JiaoTong University | Zhou M.,Shanghai Key Laboratory of Fundus Disease | Zhang P.,Shanghai JiaoTong University | Zhang P.,Shanghai Key Laboratory of Fundus Disease | And 4 more authors.
Investigative Ophthalmology and Visual Science | Year: 2015

PURPOSE. Studies investigating the associations between aldose reductase (ALR) genetic polymorphisms and diabetic retinopathy (DR) have reported controversial results. Therefore, to shed light on these inconclusive findings, we performed this meta-analysis to clarify the effects of ALR C(-106)T polymorphism on DR risk. METHODS. Relevant studies were selected through an extensive search of PubMed, EMBASE, the Web of Science databases and Chinese National Knowledge Infrastructure, VIP, and Wan Fang databases in Chinese. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated by using random-effects model. RESULTS. The present meta-analysis included 3512 diabetes mellitus (DM) patients with DR and 4319 DM patients without DR. Overall, the pooled ORs showed a nonsignificant association between ALR C(-106)T polymorphism and DR susceptibility in all genetic models (C allele versus T allele: OR = 1.08, 95% CI = 0.90-1.29; CT/TT versus CC: OR = 0.90, 95% CI = 0.72-1.13; TT versus CT/CC: OR = 0.87, 95% CI = 0.69-1.10; TT versus CC: OR = 0.87, 95% CI = 0.64-1.18; CT versus CC: OR = 0.93, 95% CI = 0.73-1.19). No significant association was detected between ALR C(-106)T polymorphism and nonproliferative diabetic retinopathy or proliferative diabetic retinopathy. An additional analysis showed that the association of C(-106)T polymorphism with DR was significant in type 1 DM (C allele versus T allele: OR = 1.78, 95% CI = 1.39-2.28; CT/TT versus CC: OR = 0.49, 95% CI = 0.36-0.68; TT versus CT/CC: OR = 0.48, 95% CI = 0.28-0.84; TT versus CC: OR = 0.33, 95% CI = 0.17-0.67; CT versus CC: OR = 0.52, 95% CI = 0.37-0.74) but not in type 2 DM. CONCLUSIONS. The results of this meta-analysis showed that ALR C(-106)T polymorphism was not associated with an increased risk of DR. However, subgroup analysis showed a genetic association between ALR C(-106)T polymorphism and the risk of DR of type 1 DM but not DR of type 2 DM. © 2015 The Association for Research in Vision and Ophthalmology, Inc.

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