The comparison of two different strategies of intravitreal conbercept for polypoidal choroidal vasculopathy in Chinese patients results from a 48-week randomized phase 4 study: STAR study.

PURPOSE: To compare a treat-and-extend (TAE) strategy with a fixed dosing regimen of intravitreal conbercept (IVC) for the management of treatment-naïve polypoidal choroidal vasculopathy (PCV) patients. METHODS: 249 patients with treatment-naïve PCV were randomized 1:1 to fixed dosing regimen with injections every 12 weeks (3 + Q12W) group or treat-and-extend regimen(3 + TAE) group. Patients received 3 monthly intravitreal injections of 0.5 mg conbercept as loading dose in both groups. The 3 + Q12W patients were monitored monthly and received mandated injections every 12 weeks; the 3 + TAE patients were monitored and treated monthly until the resolution of exudative disease activity; the interval between visits was then individualized according to study protocol. Visual and anatomical outcomes were compared between the two groups. RESULTS: At 48 weeks, there was no significant difference between the 3 + Q12W group and 3 + TAE group in mean BCVA improvement (p = 0.421), mean changes in central retinal thickness (CRT) (p = 0.818), maximum retinal thickness (MRT) (p = 0.448), pigment epithelial detachment (PED) height (p = 0.221), PED volume (p = 0.076), branching vascular network (BVN) area (p = 0.615), polypoidal lesion number (p = 0.701), polypoidal lesion area (p = 0.424), rates of patients who avoided vision loss of ≥15 ETDRS letters (p = 0.397) or complete polypoidal lesion regression rate (43.8% vs. 41.8%, p = 0.814). The 3 + Q12W group had more decreased retinal haemorrhage area (p = 0.014) and fewer mean numbers of injections comparing with 3 + TAE group (6.6 vs. 9.4, p < 0.001). Mean maximum extension interval between injections after loading injections was 9.6 ± 2.0 weeks for 3 + TAE group, with 27.8% of patients achieving an extension interval of 12 weeks and 61.1% patients 8 weeks or more. CONCLUSIONS: Both 3 + Q12W and 3 + TAE regimens of IVC could result in improvement in visual and anatomical outcomes in PCV patients.

Safety and Efficacy of Systemic Anti-Scg3 Therapy to Treat Oxygen-Induced Retinopathy.

BACKGROUND: To circumvent possible systemic side effects, anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) for ocular neovascular diseases in adults are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects, and premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor and that systemic anti-Scg3 mAb alleviates ROP in animal models with minimal side effects on developing eyes and organs. The aim of this study is to investigate the safety and efficacy of a humanized anti-Scg3 antibody via systemic administration. METHODS: We analyzed the safety and efficacy of a humanized anti-Scg3 antibody Fab fragment (hFab) delivered by intraperitoneal injection in oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP. RESULTS: The results showed that systemic anti-Scg3 hFab effectively alleviated pathological retinal neovascularization in OIR mice with similar efficacy to the anti-VEGF drug aflibercept. Systemic aflibercept conferred significant adverse side effects in neonatal mice, including reduced body weight, abnormalities in retinal and renal development, and retarded physiological neovascularization, whereas systemic anti-Scg3 hFab elicited no such side effects. CONCLUSIONS: The findings suggest that systemic anti-Scg3 hFab is a safe and effective therapy for OIR and support further development for ROP treatment.

Neurovascular abnormalities in retinopathy of prematurity and emerging therapies.

Blood vessels in the developing retina are formed in concert with neural growth, resulting in functional neurovascular network. Disruption of the neurovascular coordination contributes to the pathogenesis of retinopathy of prematurity (ROP), a potentially blinding retinal neovascular disease in preterm infants that currently lacks an approved drug therapy in the USA. Despite vasculopathy as predominant clinical manifestations, an increasing number of studies revealed complex neurovascular interplays among neurons, glial cells and blood vessels during ROP. Coordinated expression of glia-derived vascular endothelial growth factor (VEGF) in spatio-temporal gradients is pivotal to the formation of well-organized vascular plexuses in the healthy retina, whereas uncoordinated VEGF expression triggers pathological angiogenesis with disorganized vascular tufts in ROP. In contrast with VEGF driving both pathological and physiological angiogenesis, neuron-derived angiogenic factor secretogranin III (Scg3) stringently regulates ROP but not healthy retinal vessels in animal models. Anti-VEGF and anti-Scg3 therapies confer similar high efficacies to alleviate ROP in preclinical studies but are distinct in their disease selectivity and safety. This review discusses neurovascular communication among retinal blood vessels, neurons and glial cells during retinal development and ROP pathogenesis and summarizes the current and emerging therapies to address unmet clinical needs for the disease.

Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.

Iron-induced oxidative stress can cause or exacerbate retinal degenerative diseases. Retinal iron overload has been reported in several mouse disease models with systemic or neural retina-specific knockout (KO) of homologous ferroxidases ceruloplasmin (Cp) and hephaestin (Heph). Cp and Heph can potentiate ferroportin (Fpn) mediated cellular iron export. Here, we used retina-specific Fpn KO mice to test the hypothesis that retinal iron overload in Cp/Heph DKO mice is caused by impaired iron export from neurons and glia. Surprisingly, there was no indication of retinal iron overload in retina-specific Fpn KO mice: the mRNA levels of transferrin receptor in the retina were not altered at 7-10-months age. Consistent with this, levels and localization of ferritin light chain were unchanged. To "stress the system", we injected iron intraperitoneally into Fpn KO mice with or without Cp KO. Only mice with both retina-specific Fpn KO and Cp KO had modestly elevated retinal iron levels. These results suggest that impaired iron export through Fpn is not sufficient to explain the retinal iron overload in Cp/Heph DKO mice. An increase in the levels of retinal ferrous iron caused by the absence of these ferroxidases, followed by uptake into cells by ferrous iron importers, is most likely necessary.

Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.

Intraocular iron injection induces oxidative stress followed by elements of geographic atrophy and sympathetic ophthalmia.

Iron has been implicated in the pathogenesis of age-related retinal diseases, including age-related macular degeneration (AMD). Previous work showed that intravitreal (IVT) injection of iron induces acute photoreceptor death, lipid peroxidation, and autofluorescence (AF). Herein, we extend this work, finding surprising chronic features of the model: geographic atrophy and sympathetic ophthalmia. We provide new mechanistic insights derived from focal AF in the photoreceptors, quantification of bisretinoids, and localization of carboxyethyl pyrrole, an oxidized adduct of docosahexaenoic acid associated with AMD. In mice given IVT ferric ammonium citrate (FAC), RPE died in patches that slowly expanded at their borders, like human geographic atrophy. There was green AF in the photoreceptor ellipsoid, a mitochondria-rich region, 4 h after injection, followed later by gold AF in rod outer segments, RPE and subretinal myeloid cells. The green AF signature is consistent with flavin adenine dinucleotide, while measured increases in the bisretinoid all-trans-retinal dimer are consistent with the gold AF. FAC induced formation carboxyethyl pyrrole accumulation first in photoreceptors, then in RPE and myeloid cells. Quantitative PCR on neural retina and RPE indicated antioxidant upregulation and inflammation. Unexpectedly, reminiscent of sympathetic ophthalmia, autofluorescent myeloid cells containing abundant iron infiltrated the saline-injected fellow eyes only if the contralateral eye had received IVT FAC. These findings provide mechanistic insights into the potential toxicity caused by AMD-associated retinal iron accumulation. The mouse model will be useful for testing antioxidants, iron chelators, ferroptosis inhibitors, anti-inflammatory medications, and choroidal neovascularization inhibitors.

Concurrent Physiological and Pathological Angiogenesis in Retinopathy of Prematurity and Emerging Therapies.

Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.

Therapeutic potential of curcumin in diabetic retinopathy (Review).

Diabetic retinopathy (DR) is a type of retinal microangiopathy caused by diabetes mellitus. It has become the leading cause of blindness among working individuals worldwide. DR is becoming increasingly common among younger diabetic patients and there is a need for lifelong treatment. The pathogenic mechanisms of DR are influenced by a number of factors, such as hyperglycemia, hyperlipidemia, inflammatory response and oxidative stress, among others. Currently, the treatment methods for DR mainly include retinal photocoagulation, vitrectomy, or anti­vascular endothelial growth factor (VEGF) therapy. However, these methods have some disadvantages and limitations. Therefore, it is a matter of great interest and urgency to discover drugs that can target the pathogenesis of DR. Since ancient times, traditional Chinese medicine practitioners have accumulated extensive experiences in the use of Chinese herbal medicine for the prevention and treatment of diseases. In the theory of traditional Chinese medicine, curcumin has the effects of promoting blood circulation and relieving pain. A number of studies have also demonstrated that curcumin has multiple biological activities, including exerting anti­apoptotic, anti­inflammatory, antioxidant and antitumor properties. In recent years, studies have also confirmed that curcumin can prevent a variety of diabetic complications, including diabetic nephropathy (DN). However, the preventive and curative effects of curcumin on DR and its mechanisms of action have not yet been fully elucidated. The present review aimed to explore the therapeutic potential of curcumin in diabetes mellitus and DR.

Analysis of risk factors for progressive fibrovascular proliferation in proliferative diabetic retinopathy.

PURPOSE: To investigate the risk factors associated with progressive fibrovascular proliferation (FVP) in proliferative diabetic retinopathy (PDR). METHODS: We retrospectively reviewed the clinical data of patients who underwent pars plana vitrectomy for PDR between August 2017 and October 2019 at our department of ophthalmology. The FVP was divided into five grades based on the coverage area of proliferative membrane. Then we compared the patients with different severities of FVP to analyze the risk factors for higher grade of FVP in PDR. RESULTS: Univariate analysis showed that positive urinary protein (p = 0.007), higher levels of serum blood urea nitrogen (BUN) (p < 0.001) and serum creatinine (p < 0.001), more severe stage of estimated glomerular filtration rate (p < 0.001), age < 45 years (p = 0.005), longer duration of diabetic retinopathy (p = 0.007), history of hypertension (p = 0.034) and smoking (p = 0.008) were related to FVP grade ≥ 3. Multivariate analysis showed that the level of BUN, age < 45 years and smoking were independent risk factors for FVP grade ≥ 3 in PDR patients. CONCLUSION: This study demonstrated that BUN (odds ratio [OR] = 1.318, 95% confidence interval [CI] = 1.150-1.511, p < 0.001), age ≤ 45 years (OR = 3.774, 95% CI = 1.762-8.082, p = 0.001) and smoking (OR = 2.111, 95% CI = 1.040-4.288, p = 0.039) were independent risk factors for progressive FVP in PDR among northeastern Chinese patients.

Bone marrow mesenchymal stem cells enhance autophagy and help protect cells under hypoxic and retinal detachment conditions.

Our study aimed to evaluate the protective role and mechanisms of bone marrow mesenchymal stem cells (BMSCs) in hypoxic photoreceptors and experimental retinal detachment. The cellular morphology, viability, apoptosis and autophagy of hypoxic 661w cells and cells cocultured with BMSCs were analysed. In retinal detachment model, BMSCs were intraocularly transplanted, and then, the retinal morphology, outer nuclear layer (ONL) thickness and rhodopsin expression were studied as well as apoptosis and autophagy of the retinal cells. The hypoxia-induced apoptosis of 661w cells obviously increased together with autophagy levels increasing and peaking at 8 hours after hypoxia. Upon coculturing with BMSCs, hypoxic 661w cells had a better morphology and fewer apoptosis. After autophagy was inhibited, the apoptotic 661w cells under the hypoxia increased, and the cell viability was reduced, even in the presence of transplanted BMSCs. In retina-detached eyes transplanted with BMSCs, the retinal ONL thickness was closer to that of the normal retina. After transplantation, apoptosis decreased significantly and retinal autophagy was activated in the BMSC-treated retinas. Increased autophagy in the early stage could facilitate the survival of 661w cells under hypoxic stress. Coculturing with BMSCs protects 661w cells from hypoxic damage, possibly due to autophagy activation. In retinal detachment models, BMSC transplantation can significantly reduce photoreceptor cell death and preserve retinal structure. The capacity of BMSCs to reduce retinal cell apoptosis and to initiate autophagy shortly after transplantation may facilitate the survival of retinal cells in the low-oxygen and nutrition-restricted milieu after retinal detachment.

Protein Expression Profile on Differentiation of Bone Marrow Mesenchymal Stem Cells into Retinal Ganglion-Like Cells.

To explore possible approaches to differentiating rat bone marrow mesenchymal stem cells (BMSCs) into retinal ganglion-like cells and to demonstrate the dynamic changes in protein expression profiles of BMSCs throughout the differentiation. BMSCs were isolated from adult rats and cultured in medium conditioned by neonatal rat retinal cells to induce BMSC differentiation into retinal ganglion-like cells. Immunostaining for neurofilament, nestin, Map2, and Thy1.1 was used to follow the differentiation process. Two types of protein arrays were employed to profile the BMSCs, the differentiated retinal ganglion-like cells, and the primary retinal ganglion cells (RGCs) using the Biomarker Wizard System. After 7 days of culture in conditioned medium, cells showing a neural-cell-like modality appeared. The differentiated retinal ganglion-like cells showed that network-like connections were positive for nestin, neurofilament, Map2, and Thy1.1. In total, 16 marker proteins were highly expressed in both retinal ganglion-like cells and RGCs and no obvious expression was observed in BMSCs. Among them, nine proteins were expressed more highly in RGCs than in retinal ganglion-like cells. BMSCs can be induced to differentiate into retinal ganglion-like cells by neonatal rat retinal cells, and the induced cells show protein profiles resembling those of isolated RGCs.

NANOG Attenuates Hair Follicle-Derived Mesenchymal Stem Cell Senescence by Upregulating PBX1 and Activating AKT Signaling.

Stem cells derived from elderly donors or harvested by repeated subculture exhibit a marked decrease in proliferative capacity and multipotency, which not only compromises their therapeutic potential but also raises safety concerns for regenerative medicine. NANOG-a well-known core transcription factor-plays an important role in maintaining the self-renewal and pluripotency of stem cells. Unfortunately, the mechanism that NANOG delays mesenchymal stem cell (MSC) senescence is not well-known until now. In our study, we showed that both ectopic NANOG expression and PBX1 overexpression (i) significantly upregulated phosphorylated AKT (p-AKT) and PARP1; (ii) promoted cell proliferation, cell cycle progression, and osteogenesis; (iii) reduced the number of senescence-associated-ß-galactosidase- (SA-ß-gal-) positive cells; and (iv) downregulated the expression of p16, p53, and p21. Western blotting and dual-luciferase activity assays showed that ectopic NANOG expression significantly upregulated PBX1 expression and increased PBX1 promoter activity. In contrast, PBX1 knockdown by RNA interference in hair follicle- (HF-) derived MSCs that were ectopically expressing NANOG resulted in the significant downregulation of p-AKT and the upregulation of p16 and p21. Moreover, blocking AKT with the PI3K/AKT inhibitor LY294002 or knocking down AKT via RNA interference significantly decreased PBX1 expression, while increasing p16 and p21 expression and the number of SA-ß-gal-positive cells. In conclusion, our findings show that NANOG delays HF-MSC senescence by upregulating PBX1 and activating AKT signaling and that a feedback loop likely exists between PBX1 and AKT signaling.

Autophagy, lysosome dysfunction and mTOR inhibition in MNU-induced photoreceptor cell damage.

Progressive photoreceptor death is the main cause of retinal degeneration diseases. Determining the underlying mechanism of this process is essential for therapy improvement. Autophagy has long been considered to be involved in neuronal degeneration diseases, and the regulation of autophagy is thought to have potential implications for neurodegenerative disease therapies. However, whether autophagy is protective or destructive varies among diseases and is controversial. In the present study, we established an N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell damage model in vitro that faithfully replicated photoreceptor cell death in retinal degeneration diseases. Cell viability was tested by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays. Reactive oxygen species (ROS) levels were assessed through 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence. Autophagy was confirmed by observing autophagosomes using transmission electron microscopy (TEM). A lysosome tracker was used to identify acidic lysosomes in cells. We also measured the expression of some proteins related to autophagy, apoptosis and lysosomal degradation by western blot and immunofluorescence assays. We found that MNU could decrease photoreceptor cell viability in a time- and dose-dependent manner, and this change was accompanied by concomitant increases in ROS and the expression of the apoptosis-inducing protein cleaved caspase-3. Moreover, autophagy was activated by MNU treatment during this process. Inhibition of autophagy with 3-methyladenine accelerated cell damage. Lysosome dysfunction was confirmed by autophagosome enlargement and increased cathepsin expression, which was accompanied by mTOR dephosphorylation. In conclusion, autophagy was activated through inhibition of the PI3K/mTOR pathway in the context of MNU-induced photoreceptor cell death. Prolonged mTOR dephosphorylation and autophagy activation resulted in autophagic vacuole accumulation, as indicated by inefficient degradation in lysosomes, and further led to apoptosis.

Regulatory mechanisms of Robo4 and their effects on angiogenesis.

Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis.

Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy.

Retinal cell damage caused by diabetes leads to retinal microvascular injury. Roundabout 4 (ROBO4) is involved in angiogenesis, which varies with the development of diabetic retinopathy (DR). Here, we explored the transcriptional regulation and microRNA-mediated modulation of ROBO4 expression and related retinal cell function in DR. A streptozotocin-induced type I diabetic animal model was established to detect the expression of hypoxia inducible factor-1α (HIF-1α), specificity protein 1 (SP1) and ROBO4. Retinal pigment epithelium (RPE) cells were cultured under hyperglycaemia or hypoxia and used for mechanistic analysis. Furthermore, roles of miR-125b-5p and miR-146a-5p were evaluated, and their targets were identified using luciferase assays. The cell functions were evaluated by MTS assays, permeability analysis and migration assays. The development of DR increased the levels of HIF-1α, SP1 and ROBO4 both in the DR model and in hyperglycaemic/hypoxic RPE cells. They were co-expressed and up-regulated in diabetic retinas and in RPE cells under hyperglycaemia/hypoxia. Knockdown of HIF-1α significantly inhibited SP1 and ROBO4, whereas SP1 down-regulation abolished ROBO4 expression in RPE cells under hyperglycaemia/hypoxia. miR-125b-5p and miR-146a-5p were down-regulated by hyperglycaemia and/or hypoxia. Up-regulation of miRNAs reversed these changes and resulted in recovery of target gene expression. Moreover, luciferase assays confirmed miR-125b-5p targeted SP1 and ROBO4, and miR-146a-5p targeted HIF-1α and ROBO4 directly. The decreased cell viability, enhanced permeability, and increased cell migration under DR conditions were mitigated by knockdown of HIF-1α/SP1/ROBO4 or up-regulation of miR-125b-5p/miR-146a-5p. In general, our results identified a novel mechanism that miR-125b-5p/miR-146a-5p targeting HIF-1α/SP1-dependent ROBO4 expression could retard DR progression.

Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy.

PURPOSE: Vascular endothelial growth factor (VEGF) plays implicated roles in diabetic retinopathy (DR). The role of roundabout 4 (Robo 4) in angiogenesis and vasculogenesis is controversial; however, the interdependent relationship between these two factors has not been studied in DR. This study determined the colocalization of VEGF and Robo4 in fibrovascular membranes (FVM) from patients with proliferative diabetic retinopathy (PDR). MicroRNA (miRNA)-mediated modulation of VEGF and Robo4 was explored in diabetic rats and ARPE-19 tissue culture cells under hyperglycemia. METHODS: VEGF and Robo4 co-expression in the FVM was analyzed using immunofluorescence. VEGF and Robo4 levels were determined in diabetic retinas and ARPE-19 tissue culture cells under high glucose using western blotting and RT-qPCR. MicroRNA agomir was intraocularly injected to increase miR-15a expression and downregulate VEGF and Robo4 levels in diabetic retinas. RESULTS: VEGF and Robo4 colocalization in FVM vessels was observed. Increased VEGF levels were consistent in diabetic retinas and ARPE-19 tissue culture cells cultured under hyperglycemia. Robo4 decreased in ARPE-19 tissue culture cells exposed to hyperglycemia for 72 h, whereas it increased in diabetic rat retinas. Several miRNAs were differentially expressed during DR progression. Furthermore, miR-15a agomir injection inhibited high levels of VEGF and Robo4 in diabetic retinas. CONCLUSIONS: VEGF and Robo4 were co-expressed in FVMs from PDR patients. In the early stages of DR, VEGF was upregulated and contributed to DR development, whereas, in the late stage of DR, VEGF and Robo4 worked together to aggravate DR progression. However, miR-15a could downregulate VEGF and Robo4 to ameliorate DR development.

Immunopathogenesis of Behcet's Disease.

Behcet's disease (BD) is a chronic systemic inflammatory vasculitis of unknown etiology characterized by recurrent episodes of oral aphthous ulcers, genital ulcers, skin lesions, ocular lesions, and other manifestations. Although the pathogenesis of BD is unclear, some studies have shown that immunological aberrations play an important role in the development and progression of BD. Infection-related trigger factors, including antigens and autoantigens, are believed to mediate the development of BD in patients with a genetic predisposition and subsequently activate the innate and adaptive immune systems, resulting in the production of numerous cytokines and chemokines to combat the infection-related factors. The study of the immunological mechanism of BD paves the way for the development of innovative therapies. Recently, novel biotherapy approaches, including interferon-α (IFN-α), tumor necrosis factor-α (TNF-α) antagonists, and other agents that target interleukins and their receptors, have shown promising results in the treatment of patients with refractory BD and have improved the prognosis of BD. In this review, we provide the current concepts of BD immunopathogenesis.

Intraocular Foreign Bodies: Clinical Characteristics and Prognostic Factors Influencing Visual Outcome and Globe Survival in 373 Eyes.

AIM: To describe epidemiologic and clinical characteristics and prognostic factors influencing visual outcome after intraocular foreign bodies (IOFBs) injury. METHODS: Medical records of 370 patients (373 eyes) with IOFBs were reviewed to identify the factors influencing visual acuity by univariate and multivariate analyses. RESULTS: The majority of patients (97.0%) were men, with a mean age of 38.1 years. The most common cause of ocular injury was hammering (52.6%); magnetic IOFBs occurred in 84.7% of these cases. Factors associated with poor visual outcome (defined as <1.3 logMAR) included the following: age ≥50 years (P=0.046); worse presenting visual acuity (P < 0.001); complications of retinal breaks (P=0.006) and endophthalmitis (P=0.032); vitrectomy (P=0.035); and intraocular C3F8 gas tamponade (P=0.038). Excellent visual outcome (defined as ≥0.5 logMAR) was associated with age <50 years (P=0.003); better presenting visual acuity (PVA) (P < 0.001); wound length <4 mm (P=0.005); absence of vitreous hemorrhage (P=0.026) and retinal breaks (P < 0.001); nonvitrectomy surgery (P=0.043); and use of balanced saline (P=0.029). CONCLUSIONS: Multiple prognostic factors were identified that may predict visual outcome and globe survival after IOFBs injury. Age, initial presenting visual acuity, wound length, complications (vitreous hemorrhage, retinal breaks, and endophthalmitis), surgical approach, and intraocular tamponade were significant predictors of visual outcome.

Recent advances in the diagnosis and treatment of Coats' disease.

PURPOSE: To review and summarize the recent progress in the diagnosis and treatment of Coats' disease. METHODS: Literature was collected from Web of Science, Medline and Pubmed, through searching of these keywords: "Coats' disease", "diagnosis" and "treatment". RESULTS: Coats' disease is characterized by idiopathic leaky retinal vascular telangiectasia and microvascular abnormalities often accompanied by intraretinal or subretinal exudation and retinal detachment. Neovascular glaucoma and phthisis bulbi often occur in advanced cases. Coats' disease has significant diversity in terms of its clinical presentation and morphology. Anti-VEGF therapy combined with laser photocoagulation for early Coats' disease and anti-VEGF therapy combined with minimally invasive vitrectomy for advanced Coats' disease can achieve good efficacy. CONCLUSION: Early diagnosis and timely treatment based on clinical stage are critical to retaining the patient's visual function. Patients should be aware that close long-term follow-up is necessary.

The essential role of tumor suppressor gene ING4 in various human cancers and non-neoplastic disorders.

Inhibitor of growth 4 (ING4), a member of the ING family discovered in 2003, has been shown to act as a tumor suppressor and is frequently down-regulated in various human cancers. Numerous published in vivo and in vitro studies have shown that ING4 is responsible for important cancer hallmarks such as pathologic cell cycle arrest, apoptosis, autophagy, contact inhibition, and hypoxic adaptation, and also affects tumor angiogenesis, invasion, and metastasis. These characteristics are typically associated with regulation through chromatin acetylation by binding histone H3 trimethylated at lysine 4 (H3K4me3) and through transcriptional activity of transcription factor P53 and NF-κB. In addition, emerging evidence has indicated that abnormalities in ING4 expression and function play key roles in non-neoplastic disorders. Here, we provide an overview of ING4-modulated chromosome remodeling and transcriptional function, as well as the functional consequences of different genetic variants. We also present the current understanding concerning the role of ING4 in the development of neoplastic and non-neoplastic diseases. These studies offer inspiration for pursuing novel therapeutics for various cancers.