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1.
Adam Walker Chun-Wa Chung Margarete Neu Manish Burman Thil Batuwangala Gavin Jones Chi-Man Tang Michael Steward Michael Mullin Nadia Tournier Alan Lewis Justyna Korczynska Vicky Chung Ian Catchpole 《The Journal of biological chemistry》2016,291(11):5500-5511
A potent VEGF inhibitor with novel antibody architecture and antigen binding mode has been developed. The molecule, hereafter referred to as VEGF dual dAb (domain antibody), was evaluated in vitro for binding to VEGF and for potency in VEGF-driven models and compared with other anti-VEGF biologics that have been used in ocular anti-angiogenic therapeutic regimes. VEGF dual dAb is more potent than bevacizumab and ranibizumab for VEGF binding, inhibition of VEGF receptor binding assays (RBAs), and VEGF-driven in vitro models of angiogenesis and displays comparable inhibition to aflibercept (Eylea). VEGF dual dAb is dimeric, and each monomer contains two distinct anti-VEGF domain antibodies attached via linkers to a human IgG1 Fc domain. Mechanistically, the enhanced in vitro potency of VEGF dual dAb, in comparison to other anti-VEGF biologics, can be explained by increased binding stoichiometry. A consistent model of the target engagement has been built based on the x-ray complexes of each of the two isolated domain antibodies with the VEGF antigen. 相似文献
2.
《Cytokine》2016
Vascular endothelial growth factor (VEGF) secreted by the retinal pigment epithelium (RPE) plays an important role in ocular homeostasis, but also in diseases, most notably age-related macular degeneration (AMD). To date, anti-VEGF drugs like ranibizumab have been shown to be most effective in treating these pathologic conditions. However, clinical trials suggest that the RPE could degenerate and perish through anti-VEGF treatment. Herein, we evaluated possible pathways and outcomes of the interaction between ranibizumab and human RPE cells (ARPE-19). Results indicate that ranibizumab affects the VEGF-A metabolism in RPE cells from an extra- as well as intracellular site. The drug is taken up into the cells, with the VEGF receptor 2 (VEGFR-2) being involved, and decreases VEGF-A protein levels within the cells as well as extracellularly. Oxidative stress plays a key role in various inflammatory disorders of the eye. Our results suggest that oxidative stress inhibits RPE cell proliferation. This anti-proliferative effect on RPE cells is significantly enhanced through ranibizumab, which does not inhibit RPE cell proliferation substantially in absence of relevant oxidative stress. Therefore, we emphasize that anti-VEGF treatment should be selected carefully in AMD patients with preexistent extensive RPE atrophy. 相似文献
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Ferrara N 《The International journal of developmental biology》2011,55(4-5):383-388
Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor (VEGF) in 1989. His laboratory has investigated many aspects of VEGF biochemistry and molecular biology. In 1993, Ferrara reported that inhibition of VEGF-induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo. These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking VEGF action could have therapeutic value for a variety of malignancies. A further development was the design in a rational fashion in 1997 of a humanized anti-VEGF monoclonal antibody (Avastin), now in clinical trials as a treatment for several solid tumors and also outside of cancer, in the treatment of age-related macular degeneration (AMD). Ferrara's work is revolutionizing quality of life for many of the estimated 1.2 million individuals in the US who have wet AMD. Upwards of a million AMD patients worldwide have already received anti-VEGF antibody therapy. 相似文献
5.
Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of vision loss in older individuals. Although the etiology of AMD has not been clearly elucidated, genetic and environmental factors have been implicated. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), a major regulator of vascular permeability and angiogenesis, have been suggested to play an important role in the pathogenesis of AMD. This study was performed to determine whether VEGF and PEDF variations are associated with AMD in the Korean population. Four SNPs of both the VEGF gene the PEDF gene were used to screen for genetic variation. This analysis was performed using polymerase chain reaction–restriction fragment length polymorphism, direct sequencing and an allele-specific oligonucleotide analysis. The study investigated four SNPs in VEGF and PEDF in Korean patients with AMD. The frequency of the TT genotype of rs1413711 and the recessive VEGF allele significantly differed between the patient and control groups. The TT genotype of rs1136287 (M72T) in PEDF significantly differed between the patient and control groups. Six haplotypes in the VEGF gene and two haplotypes in the PEDF gene were significantly associated with AMD. In this study, rs1413711 of VEGF, rs1136287 of PEDF and haplotypes were identified as candidate variants associated with AMD in Korean patients. 相似文献
6.
Purpose
To investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD.Methods
We performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity.Results
Polymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings.Conclusions
rs1061170 might be associated with treatment response of neovascular AMD, especially for the anti-VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed. 相似文献7.
In the study, a new assay of vascular endothelial growth factor (VEGF) has been developed by the use of gold nanoparticles (GNPs)–anti-VEGF conjugates. The immunoreaction between GNPs–anti-VEGF conjugates and VEGF took place in pH?7.5 PBS buffer solution after the addition of VEGF. The formation of GNPs modified VEGF immunocomplex resulted in the enhanced resonance light scattering (RLS) intensity at 388.0 nm. Under the optimal conditions, the magnitude of enhanced RLS intensity (ΔI RLS) was proportional to the VEGF concentration in the range from 100 to 1,500 pg?mL?1, with a detection limit of 60 pg?mL?1. The surface plasma resonance absorption spectrum, the characteristics of RLS, the VEGF immunocomplex, and the optimum conditions of the immunoreaction have all been investigated. The VEGF concentrations of 20 serum specimens detected by the developed assay showed consistent results in comparison with those obtained by commercially available enzyme-linked immunosorbent assay kit. 相似文献
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Leilei Zhang Ting Si Andrew J. Fischer Alan Letson Shuai Yuan Cynthia J. Roberts Ronald X. Xu 《PloS one》2015,10(8)
Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over age 65 in industrialized nations. Intravitreous injection of anti-VEGF (vascular endothelial growth factor) therapies, such as ranibizumab (trade name: Lucentis), provides an effective treatment option for neovascular AMD. We have developed an improved coaxial electrospray (CES) process to encapsulate ranibizumab in poly(lactic-co-glycolic) acid (PLGA) microparticles (MPs) for intravitreous injection and sustained drug release. This microencapsulation process is advantageous for maintaining the stability of the coaxial cone-jet configurations and producing drug-loaded MPs with as high as 70% encapsulation rate and minimal loss of bioactivitiy. The utility of this emerging process in intravitreous drug delivery has been demonstrated in both benchtop and in vivo experiments. The benchtop test simulates ocular drug release using PLGA MPs encapsulating a model drug. The in vivo experiment evaluates the inflammation and retinal cell death after intravitreal injection of the MPs in a chick model. The experimental results show that the drug-load MPs are able to facilitate sustained drug release for longer than one month. No significant long term microglia reaction or cell death is observed after intravitreal injection of 200 μg MPs. The present study demonstrates the technical feasibility of using the improved CES process to encapsulate water-soluble drugs at a high concentration for sustained release of anti-VEGF therapy. 相似文献
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Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts 总被引:1,自引:0,他引:1
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal blood-vessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches. 相似文献
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Sajid Mushtaq Jong Kook Rho Jung Ae Kang Joong-Jae Lee Jung Young Kim You Ree Nam Seong-Jae Yun Gyeong Hee Lee Sang Hyun Park Dong-Eun Lee Hak-Sung Kim 《Bioorganic & medicinal chemistry letters》2017,27(22):5060-5064
Antibody-mimetic proteins are intensively being developed for biomedical applications including tumor imaging and therapy. Among them, repebody is a new class of protein that consists of highly diverse leucine-rich repeat (LRR) modules. Although all possible biomedical applications with repebody are ongoing, it’s in vivo biodistribution and excretion pathway has not yet been explored. In this study, hexahistidine (His6)-tag bearing repebody (rEgH9) was labeled with [99mTc]-tricarbonyl, and biodistribution was performed following intravenous (I.V.) or intraperitoneal (I.P.) injection. Repebody protein was radiolabeled with high radiolabeling efficiency (>90%) and radiolabeled compound was more than 99% pure after purification. Biodistribution data indicates radiotracer has a rapid clearance from blood and excreted through the kidneys for intravenous (I.V.) injection, but comparatively slow clearance for an intraperitoneal (I.P.) injection. SPECT-CT images were found to be in agreement with biodistribution data, high activity was found inside kidneys. The observed result for rapid blood clearance and renal excretion of repebody (rEgH9) provide useful information for the further development of therapeutic strategy. 相似文献
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María Luisa Pérez-Lozano Pilar Sandoval ángela Rynne-Vidal Abelardo Aguilera José Antonio Jiménez-Heffernan Patricia Albar-Vizcaíno Pedro L. Majano José Antonio Sánchez-Tomero Rafael Selgas Manuel López-Cabrera 《PloS one》2013,8(4)
Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/VEGFRs/co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-β1 plus IL-1β (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the co-receptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGF. 相似文献
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Claire Ward Diana Kuehn Roberta E. Burden Julie A. Gormley Thomas J. Jaquin Mihaela Gazdoiu Donna Small Roy Bicknell James A. Johnston Christopher J. Scott Shane A. Olwill 《PloS one》2010,5(9)
Background
Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development.Methodology/Principal Findings
Cathepsin S expression and secretion from endothelial cells was characterised using RT-PCR and western blotting. We further show that cathepsin S promotes pericellular hydrolysis of extracellular matrix components in the tumour microenvironment and facilitates endothelial invasion. The cathepsin S inhibitory antibody, Fsn0503, blocks extracellular proteolysis, inhibiting endothelial invasion and tube formation in cell-based assays. The anti-angiogenic effects of Fsn0503 were also shown in vivo where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed.Conclusions/Significance
Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis. 相似文献13.
《The Journal of nutritional biochemistry》2014,25(1):44-49
Copper stimulation of angiogenesis at the organ system level is vascular endothelial growth factor (VEGF) dependent, but copper stimulation of vascular endothelial cell proliferation in cultures is VEGF independent. The present study was undertaken to use isolated rat aortic rings to understand the seemly controversial observations between in vivo and in vitro studies. The thoracic aorta was isolated from Sprague Dawley rats (8–10 weeks) and sectioned into 1.0-mm thick vascular rings for culturing. Copper sulfide at a final concentration of 5, 25, 50 or 100 μM was added to the cultures and maintained for 8 days. A copper chelator, tetraethylenepentamine (TEPA) at a final concentration of 25 μM, was added to some cultures to block the effect of copper. An anti-VEGF antibody was used to determine the role of VEGF in copper promotion of angiogenesis. The data obtained showed that copper at 5 μM in cultures stimulated the vascular formation; an effect was blocked by TEPA. Copper at concentrations above 50 μM lost the proangiogenesis effect. However, copper at 5 μM did not enhance the production of VEGF, and concentrations above 50 μM significantly increased VEGF production. On the other hand, the treatment with anti-VEGF antibody completely blocked the proangiogenesis effect of 5-μM copper. This study thus demonstrates that VEGF is essential for angiogenesis but the proangiogenesis effect of copper does not act through enhanced production of VEGF. 相似文献
14.
Dongheon Lee Dongin Kim Yu Bin Choi Kyungjae Kang Eun-Sil Sung Jin-Hyung Ahn 《MABS-AUSTIN》2016,8(5):892-904
Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been approved for cancer treatment. However, VEGF inhibitors alone were shown to promote tumor invasion and metastasis by increasing intratumoral hypoxia in some preclinical and clinical studies. Emerging reports suggest that Delta-like ligand 4 (Dll4) is a promising target of angiogenesis inhibition to augment the effects of VEGF inhibitors. To evaluate the effects of simultaneous blockade against VEGF and Dll4, we developed a bispecific antibody, HD105, targeting VEGF and Dll4. The HD105 bispecific antibody, which is composed of an anti-VEGF antibody (bevacizumab-similar) backbone C-terminally linked with a Dll4-targeting single-chain variable fragment, showed potent binding affinities against VEGF (KD: 1.3 nM) and Dll4 (KD: 30 nM). In addition, the HD105 bispecific antibody competitively inhibited the binding of ligands to their receptors, i.e., VEGF to VEGFR2 (EC50: 2.84 ± 0.41 nM) and Dll4 to Notch1 (EC50: 1.14 ± 0.06 nM). Using in vitro cell-based assays, we found that HD105 effectively blocked both the VEGF/VEGFR2 and Dll4/Notch1 signaling pathways in endothelial cells, resulting in a conspicuous inhibition of endothelial cell proliferation and sprouting. HD105 also suppressed Dll4-induced Notch1-dependent activation of the luciferase gene. In vivo xenograft studies demonstrated that HD105 more efficiently inhibited the tumor progression of human A549 lung and SCH gastric cancers than an anti-VEGF antibody or anti-Dll4 antibody alone. In conclusion, HD105 may be a novel therapeutic bispecific antibody for cancer treatment. 相似文献
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Zsolt Ablonczy Annamalai Prakasam James Fant Abdul Fauq Craig Crosson Kumar Sambamurti 《The Journal of biological chemistry》2009,284(44):30177-30186
Wet age-related macular degeneration (AMD) attacks the integrity of the retinal pigment epithelium (RPE) barrier system. The pathogenic process was hypothesized to be mediated by vascular endothelial growth factor (VEGF) and antagonized by pigment epithelium-derived factor (PEDF). To dissect these functional interactions, monolayer cultures of RPE cells were established, and changes in transepithelial resistance were evaluated after administration of PEDF, placenta growth factor (VEGF-R1 agonist), and VEGF-E (VEGF-R2 agonist). A recently described mechanism of VEGF inhibition in endothelia required the release of VEGF-R1 intracellular domain by γ-secretase. To evaluate this pathway in the RPE, cells were pretreated with inhibitors DAPT or . Processing of VEGF receptors was assessed by Western blot analysis. Administration of VEGF-E rapidly increased RPE permeability, and PEDF inhibited the VEGF-E response dose-dependently. Both γ-secretase antagonists prevented the inhibitory effects of PEDF. The co-administration of PEDF and VEGF-E depleted the amount of VEGF-R2 in the membrane and increased the amount of VEGF-R2 ectodomain in the media. Therefore, the inhibitory effect of PEDF appears to be mediated via the processing of VEGF-R2 by γ-secretase. γ-Secretase generates the amyloid-β (Aβ) peptide of Alzheimer disease from its precursor (amyloid precursor protein). This peptide is also a component of drusen in dry AMD. The results support the hypothesis that misregulation of γ-secretase may not only lead to Aβ deposits in dry AMD but can also be damaging to RPE function by blocking the protective effects of PEDF to prevent VEGF from driving the dry to wet AMD transition.Age-related macular degeneration (AMD) LY4115752 is often diagnosed by the appearance of subretinal fluid. This fluid causes a local detachment of the retina in the macular area resulting in decreased visual acuity in the center of the visual field (1). The resulting macular edema can lead to complete vision loss (2). Although the excessive fluid mainly comes from capillaries in the inner retina, the removal of subretinal fluid is dependent on the RPE. The maintenance of RPE barrier function is essential for the efficient removal of the fluid (3), and the disruption of the RPE barrier can eventually lead to choroidal neovascularization.Recent clinical studies have shown that intravitreally administered anti-VEGF compounds are effective therapies for choroidal neovascularization (4–6). Originally, VEGF was described as an endothelial angiogenic and vasopermeability factor. The leakage through the vessels of the inner retina increases in response to VEGF (7, 8). However, the release of VEGF also affects RPE function (9–11). We have recently shown that RPE barrier integrity is modulated by VEGF through apically oriented VEGF-R2 receptors (12). Thus, there is a growing body of evidence that intraocular VEGF can increase the permeability of both the inner and outer blood-retina barriers, contributing to the accumulation of subretinal fluid and macular edema.Pigment epithelium-derived factor was initially identified as a neurotrophic agent secreted by fetal human RPE cells (13). Subsequent experiments have recognized that PEDF is an endogenous antagonist of VEGF (14). In the eye, studies have provided evidence that endothelial quiescence and barrier function is achieved through a balance of VEGF and PEDF (15). The PEDF secretion pattern from the RPE cells is predominantly apical, and the interphotoreceptor matrix around the RPE microvilli is a major reservoir of PEDF (16, 17). Therefore, we hypothesize that PEDF can antagonize the breakdown of RPE function induced by the apical actions of VEGF.Several schemes have been proposed for the anti-VEGF activity of PEDF. A PEDF receptor has been identified, which has phospholipase A2 activity (18). PEDF binding proteins without clear receptor activity have also been found (19). In endothelial cells, PEDF has also been shown to compete with VEGF for binding at the VEGF-R2 receptor (20). PEDF was found to regulate VEGF expression (20, 21) and decrease VEGF receptor phosphorylation (14). A recent study in endothelia has elucidated a novel inhibitory mechanism of VEGF signaling via the PEDF-induced intramembrane proteolysis of VEGF-R1 by γ-secretase (22). The goal of our study is to determine if PEDF acts as an anti-permeability agent in the RPE and to begin to understand the cellular mechanism involved in this response. 相似文献
17.
Angiogenesis, the physiological process of sprouting of new blood vessels from pre-existing ones, is a key biological feature of almost all cancers. Among the multitude of factors driving tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most potent, exerting myriad effects on vascular pruning and sprouting, permeability, network formation, proliferation, and cell death. Despite the initial unimpressive clinical performance of anti-VEGF antibody (bevacizumab) as cancer monotherapy, clear improvements in clinical outcomes following combination bevacizumab and chemotherapy regimens and multi-targeted VEGF receptor tyrosine kinase inhibitors (sorafenib and sunitinib) in select tumor types have established VEGF-targeted agents as an effective means of controlling cancer growth. Prolongation of overall survival and cure with these agents, however, remains elusive. Moreover, recent data has revealed key differences in the therapeutic and biological tumor response to antibody versus receptor kinase VEGF inhibitors and suggested, at least pre-clinically, that VEGF blockade in certain circumstances may actually promote more aggressive tumor growth. Given the diverse mechanisms and potentially opposing roles of VEGF neutralization in cancer biology, identification of novel biomarkers predictive of in vivo angiogenic responses may hold the key to optimizing therapeutic outcomes of anti-VEGF therapy in future cancer patients. 相似文献
18.
Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly. AMD patients have elevated levels of membrane attack complex (MAC) in their choroidal blood vessels and retinal pigment epithelium (RPE). MAC forms pores in cell membranes. Low levels of MAC result in an elevation of cytokine release such as vascular endothelial growth factor (VEGF) that promotes the formation of choroidal neovascularization (CNV). High levels of MAC result in cell lysis and RPE degeneration is a hallmark of advanced AMD. The current standard of care for CNV associated with wet AMD is intravitreal injection of anti-VEGF molecules every 4 to 12 weeks. Such injections have significant side effects. Recently, it has been found that membrane pore-forming proteins such as α-haemolysin can mediate their toxic effects through auto- and paracrine signaling and that complement-induced lysis is amplified through ATP release followed by P2X receptor activation. We hypothesized that attenuation of P2X receptor activation may lead to a reduction in MAC deposition and consequent formation of CNV. Hence, in this study we investigated topical application of the purinergic P2X antagonist Pyridoxalphosphate-6-azophenyl-2'',4''-disulphonic acid (PPADS) as a potential treatment for AMD. We found that 4.17 µM PPADS inhibited formation of HUVEC master junctions and master segments by 74.7%. In a human complement mediated cell lysis assay, 104 µM PPADS enabled almost complete protection of Hepa1c1c7 cells from 1% normal human serum mediated cell lysis. Daily topical application of 4.17 mM PPADS for 3 days attenuated the progression of laser induced CNV in mice by 41.8% and attenuated the deposition of MAC at the site of the laser injury by 19.7%. Our data have implications for the future treatment of AMD and potentially other ocular disorders involving CNV such as angioid streaks, choroidal rupture and high myopia. 相似文献
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