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Retinal Diseases: Bridging Basic and Clinical Research

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2017) | Viewed by 87618

Special Issue Editors

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Via S. Sofia 64, 95125 Catania, Italy
Interests: diabetic retinopathy; age-related macular degeneration; glaucoma; ocular drug delivery
Department of Surgical Sciences, University of Torino, 10126 Torino, Italy
Interests: age-related macular degeneration; retinal vascular diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Retinal diseases have a devastating impact on millions of people worldwide. The range of disorders affecting the retina is large and includes age-related macular degeneration, diabetic retinopathy, and optic neuropathies. The costs associated with retinal disorders, both in terms of resources required for healthcare, and the toll that they exact on patients and their families, are steep, and there is an urgent need for new therapeutic approaches. The last few decades have brought a great deal of progress in terms of mechanisms and drugs, but translating these discoveries into therapies remains a critical challenge for the most of retinal diseases. This special issue explores the latest developments in the evolving field of retinal diseases trying to bridge the gap between basic research discoveries and clinical applications.

Prof. Dr. Claudio Bucolo
Prof. Dr. Chiara Maria Eandi
Guest Editors

Manuscript Submission Information

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Keywords

  • Diabetic retinopathy
  • Age-related macular degeneration
  • Glaucoma
  • Drugs

Published Papers (10 papers)

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Research

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22 pages, 8653 KiB  
Article
iTRAQ Quantitative Proteomic Analysis of Vitreous from Patients with Retinal Detachment
by Fátima Milhano Santos, Leonor Mesquita Gaspar, Sergio Ciordia, Ana Sílvia Rocha, João Paulo Castro e Sousa, Alberto Paradela, Luís António Passarinha and Cândida Teixeira Tomaz
Int. J. Mol. Sci. 2018, 19(4), 1157; https://doi.org/10.3390/ijms19041157 - 11 Apr 2018
Cited by 17 | Viewed by 5143
Abstract
Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition characterized by a physical separation between neurosensory retina and retinal pigment epithelium. Quantitative proteomics can help to understand the changes that occur at the cellular level during RRD, providing additional information about the molecular [...] Read more.
Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition characterized by a physical separation between neurosensory retina and retinal pigment epithelium. Quantitative proteomics can help to understand the changes that occur at the cellular level during RRD, providing additional information about the molecular mechanisms underlying its pathogenesis. In the present study, iTRAQ labeling was combined with two-dimensional LC-ESI-MS/MS to find expression changes in the proteome of vitreous from patients with RRD when compared to control samples. A total of 150 proteins were found differentially expressed in the vitreous of patients with RRD, including 96 overexpressed and 54 underexpressed. Several overexpressed proteins, several such as glycolytic enzymes (fructose-bisphosphate aldolase A, gamma-enolase, and phosphoglycerate kinase 1), glucose transporters (GLUT-1), growth factors (metalloproteinase inhibitor 1), and serine protease inhibitors (plasminogen activator inhibitor 1) are regulated by HIF-1, which suggests that HIF-1 signaling pathway can be triggered in response to RRD. Also, the accumulation of photoreceptor proteins, including phosducin, rhodopsin, and s-arrestin, and vimentin in vitreous may indicate that photoreceptor degeneration occurs in RRD. Also, the accumulation of photoreceptor proteins, including phosducin, rhodopsin, and s-arrestin, and vimentin in vitreous may indicate that photoreceptor degeneration occurs in RRD. Nevertheless, the differentially expressed proteins found in this study suggest that different mechanisms are activated after RRD to promote the survival of retinal cells through complex cellular responses. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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11 pages, 4181 KiB  
Article
Involvement of Bradykinin B2 Receptor in Pathological Vascularization in Oxygen-Induced Retinopathy in Mice and Rabbit Cornea
by Erika Terzuoli, Lucia Morbidelli, Ginevra Nannelli, Antonio Giachetti, Sandra Donnini and Marina Ziche
Int. J. Mol. Sci. 2018, 19(2), 330; https://doi.org/10.3390/ijms19020330 - 23 Jan 2018
Cited by 7 | Viewed by 5209
Abstract
The identification of components of the kallikrein–kinin system in the vitreous from patients with microvascular retinal diseases suggests that bradykinin (BK) signaling may contribute to pathogenesis of retinal vascular complications. BK receptor 2 (B2R) signaling has been implicated in both pro-inflammatory and pro-angiogenic [...] Read more.
The identification of components of the kallikrein–kinin system in the vitreous from patients with microvascular retinal diseases suggests that bradykinin (BK) signaling may contribute to pathogenesis of retinal vascular complications. BK receptor 2 (B2R) signaling has been implicated in both pro-inflammatory and pro-angiogenic effects promoted by BK. Here, we investigated the role of BK/B2R signaling in the retinal neovascularization in the oxygen-induced retinopathy (OIR) model. Blockade of B2R signaling by the antagonist fasitibant delayed retinal vascularization in mouse pups, indicating that the retinal endothelium is a target of the BK/B2R system. In the rabbit cornea assay, a model of pathological neoangiogenesis, the B2 agonist kallidin induced vessel sprouting and promoted cornea opacity, a sign of edema and tissue inflammation. In agreement with these results, in the OIR model, a blockade of B2R signaling significantly reduced retinal neovascularization, as determined by the area of retinal tufts, and, in the retinal vessel, it also reduced vascular endothelial growth factor and fibroblast growth factor-2 expression. All together, these findings show that B2R blockade reduces retinal neovascularization and inhibits the expression of proangiogenic and pro-inflammatory cytokines, suggesting that targeting B2R signaling may be an effective strategy for treating ischemic retinopathy. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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11 pages, 7958 KiB  
Article
Anesthetic Preconditioning as Endogenous Neuroprotection in Glaucoma
by Tsung-Han Chou, Ganeswara Rao Musada, Giovanni Luca Romano, Elizabeth Bolton and Vittorio Porciatti
Int. J. Mol. Sci. 2018, 19(1), 237; https://doi.org/10.3390/ijms19010237 - 13 Jan 2018
Cited by 18 | Viewed by 6079
Abstract
Blindness in glaucoma is the result of death of Retinal Ganglion Cells (RGCs) and their axons. RGC death is generally preceded by a stage of reversible dysfunction and structural remodeling. Current treatments aimed at reducing intraocular pressure (IOP) are ineffective or incompletely effective [...] Read more.
Blindness in glaucoma is the result of death of Retinal Ganglion Cells (RGCs) and their axons. RGC death is generally preceded by a stage of reversible dysfunction and structural remodeling. Current treatments aimed at reducing intraocular pressure (IOP) are ineffective or incompletely effective in management of the disease. IOP-independent neuroprotection or neuroprotection as adjuvant to IOP lowering in glaucoma remains a challenge as effective agents without side effects have not been identified yet. We show in DBA/2J mice with spontaneous IOP elevation and glaucoma that the lifespan of functional RGCs can be extended by preconditioning RGCs with retrobulbar lidocaine in one eye at four months of age that temporary blocks RGC axonal transport. The contralateral, PBS-injected eye served as control. Lidocaine-induced impairment of axonal transport to superior colliculi was assessed by intravitreal injection of cholera toxin B. Long-term (nine months) effect of lidocaine were assessed on RGC electrical responsiveness (PERG), IOP, expression of relevant protein (BDNF, TrkB, PSD95, GFAP, Synaptophysin, and GAPDH) and RGC density. While lidocaine treatment did not alter the age-related increase of IOP, TrkB expression was elevated, GFAP expression was decreased, RGC survival was improved by 35%, and PERG function was preserved. Results suggest that the lifespan of functional RGCs in mouse glaucoma can be extended by preconditioning RGCs in early stages of the disease using a minimally invasive treatment with retrobulbar lidocaine, a common ophthalmologic procedure. Lidocaine is inexpensive, safe and is approved by Food and Drug Administration (FDA) to be administered intravenously. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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1953 KiB  
Article
Short-Term Choriocapillaris Changes in Patients with Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy
by Marco Nassisi, Carlo Lavia, Camilla Alovisi, Luca Musso and Chiara M. Eandi
Int. J. Mol. Sci. 2017, 18(11), 2468; https://doi.org/10.3390/ijms18112468 - 20 Nov 2017
Cited by 34 | Viewed by 4037
Abstract
Background: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term [...] Read more.
Background: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term CC changes induced by Half-Dose PDT (HD-PDT) in chronic CSC using optical coherence tomography-angiography (OCTA). Methods: This is a prospective interventional case series. Chronic CSC eyes underwent Spectral-Domain OCT, Fundus Autofluorescence, FA, ICGA (Heidelberg Spectralis, Heidelberg, Germany) and OCTA (RTVue XR Avanti with AngioVue; Optovue Inc., Fremont, CA, USA) before HD-PDT, with follow-up after one hour, one week, and one month. Vascular changes after PDT were analyzed within the CC layer. The CC vessel density was defined as the percentage of an area occupied by flow pixels, using Image J software to obtain measurements by applying a grey level threshold. All pixels with a grey level above the threshold were considered as indicators of blood flow. Results: 20 eyes of 19 patients were included. At baseline the mean CC vessel density was 94.87 ± 2.32%. It significantly differed from the density at 1 week and 1 month (92.79 ± 3.16% and 95.55 ± 2.05%, p < 0.001, respectively), but not with values at 1 h (94.8 ± 2.28%, p = 0.516). Conclusions: CC vessel density was significantly reduced at 1 week as compared with baseline, suggesting a possible short-term effect of PDT on CC perfusion. After 1 month however, the CC vessel density was even higher than the baseline, probably due to a CC recovery. OCTA seems to be useful in the visualization of CC vessels and in confirming the mechanism of action of PDT treatment in eyes with chronic CSC. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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2351 KiB  
Communication
Topical Ocular Delivery of TGF-β1 to the Back of the Eye: Implications in Age-Related Neurodegenerative Diseases
by Chiara Bianca Maria Platania, Vincenzo Fisichella, Annamaria Fidilio, Federica Geraci, Francesca Lazzara, Gian Marco Leggio, Salvatore Salomone, Filippo Drago, Rosario Pignatello, Filippo Caraci and Claudio Bucolo
Int. J. Mol. Sci. 2017, 18(10), 2076; https://doi.org/10.3390/ijms18102076 - 30 Sep 2017
Cited by 35 | Viewed by 4200
Abstract
Dysregulation of the transforming growth factor-β1 (TGF-β1)/selected small mother against decapentaplegic (SMAD) pathway can be implicated in development of age-related macular degeneration (AMD), and the delivery of TGF-β1 could be beneficial for AMD. We developed a new ophthalmic formulation of TGF-β1 assessing the [...] Read more.
Dysregulation of the transforming growth factor-β1 (TGF-β1)/selected small mother against decapentaplegic (SMAD) pathway can be implicated in development of age-related macular degeneration (AMD), and the delivery of TGF-β1 could be beneficial for AMD. We developed a new ophthalmic formulation of TGF-β1 assessing the ocular pharmacokinetic profile of TGF-β1 in the rabbit eye. Small unilamellar vesicles (SUV) loaded with TGF-β1 were complemented with Annexin V and Ca2+, and the vitreous bioavailability of TGF-β1 was assessed after topical ocular administration by a commercial ELISA kit. We detected high levels of TGF-β1 (Cmax 114.7 ± 12.40 pg/mL) in the vitreous after 60 min (Tmax) from the topical application of the liposomal suspension. Ocular tolerability was also assessed by a modified Draize’s test. The new formulation was well tolerated. In conclusion, we demonstrated that the novel formulation was able to deliver remarkable levels of TGF-β1 into the back of the eye after topical administration. Indeed, this TGF-β1 delivery system may be useful in clinical practice to manage ophthalmic conditions such as age-related macular degeneration, skipping invasive intraocular injections. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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482 KiB  
Article
Qualitative and Quantitative Assessment of Vascular Changes in Diabetic Macular Edema after Dexamethasone Implant Using Optical Coherence Tomography Angiography
by Lisa Toto, Rossella D’Aloisio, Marta Di Nicola, Giuseppe Di Martino, Silvio Di Staso, Marco Ciancaglini, Daniele Tognetto and Leonardo Mastropasqua
Int. J. Mol. Sci. 2017, 18(6), 1181; https://doi.org/10.3390/ijms18061181 - 02 Jun 2017
Cited by 61 | Viewed by 5183
Abstract
The aim of this study was to investigate retinal and choriocapillaris vessel changes in diabetic macular edema (DME) after the intravitreal dexamethasone implant (IDI) using optical coherence tomography angiography (OCTA). Moreover, a comparison between morphological and functional parameters of DME and healthy patients [...] Read more.
The aim of this study was to investigate retinal and choriocapillaris vessel changes in diabetic macular edema (DME) after the intravitreal dexamethasone implant (IDI) using optical coherence tomography angiography (OCTA). Moreover, a comparison between morphological and functional parameters of DME and healthy patients was performed. Twenty-five eyes of 25 type 2 diabetic retinopathy patients complicated by macular edema (DME group) and 25 healthy subjects (control group) were enrolled. Superficial capillary plexus density (SCPD) and deep capillary plexus density (DCPD) in the foveal and parafoveal areas, choricapillary density (CCD) and optic disc vessel density (ODVD) were detected using OCTA at baseline and after 7, 30, 60, 90 and 120 days post injection. Best corrected visual acuity (BCVA), retinal sensitivity, and central retinal thickness (CMT) were also evaluated in both groups of patients. A statistically significant difference between the two groups (DME and controls) was found in terms of functional (MP, p < 0.001 and BCVA, p < 0.001) and morphological (CMT, p < 0.001; SCPD in the parafoveal area, p < 0.001; DCPD in the foveal area, p < 0.05 and parafoveal area, p < 0.001; CCD, p < 0.001) parameters. After the treatment, SCPD and DCPD in the foveal and parafoveal areas did not modify significantly during the follow up. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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13117 KiB  
Article
Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells
by Kati Juuti-Uusitalo, Ali Koskela, Niko Kivinen, Johanna Viiri, Juha M. T. Hyttinen, Mika Reinisalo, Arto Koistinen, Hannu Uusitalo, Debasish Sinha, Heli Skottman and Kai Kaarniranta
Int. J. Mol. Sci. 2017, 18(5), 1089; https://doi.org/10.3390/ijms18051089 - 19 May 2017
Cited by 10 | Viewed by 7253
Abstract
The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal [...] Read more.
The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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6111 KiB  
Article
Effects of Ranibizumab and Aflibercept on Human Müller Cells and Photoreceptors under Stress Conditions
by Weiyong Shen, Belinda Yau, So-Ra Lee, Ling Zhu, Michelle Yam and Mark C. Gillies
Int. J. Mol. Sci. 2017, 18(3), 533; https://doi.org/10.3390/ijms18030533 - 01 Mar 2017
Cited by 6 | Viewed by 5102
Abstract
Anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of retinal vascular diseases. However, constitutive VEGF also acts as a trophic factor on retinal nonvascular cells. We have studied the effects of aflibercept and ranibizumab on human Müller cells and photoreceptors exposed [...] Read more.
Anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of retinal vascular diseases. However, constitutive VEGF also acts as a trophic factor on retinal nonvascular cells. We have studied the effects of aflibercept and ranibizumab on human Müller cells and photoreceptors exposed to starvation media containing various concentrations of glucose, with or without CoCl2-induced hypoxia. Cell survival was assessed by calcein-AM cell viability assays. Expression of heat shock proteins (Hsp) and redox proteins thioredoxin 1 and 2 (TRX1, TRX2) was studied by Western blots. The production of neurotrophic factors in Müller cells and interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors was measured by enzymelinked immunosorbent assays. Aflibercept and ranibizumab did not affect the viability of both types of cells. Neither aflibercept nor ranibizumab affected the production of neurotrophic factors or expression of Hsp60 and Hsp90 in Müller cells. However, aflibercept but not ranibizumab affected the expression of Hsp60, Hsp9, TRX1 and TRX2 in photoreceptors. Aflibercept and ranibizumab both inhibited the production of IRBP in photoreceptors, aflibercept more so than ranibizumab. Our data indicates that the potential influence of aflibercept and ranibizumab on photoreceptors should be specifically monitored in clinical studies. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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4429 KiB  
Article
Identification of Potential Biomarkers for Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment by Vitreous iTRAQ-Based Proteomic Profiling
by Zhifeng Wu, Nannan Ding, Mengxi Yu, Ke Wang, Shasha Luo, Wenjun Zou, Ying Zhou, Biao Yan and Qin Jiang
Int. J. Mol. Sci. 2016, 17(12), 2052; https://doi.org/10.3390/ijms17122052 - 07 Dec 2016
Cited by 18 | Viewed by 6268
Abstract
Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complicated and serious type of rhegmatogenous retinal detachment (RRD). In this study, we identified differentially expressed proteins in the vitreous humors of RRDCD and RRD using isobaric tags for relative and absolute quantitation [...] Read more.
Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complicated and serious type of rhegmatogenous retinal detachment (RRD). In this study, we identified differentially expressed proteins in the vitreous humors of RRDCD and RRD using isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography-electrospray ion trap-mass spectrometry-mass spectrometry (nano-LC-ESI-MS/MS) and bioinformatic analysis. Our result shows that 103 differentially expressed proteins, including 54 up-regulated and 49 down-regulated proteins were identified in RRDCD. Gene ontology (GO) analysis suggested that most of the differentially expressed proteins were extracellular.The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis suggested that proteins related to complement and coagulation cascades were significantly enriched. iTRAQ-based proteomic profiling reveals that complement and coagulation cascades and inflammation may play important roles in the pathogenesis of RRDCD. This study may provide novel insights into the pathogenesis of RRDCD and offer potential opportunities for the diagnosis and treatment of RRDCD. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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Review

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14 pages, 557 KiB  
Review
Diabetic Retinopathy: Pathophysiology and Treatments
by Wei Wang and Amy C. Y. Lo
Int. J. Mol. Sci. 2018, 19(6), 1816; https://doi.org/10.3390/ijms19061816 - 20 Jun 2018
Cited by 711 | Viewed by 38266
Abstract
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial [...] Read more.
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial growth factor (VEGF) therapy demonstrated remarkable clinical benefits in DR patients; however, the majority of patients failed to achieve clinically-significant visual improvement. Therefore, there is an urgent need for the development of new treatments. Laboratory and clinical evidence showed that in addition to microvascular changes, inflammation and retinal neurodegeneration may contribute to diabetic retinal damage in the early stages of DR. Further investigation of the underlying molecular mechanisms may provide targets for the development of new early interventions. Here, we present a review of the current understanding and new insights into pathophysiology in DR, as well as clinical treatments for DR patients. Recent laboratory findings and related clinical trials are also reviewed. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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