Research

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17 pages, 1574 KiB

Open AccessArticle

Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye

by Manuela Santonocito, Cristina Zappulla, Santa Viola, Luca Rosario La Rosa, Elena Solfato, Ilenia Abbate, Valeria Tarallo, Ivana Apicella, Chiara Bianca Maria Platania, Grazia Maugeri, Velia D’Agata, Claudio Bucolo, Sandro De Falco, Maria Grazia Mazzone and Francesco Giuliano

Int. J. Mol. Sci. 2021, 22(9), 4404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094404 - 22 Apr 2021

Cited by 12 | Viewed by 3179

Abstract

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. [...] Read more.

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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22 pages, 6819 KiB

Open AccessArticle

Prolyl 3-Hydroxylase 2 Is a Molecular Player of Angiogenesis

by Paola Pignata, Ivana Apicella, Valeria Cicatiello, Caterina Puglisi, Sara Magliacane Trotta, Remo Sanges, Valeria Tarallo and Sandro De Falco

Int. J. Mol. Sci. 2021, 22(8), 3896; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083896 - 09 Apr 2021

Cited by 2 | Viewed by 2103

Abstract

Prolyl 3-hydroxylase 2 (P3H2) catalyzes the post-translational formation of 3-hydroxyproline on collagens, mainly on type IV. Its activity has never been directly associated to angiogenesis. Here, we identified P3H2 gene through a deep-sequencing transcriptome analysis of human umbilical vein endothelial cells [...] Read more.

Prolyl 3-hydroxylase 2 (P3H2) catalyzes the post-translational formation of 3-hydroxyproline on collagens, mainly on type IV. Its activity has never been directly associated to angiogenesis. Here, we identified P3H2 gene through a deep-sequencing transcriptome analysis of human umbilical vein endothelial cells (HUVECs) stimulated with vascular endothelial growth factor A (VEGF-A). Differently from many previous studies we carried out the stimulation not on starved HUVECs, but on cells grown to maintain the best condition for their in vitro survival and propagation. We showed that P3H2 is induced by VEGF-A in two primary human endothelial cell lines and that its transcription is modulated by VEGF-A/VEGF receptor 2 (VEGFR-2) signaling pathway through p38 mitogen-activated protein kinase (MAPK). Then, we demonstrated that P3H2, through its activity on type IV Collagen, is essential for angiogenesis properties of endothelial cells in vitro by performing experiments of gain- and loss-of-function. Immunofluorescence studies showed that the overexpression of P3H2 induced a more condensed status of Collagen IV, accompanied by an alignment of the cells along the Collagen IV bundles, so towards an evident pro-angiogenic status. Finally, we found that P3H2 knockdown prevents pathological angiogenesis in vivo, in the model of laser-induced choroid neovascularization. Together these findings reveal that P3H2 is a new molecular player involved in new vessels formation and could be considered as a potential target for anti-angiogenesis therapy. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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16 pages, 2152 KiB

Open AccessArticle

TGF-β Serum Levels in Diabetic Retinopathy Patients and the Role of Anti-VEGF Therapy

by Vincenza Bonfiglio, Chiara Bianca Maria Platania, Francesca Lazzara, Federica Conti, Corrado Pizzo, Michele Reibaldi, Andrea Russo, Matteo Fallico, Elina Ortisi, Francesco Pignatelli, Antonio Longo, Teresio Avitabile, Filippo Drago and Claudio Bucolo

Int. J. Mol. Sci. 2020, 21(24), 9558; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249558 - 15 Dec 2020

Cited by 40 | Viewed by 3016

Abstract

Transforming growth factor β1 (TGFβ1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGFβ1 as a diagnostic and prognostic [...] Read more.

Transforming growth factor β1 (TGFβ1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGFβ1 as a diagnostic and prognostic biomarker of DR stages. Thirty-eight subjects were enrolled and, after diagnosis and evaluation of inclusion and exclusion criteria, were assigned to six groups: (1) healthy age-matched control, (2) diabetic without DR, (3) non-proliferative diabetic retinopathy (NPDR) naïve to treatment, (4) NPDR treated with intravitreal (IVT) aflibercept, (5) proliferative diabetic retinopathy (PDR) naïve to treatment and (6) PDR treated with IVT aflibercept. Serum levels of vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF) and TGFβ1 were measured by means of enzyme-linked immunosorbent assay (ELISA). Foveal macular thickness (FMT) in enrolled subjects was evaluated by means of structural-optical coherence tomography (S-OCT). VEGF-A serum levels decreased in NPDR and PDR patients treated with aflibercept, compared to naïve DR patients. PlGF serum levels were modulated only in aflibercept-treated NPDR patients. Particularly, TGFβ1 serum levels were predictive of disease progression from NPDR to PDR. A Multivariate ANOVA analysis (M-ANOVA) was also carried out to assess the effects of fixed factors on glycated hemoglobin (HbA1c) levels, TGFβ1, and diabetes duration. In conclusion, our data have strengthened the hypothesis that TGFβ1 would be a biomarker and pharmacological target of diabetic retinopathy. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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Review

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13 pages, 2777 KiB

Open AccessReview

Rho GTPases in Retinal Vascular Diseases

by Akiyoshi Uemura and Yoko Fukushima

Int. J. Mol. Sci. 2021, 22(7), 3684; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073684 - 01 Apr 2021

Cited by 11 | Viewed by 3403

Abstract

The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular [...] Read more.

The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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25 pages, 1976 KiB

Open AccessReview

Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy

by Arunbalaji Pugazhendhi, Margaret Hubbell, Pooja Jairam and Balamurali Ambati

Int. J. Mol. Sci. 2021, 22(3), 1170; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031170 - 25 Jan 2021

Cited by 42 | Viewed by 7830

Abstract

Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, [...] Read more.

Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, drinking, BMI, and diet all play a part in nvAMD’s progression, with anti-vascular endothelial growth factor (anti-VEGF) therapy being the mainstay of treatment. Current therapeutic advancements slow the progression of the disease but do not cure or reverse its course. Newer therapies such as gene therapies, Rho-kinase inhibitors, and levodopa offer potential new targets for treatment. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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40 pages, 2426 KiB

Open AccessReview

Neovascular Age-Related Macular Degeneration: Therapeutic Management and New-Upcoming Approaches

by Federico Ricci, Francesco Bandello, Pierluigi Navarra, Giovanni Staurenghi, Michael Stumpp and Marco Zarbin

Int. J. Mol. Sci. 2020, 21(21), 8242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218242 - 03 Nov 2020

Cited by 94 | Viewed by 6334

Abstract

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease [...] Read more.

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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18 pages, 3284 KiB

Open AccessReview

Pericyte-Endothelial Interactions in the Retinal Microvasculature

by Hu Huang

Int. J. Mol. Sci. 2020, 21(19), 7413; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197413 - 08 Oct 2020

Cited by 101 | Viewed by 8687

Abstract

Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal [...] Read more.

Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal vascular disorders, such as retinopathy of prematurity, retinal vein occlusion, and diabetic retinopathy. Understanding the cellular and molecular mechanisms of pericyte-endothelial interaction and perturbation can facilitate the design of therapeutic intervention for the prevention and treatment of retinal vascular disorders. Pericyte-endothelial interactions are indispensable for the integrity and functionality of retinal neurovascular unit (NVU), including vascular cells, retinal neurons, and glial cells. The essential autocrine and paracrine signaling pathways, such as Vascular endothelial growth factor (VEGF), Platelet-derived growth factor subunit B (PDGFB), Notch, Angipointein, Norrin, and Transforming growth factor-beta (TGF-β), have been well characterized for the regulation of pericyte-endothelial interactions in the neo-vessel formation processes (vasculogenesis and angiogenesis) during embryonic development. They also play a vital role in stabilizing and remodeling mature vasculature under pathological conditions. Awry signals, aberrant metabolisms, and pathological conditions, such as oxidative stress and inflammation, can disrupt the communication between pericytes and endothelial cells, thereby resulting in the breakdown of the blood-retinal barrier (BRB) and other microangiopathies. The emerging evidence supports extracellular exosomes’ roles in the (mis)communications between the two cell types. This review summarizes the essential knowledge and updates about new advancements in pericyte-EC interaction and communication, emphasizing the retinal microvasculature. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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22 pages, 5954 KiB

Open AccessReview

Lipid Signaling in Ocular Neovascularization

by Ryo Terao and Hiroki Kaneko

Int. J. Mol. Sci. 2020, 21(13), 4758; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134758 - 04 Jul 2020

Cited by 15 | Viewed by 4771

Abstract

Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling [...] Read more.

Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling pathways and is regulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Modulating these circuits may represent a promising strategy to treat ocular neovascular diseases. Lipid mediators derived from membrane lipids are abundantly present in most tissues and exert a wide range of biological functions by regulating various signaling pathways. In particular, glycerophospholipids, sphingolipids, and polyunsaturated fatty acids exert potent pro-angiogenic or anti-angiogenic effects, according to the findings of numerous preclinical and clinical studies. In this review, we summarize the current knowledge regarding the regulation of ocular neovascularization by lipid mediators and their metabolites. A better understanding of the effects of lipid signaling in neovascularization may provide novel therapeutic strategies to treat ocular neovascular diseases and other human disorders. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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