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Diabetic Retinopathy: From Molecular Mechanisms to Therapeutic Opportunities

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Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 4368

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Special Issue Editors

Prof. Dr. Paola Bagnoli

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Guest Editor

Department of Biology, University of Pisa, Pisa, Italy
Interests: animal models; retinal diseases; retinal function; angiogenesis; inflammation; hypoxia-inducible factor 1; vascular endothelial growth factor; β2 adrenoceptor signaling; β3 adrenoceptor function
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Giovanni Casini

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Guest Editor

Department of Biology, University of Pisa, Pisa, Italy
Interests: neuroprotection; physiology and pathology of the retina; physiology and pathology of the neurovascular unit; regulation of growth factor expression; nutraceuticals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetic retinopathy (DR) is a multifactorial progressive disease characterized by an extremely complex pathogenesis. It involves different factors and a variety of pathophysiologic mechanisms, which cause the dysregulation of a number of mediators, including growth factors, cytokines/chemokines, vasoactive agents, and inflammatory and adhesion molecules. Neurodegeneration, oxidative stress, inflammation, and vascular changes have been found to play key roles in DR; however, further studies are needed to decipher the exact mechanisms leading to retinal dysfunction. The available therapies treat only the advanced stages of DR; therefore, current investigations focus on the development of new treatments, including antioxidants, neuroprotectants, anti-inflammatory, and vasculoprotective agents, that may prevent disease progression. Further technological advances in retinal imaging for screening the early pathology and its progression, together with new therapeutics, are essential in improving patient life quality and the burden on public health. The main goal of the present Special Issue is to attract contributions with state-of-the art findings related to the pathophysiology and therapeutics of DR. Potential topics may include, but are not limited to, an understanding of the mechanisms leading to neovascularization and cell death in DR, role of oxidative stress and inflammation, animal models of DR, therapeutic potential of nutraceuticals, new methods for drug delivery to the retina, retinal imaging for screening and early identification of the disease, proteomic and metabolomic approaches and gene therapy.

We warmly invite you and your colleagues to provide both original research and review articles, which will be peer-reviewed for publication in the open access journal Cells. We look forward to your contributions.

Prof. Dr. Paola Bagnoli
Prof. Dr. Giovanni Casini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurodegeneration
oxidative stress
inflammation
vasculopathy
nutraceuticals
drug delivery
retinal imaging
proteomics
metabolomics
gene therapy

Published Papers (4 papers)

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Research

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13 pages, 4831 KiB

Open AccessArticle

Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy

by Jose-Andres C. Portillo, Amelia Pfaff, Sarah Vos, Matthew Weng, Ram H. Nagaraj and Carlos S. Subauste

Cells 2024, 13(5), 429; https://doi.org/10.3390/cells13050429 - 29 Feb 2024

Viewed by 724

Abstract

CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven inflammatory disorders. What drives CD40 upregulation in the diabetic retina remains unknown. We examined the role of advanced glycation end products (AGEs) in CD40 upregulation in endothelial cells and Müller cells. Human endothelial cells and Müller cells were incubated with unmodified or methylglyoxal (MGO)-modified fibronectin. CD40 expression was assessed by flow cytometry. The expression of ICAM-1 and CCL2 was examined by flow cytometry or ELISA after stimulation with CD154 (CD40 ligand). The expression of carboxymethyl lysine (CML), fibronectin, and laminin as well as CD40 in endothelial and Müller cells from patients with DR was examined by confocal microscopy. Fibronectin modified by MGO upregulated CD40 in endothelial and Müller cells. CD40 upregulation was functionally relevant. MGO-modified fibronectin enhanced CD154-driven upregulation of ICAM-1 and CCL2 in endothelial and Müller cells. Increased CD40 expression in endothelial and Müller cells from patients with DR was associated with increased CML expression in fibronectin and laminin. These findings identify AGEs as inducers of CD40 upregulation in endothelial and Müller cells and enhancers of CD40-dependent pro-inflammatory responses. CD40 upregulation in these cells is associated with higher CML expression in fibronectin and laminin in patients with DR. This study revealed that CD40 and AGEs, two important drivers of DR, are interconnected. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: From Molecular Mechanisms to Therapeutic Opportunities)

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Graphical abstract

18 pages, 10175 KiB

Open AccessArticle

Liposome-Mediated Delivery Improves the Efficacy of Lisosan G against Retinopathy in Diabetic Mice

by Rosario Amato, Alberto Melecchi, Laura Pucci, Alessio Canovai, Silvia Marracci, Maurizio Cammalleri, Massimo Dal Monte, Carla Caddeo and Giovanni Casini

Cells 2023, 12(20), 2448; https://doi.org/10.3390/cells12202448 - 13 Oct 2023

Viewed by 1076

Abstract

Nutraceuticals are natural substances whose anti-oxidant and anti-inflammatory properties may be used to treat retinal pathologies. Their efficacy is limited by poor bioavailability, which could be improved using nanocarriers. Lisosan G (LG), a fermented powder from whole grains, protects the retina from diabetic retinopathy (DR)-induced damage. For this study, we tested whether the encapsulation of LG in liposomes (LipoLG) may increase its protective effects. Diabetes was induced in mice via streptozotocin administration, and the mice were allowed to freely drink water or a water dispersion of two different doses of LG or of LipoLG. Electroretinographic recordings after 6 weeks showed that only the highest dose of LG could partially protect the retina from diabetes-induced functional deficits, while both doses of LipoLG were effective. An evaluation of molecular markers of oxidative stress, inflammation, apoptosis, vascular endothelial growth factor, and the blood–retinal barrier confirmed that the highest dose of LG only partially protected the retina from DR-induced changes, while virtually complete prevention was obtained with either dose of LipoLG. These data indicate that the efficacy of LG in contrasting DR is greatly enhanced by its encapsulation in liposomes and may lay the ground for new dietary supplements with improved therapeutic effects against DR. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: From Molecular Mechanisms to Therapeutic Opportunities)

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15 pages, 3303 KiB

Open AccessArticle

Retinoid X Receptor Activation Prevents Diabetic Retinopathy in Murine Models

by Iuliia Dorofeeva, Assylbek Zhylkibayev, Irina V. Saltykova, Venkatram Atigadda, Bibek Adhikari, Oleg S. Gorbatyuk, Maria B. Grant and Marina S. Gorbatyuk

Cells 2023, 12(19), 2361; https://doi.org/10.3390/cells12192361 - 26 Sep 2023

Viewed by 1229

Abstract

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess the effects of UAB126 on the progression of diabetic retinopathy (DR) in rodent models of type 1 diabetes (T1D), streptozotocin-induced, and type 2 diabetes (T2D), in db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar and the expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

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23 pages, 2547 KiB

Open AccessReview

Complementary Approaches to Retinal Health Focusing on Diabetic Retinopathy

by Tibor Rák, Andrea Kovács-Valasek, Etelka Pöstyéni, Adrienne Csutak and Róbert Gábriel

Cells 2023, 12(23), 2699; https://doi.org/10.3390/cells12232699 - 24 Nov 2023

Cited by 1 | Viewed by 861

Abstract

Diabetes mellitus affects carbohydrate homeostasis but also influences fat and protein metabolism. Due to ophthalmic complications, it is a leading cause of blindness worldwide. The molecular pathology reveals that nuclear factor kappa B (NFκB) has a central role in the progression of diabetic retinopathy, sharing this signaling pathway with another major retinal disorder, glaucoma. Therefore, new therapeutic approaches can be elaborated to decelerate the ever-emerging “epidemics” of diabetic retinopathy and glaucoma targeting this critical node. In our review, we emphasize the role of an improvement of lifestyle in its prevention as well as the use of phytomedicals associated with evidence-based protocols. A balanced personalized therapy requires an integrative approach to be more successful for prevention and early treatment. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: From Molecular Mechanisms to Therapeutic Opportunities)

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