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Diabetic Retinopathy: Biomolecules and Pathophysiology
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Diabetic Retinopathy: Biomolecules and Pathophysiology

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Ophthalmology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 62255

Special Issue Editors

Prof. Dr. Ruth B. Caldwell

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Guest Editor
Cellular Biology & Anatomy, Vascular Biology Center, Augusta University, Augusta, GA, USA
Interests: vascular biology; angiogenesis; neurodegeneration; inflammation; ischemia; diabetes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Manuela Bartoli

E-Mail Website
Guest Editor
Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: miRNA; retinopathy of prematurity; diabetic retinopathy; oxidative stress; senescence
Special Issues, Collections and Topics in MDPI journals
Dr. S. Priya Narayanan

E-Mail Website
Guest Editor
Clinical and Administrative Pharmacy, University of Georgia, Augusta, GA 30912, USA
Interests: retina; ischemic retinopathy; neurovascular injury; neurodegeneration; oxidative stress; polyamine oxidase
Prof. Dr. R. William Caldwell

E-Mail Website
Guest Editor
Department of Pharmacology & Toxicology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
Interests: nitric oxide synthase; arginase; metabolic disease; vascular function

Special Issue Information

Dear Colleagues,

Diabetes has become a global epidemic. According to the World Health Organization the number of adults living with diabetes worldwide was estimated at 422 million in 2016 and the projected estimate for 2035 is 592 million. Diabetic Retinopathy (DR) is the most common complication of diabetes and represents a leading cause of acquired vision loss in adults of working age worldwide. Thus, DR has a major impact on economic well-being as well as overall public health. The role of hyperglycemia in the complications of diabetes is well established. In 1993, the Diabetes Control and Complications Trial (DCCT) clearly showed that intensive control of hyperglycemia slows down the development and progression of the microvascular complications of diabetes including DR.

While DR is diagnosed based on signs of retinal vascular pathology, including the presence of microaneurysms, hemorrhages and exudates, recent studies indicate that injury/dysfunction of retinal photoreceptors, neurons and glial cells is also involved. The aim of this Special Issue is to provide an updated point of view about multiple pathophysiological mechanisms implicated in DR.

Prof. Ruth B. Caldwell
Prof. Manuela Bartoli
Dr. S. Priya Narayanan
Prof. R. William Caldwell
Guest Editors

Manuscript Submission Information

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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. Journal of Clinical Medicine 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 2600 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

  • Diabetic retinopathy
  • Neurovascular injury
  • Vascular dysfunction
  • Epigenetic mechanisms
  • Oxidative injury
  • Inflammation

Published Papers (15 papers)

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Research

Jump to: Review

17 pages, 4841 KiB  
Article
Ursodeoxycholic Acid Halts Pathological Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy
by Menaka C. Thounaojam, Ravirajsinh N. Jadeja, Shubhra Rajpurohit, Diana R. Gutsaeva, Brian K. Stansfield, Pamela M. Martin and Manuela Bartoli
J. Clin. Med. 2020, 9(6), 1921; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9061921 - 19 Jun 2020
Cited by 5 | Viewed by 3383
Abstract
Retinopathy of prematurity (ROP) is the leading cause of blindness in infants. We have investigated the efficacy of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine and glycine conjugated derivatives tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization [...] Read more.
Retinopathy of prematurity (ROP) is the leading cause of blindness in infants. We have investigated the efficacy of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine and glycine conjugated derivatives tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization (RNV) in an experimental model of ROP. Seven-day-old mice pups (P7) were subjected to oxygen-induced retinopathy (OIR) and were treated with bile acids for various durations. Analysis of retinal vascular growth and distribution revealed that UDCA treatment (50 mg/kg, P7–P17) of OIR mice decreased the extension of neovascular and avascular areas, whereas treatments with TUDCA and GUDCA showed no changes. UDCA also prevented reactive gliosis, preserved ganglion cell survival, and ameliorated OIR-induced blood retinal barrier dysfunction. These effects were associated with decreased levels of oxidative stress markers, inflammatory cytokines, and normalization of the VEGF–STAT3 signaling axis. Furthermore, in vitro tube formation and permeability assays confirmed UDCA inhibitory activity toward VEGF-induced pro-angiogenic and pro-permeability effects on human retinal microvascular endothelial cells. Collectively, our results suggest that UDCA could represent a new effective therapy for ROP. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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17 pages, 2361 KiB  
Article
Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy
by Lamiaa Shalaby, Menaka Thounaojam, Amany Tawfik, Junnan Li, Khaled Hussein, Wan Jin Jahng, Mohamed Al-Shabrawey, Hang Fai Kwok, Manuela Bartoli and Diana Gutsaeva
J. Clin. Med. 2020, 9(2), 400; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9020400 - 02 Feb 2020
Cited by 15 | Viewed by 3455
Abstract
ADAM17, a disintegrin and metalloproteinase 17, is a transmembrane metalloproteinase that regulates bioavailability of multiple membrane-bound proteins via ectodomain shedding. ADAM17 activity was shown to contribute to a number of vascular pathologies, but its role in the context of diabetic retinopathy (DR) is [...] Read more.
ADAM17, a disintegrin and metalloproteinase 17, is a transmembrane metalloproteinase that regulates bioavailability of multiple membrane-bound proteins via ectodomain shedding. ADAM17 activity was shown to contribute to a number of vascular pathologies, but its role in the context of diabetic retinopathy (DR) is not determined. We found that expression and enzymatic activity of ADAM17 are upregulated in human diabetic postmortem retinas and a mouse model of streptozotocin-induced diabetes. To further investigate the contribution of ADAM17 to vascular alterations associated with DR, we used human retinal endothelial cells (HREC) treated with ADAM17 neutralizing antibodies and exposed to glucidic stress and streptozotocin-induced endothelial ADAM17 knockout mice. Evaluation of vascular permeability, vascular inflammation, and oxidative stress was performed. Loss of ADAM17 in endothelial cells markedly reduced oxidative stress evidenced by decreased levels of superoxide, 3-nitrotyrosine, and 4-hydroxynonenal and decreased leukocyte-endothelium adhesive interactions in vivo and in vitro. Reduced leukostasis was associated with decreased vascular permeability and was accompanied by downregulation of intercellular adhesion molecule-1 expression. Reduction in oxidative stress in HREC was associated with downregulation of NAD(P)H oxidase 4 (Nox4) expression. Our data suggest a role for endothelial ADAM17 in DR pathogenesis and identify ADAM17 as a potential new therapeutic target for DR. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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18 pages, 4178 KiB  
Article
Pharmacological Inhibition of Spermine Oxidase Reduces Neurodegeneration and Improves Retinal Function in Diabetic Mice
by Fang Liu, Alan B. Saul, Prahalathan Pichavaram, Zhimin Xu, Madhuri Rudraraju, Payaningal R. Somanath, Sylvia B. Smith, Ruth B. Caldwell and S. Priya Narayanan
J. Clin. Med. 2020, 9(2), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9020340 - 25 Jan 2020
Cited by 27 | Viewed by 3824
Abstract
Diabetic retinopathy (DR) is a significant cause of blindness in working-age adults worldwide. Lack of effective strategies to prevent or reduce vision loss is a major problem. Since the degeneration of retinal neurons is an early event in the diabetic retina, studies to [...] Read more.
Diabetic retinopathy (DR) is a significant cause of blindness in working-age adults worldwide. Lack of effective strategies to prevent or reduce vision loss is a major problem. Since the degeneration of retinal neurons is an early event in the diabetic retina, studies to characterize the molecular mechanisms of diabetes-induced retinal neuronal damage and dysfunction are of high significance. We have demonstrated that spermine oxidase (SMOX), a mediator of polyamine oxidation is critically involved in causing neurovascular damage in the retina. The involvement of SMOX in diabetes-induced retinal neuronal damage is completely unknown. Utilizing the streptozotocin-induced mouse model of diabetes, the impact of the SMOX inhibitor, MDL 72527, on neuronal damage and dysfunction in the diabetic retina was investigated. Retinal function was assessed by electroretinography (ERG) and retinal architecture was evaluated using spectral domain-optical coherence tomography. Retinal cryosections were prepared for immunolabeling of inner retinal neurons and retinal lysates were used for Western blotting. We observed a marked decrease in retinal function in diabetic mice compared to the non-diabetic controls. Treatment with MDL 72527 significantly improved the ERG responses in diabetic retinas. Diabetes-induced retinal thinning was also inhibited by the MDL 72527 treatment. Our analysis further showed that diabetes-induced retinal ganglion cell damage and neurodegeneration were markedly attenuated by MDL 72527 treatment. These results strongly implicate SMOX in diabetes-induced retinal neurodegeneration and visual dysfunction. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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17 pages, 3726 KiB  
Article
Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity
by Reem T. Atawia, Katharine L. Bunch, Abdelrahman Y. Fouda, Tahira Lemtalsi, Wael Eldahshan, Zhimin Xu, Alan Saul, Khaled Elmasry, Mohamed Al-Shabrawey, Ruth B. Caldwell and R. William Caldwell
J. Clin. Med. 2020, 9(2), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9020317 - 22 Jan 2020
Cited by 16 | Viewed by 3299
Abstract
Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical [...] Read more.
Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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14 pages, 3873 KiB  
Article
Identification of Diagnostic and Prognostic microRNAs for Recurrent Vitreous Hemorrhage in Patients with Proliferative Diabetic Retinopathy
by Parviz Mammadzada, Juliette Bayle, Johann Gudmundsson, Anders Kvanta and Helder André
J. Clin. Med. 2019, 8(12), 2217; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8122217 - 15 Dec 2019
Cited by 20 | Viewed by 2937
Abstract
MicroRNAs (miRNAs) can provide insight into the pathophysiological states of ocular tissues such as proliferative diabetic retinopathy (PDR). In this study, differences in miRNA expression in vitreous from PDR patients with and without incidence of recurrent vitreous hemorrhage (RVH) after the initial pars-plana [...] Read more.
MicroRNAs (miRNAs) can provide insight into the pathophysiological states of ocular tissues such as proliferative diabetic retinopathy (PDR). In this study, differences in miRNA expression in vitreous from PDR patients with and without incidence of recurrent vitreous hemorrhage (RVH) after the initial pars-plana vitrectomy (PPV) were analyzed, with the aim of identifying biomarkers for RVH. Fifty-four consented vitreous samples were analyzed from patients undergoing PPV for PDR, of which eighteen samples underwent a second surgery due to RVH. Ten of the sixty-six expressed miRNAs (miRNAs-19a, -20a, -22, -27a, -29a, -93, -126, -128, -130a, and -150) displayed divergences between the PDR vitreous groups and to the control. A significant increase in the miRNA-19a and -27a expression was determined in PDR patients undergoing PPV as compared to the controls. miRNA-20a and -93 were significantly upregulated in primary PPV vitreous samples of patients afflicted with RVH. Moreover, this observed upregulation was not significant between the non-RVH and control group, thus emphasizing the association with RVH incidence. miRNA-19a and -27a were detected as putative vitreous biomarkers for PDR, and elevated levels of miRNA-20a and -93 in vitreous with RVH suggest their biomarker potential for major PDR complications such as recurrent hemorrhage incidence. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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13 pages, 2254 KiB  
Article
Assessment of Inner Retinal Layers and Choroidal Thickness in Type 1 Diabetes Mellitus: A Cross-Sectional Study
by Marc Carbonell, Núria Alonso, Esmeralda Castelblanco, Jordi Real, Anna Ramírez-Morros, Rafael Simó, Cristina Hernández, Carme Jurjo, Alícia Traveset, Xavier Valldeperas and Dídac Mauricio
J. Clin. Med. 2019, 8(9), 1412; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091412 - 08 Sep 2019
Cited by 20 | Viewed by 2602
Abstract
Recent studies have shown that retinal neurodegeneration may precede visible vascular changes in diabetic retinopathy (DR). In addition, the relationship of choroidal thickness (CT) with DR stage is not well defined. To assess the inner retinal and choroidal structural changes in type 1 [...] Read more.
Recent studies have shown that retinal neurodegeneration may precede visible vascular changes in diabetic retinopathy (DR). In addition, the relationship of choroidal thickness (CT) with DR stage is not well defined. To assess the inner retinal and choroidal structural changes in type 1 diabetic subjects (T1D), a cross-sectional study was conducted in 242 T1D patients and in 69 age-matched, non-diabetic individuals. The nasal retinal nerve fibre layer (RNFL) thickness was lower in T1D patients without DR (p < 0.001), with mild DR (p < 0.001), and with advanced DR (p < 0.001) compared to control subjects. The ganglion cell layer (GCL) thickness was lower in T1D patients with advanced DR compared to those with mild DR (p = 0.003) and without DR (p < 0.001) and compared to the control subjects (p < 0.001). T1D subjects with no DR and mild DR had higher CT than the control subjects, but the CT in T1D patients with advanced DR was lower (p = 0.038) than that in T1D subjects with mild DR and was not significantly different from that of the control subjects. In conclusion, T1D subjects showed a significant thinning of the nasal RNFL in the early stages of the disease, even before any vascular changes in the retina. A decrease in the GCL thickness during advanced DR stages was observed. Choroidal thickness was higher in T1D subjects without DR and in early DR stages but decreased in advanced stages. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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16 pages, 1903 KiB  
Article
Retinal Blood Velocity and Flow in Early Diabetes and Diabetic Retinopathy Using Adaptive Optics Scanning Laser Ophthalmoscopy
by Cherilyn Mae A. Palochak, Hee Eun Lee, Jessica Song, Andrew Geng, Robert A. Linsenmeier, Stephen A. Burns and Amani A. Fawzi
J. Clin. Med. 2019, 8(8), 1165; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8081165 - 03 Aug 2019
Cited by 46 | Viewed by 5135
Abstract
Using adaptive optics scanning laser ophthalmoscopy (AOSLO), we measured retinal blood velocity and flow in healthy control eyes and eyes of diabetic patients with or without retinopathy. This cross-sectional study included 39 eyes of 30 patients with diabetes (DM) with mild non-proliferative diabetic [...] Read more.
Using adaptive optics scanning laser ophthalmoscopy (AOSLO), we measured retinal blood velocity and flow in healthy control eyes and eyes of diabetic patients with or without retinopathy. This cross-sectional study included 39 eyes of 30 patients with diabetes (DM) with mild non-proliferative diabetic retinopathy (NPDR) or without retinopathy (DM no DR) and 21 eyes of 17 healthy age-matched controls. Participants were imaged with a commercial optical coherence tomography angiography (OCTA) device (RTVue-XR Avanti) and AOSLO device (Apaeros Retinal Imaging System, Boston Micromachines). We analyzed AOSLO-based retinal blood velocity and flow, and OCTA-based vessel density of the superficial (SCP), deep retinal capillary plexus (DCP), and full retina. Retinal blood velocity was significantly higher in eyes with DM no DR and lower in NPDR across all vessel diameters compared to controls. Retinal blood flow was significantly higher in DM no DR and lower in NPDR in vessel diameters up to 60 μm compared to controls. When comparing flow outliers (low-flow DM no DR eyes and high-flow NPDR eyes), we found they had a significantly different retinal vessel density compared to the remaining eyes in the respective groups. Retinal blood velocity and flow is increased in eyes with DM no DR, while these parameters are decreased in eyes with mild NPDR compared to healthy age-matched controls. The similarity of OCTA vessel density among outliers in the two diabetic groups suggests an initial increase followed by progressive decline in blood flow and OCTA vessel density with progression to clinical retinopathy, which warrants further investigation. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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12 pages, 2892 KiB  
Article
Glycyrrhizin Protects the Diabetic Retina against Permeability, Neuronal, and Vascular Damage through Anti-Inflammatory Mechanisms
by Li Liu, Youde Jiang and Jena J. Steinle
J. Clin. Med. 2019, 8(7), 957; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8070957 - 02 Jul 2019
Cited by 28 | Viewed by 3125
Abstract
Damage associated molecular pattern (DAMPs), such as high mobility group box 1 (HMGB1), may be involved in retinal inflammation in response to high glucose. To test whether HMGB1 inhibition could protect the diabetic retina, C57BL/6J mice were made diabetic and treated with glycyrrhizin, [...] Read more.
Damage associated molecular pattern (DAMPs), such as high mobility group box 1 (HMGB1), may be involved in retinal inflammation in response to high glucose. To test whether HMGB1 inhibition could protect the diabetic retina, C57BL/6J mice were made diabetic and treated with glycyrrhizin, a HMGB1 inhibitor, for up to six months. Measurements of permeability, neuronal, and vascular changes were done, as well as assessments of HMGB1, tumor necrosis factor alpha (TNFα), and interleukin-1-beta (IL1β) levels. Retinal endothelial cells (REC) treated with glycyrrhizin had reduced IL1β and cleaved caspase 3 levels. Data also demonstrate that glycyrrhizin effectively reduced HMGB1 levels throughout the retina, as well as maintained normal retinal permeability and retinal capillary coverage. Glycyrrhizin maintained normal cell numbers in the ganglion cell layer and prevented thinning of the retina at two months. These histological changes were associated with reduced reactive oxygen species, as well as reduced HMGB1, TNFα, and IL1β levels. The data strongly imply that HMGB1 inhibition prevented diabetic retinal changes through anti-inflammatory pathways. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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14 pages, 2966 KiB  
Article
Loss of XBP1 Leads to Early-Onset Retinal Neurodegeneration in a Mouse Model of Type I Diabetes
by Todd McLaughlin, Manhal Siddiqi, Joshua J. Wang and Sarah X. Zhang
J. Clin. Med. 2019, 8(6), 906; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8060906 - 25 Jun 2019
Cited by 17 | Viewed by 3733
Abstract
Retinal neuronal injury and degeneration is one of the primary manifestations of diabetic retinopathy, a leading cause of vision loss in working age adults. In pathological conditions, including diabetes and some physiological conditions such as aging, protein homeostasis can become disrupted, leading to [...] Read more.
Retinal neuronal injury and degeneration is one of the primary manifestations of diabetic retinopathy, a leading cause of vision loss in working age adults. In pathological conditions, including diabetes and some physiological conditions such as aging, protein homeostasis can become disrupted, leading to endoplasmic reticulum (ER) stress. Severe or unmitigated ER stress can lead to cell death, which in retinal neurons results in irreversible loss of visual function. X-box binding protein 1 (XBP1) is a major transcription factor responsible for the adaptive unfolded protein response (UPR) to maintain protein homeostasis in cells undergoing ER stress. The purpose of this study is to determine the role of XBP1-mediated UPR in retinal neuronal survival and function in a mouse model of type 1 diabetes. Using a conditional retina-specific XBP1 knockout mouse line, we demonstrate that depletion of XBP1 in retinal neurons results in early onset retinal function decline, loss of retinal ganglion cells and photoreceptors, disrupted photoreceptor ribbon synapses, and Müller cell activation after induction of diabetes. Our findings suggest an important role of XBP1-mediated adaptive UPR in retinal neuronal survival and function in diabetes. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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11 pages, 4321 KiB  
Article
Epac1 and Glycyrrhizin Both Inhibit HMGB1 Levels to Reduce Diabetes-Induced Neuronal and Vascular Damage in the Mouse Retina
by Li Liu, Youde Jiang and Jena J. Steinle
J. Clin. Med. 2019, 8(6), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8060772 - 31 May 2019
Cited by 24 | Viewed by 3415
Abstract
The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the [...] Read more.
The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the role of exchange protein for cAMP 1 (Epac1) on HMGB1 and the actions of glycyrrhizin. Using endothelial cell specific knockout mice for Epac1, we made some mice diabetic using streptozotocin, and treated some with glycyrrhizin for up to 6 months. We measured permeability, neuronal, and vascular changes in the Epac1 floxed and knockout mice. We also investigated whether Epac1 and glycyrrhizin work synergistically to reduce the retinal inflammatory mediators, tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL1β), as well as sirtuin 1 (SIRT1) levels. Epac1 and glycyrrhizin reduced inflammatory mediators with synergistic actions. Glycyrrhizin also increased SIRT1 levels in the Epac1 mice. Overall, these studies demonstrate that glycyrrhizin and Epac1 can work together to protect the retina. Finally, glycyrrhizin may regulate HMGB1 through increased SIRT1 actions. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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Review

Jump to: Research

18 pages, 1128 KiB  
Review
Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?
by Esraa Shosha, Abdelrahman Y. Fouda, S. Priya Narayanan, R. William Caldwell and Ruth B. Caldwell
J. Clin. Med. 2020, 9(2), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9020425 - 05 Feb 2020
Cited by 17 | Viewed by 4851
Abstract
Diabetic retinopathy (DR) is the leading cause of blindness in working age Americans. Clinicians diagnose DR based on its characteristic vascular pathology, which is evident upon clinical exam. However, extensive research has shown that diabetes causes significant neurovascular dysfunction prior to the development [...] Read more.
Diabetic retinopathy (DR) is the leading cause of blindness in working age Americans. Clinicians diagnose DR based on its characteristic vascular pathology, which is evident upon clinical exam. However, extensive research has shown that diabetes causes significant neurovascular dysfunction prior to the development of clinically apparent vascular damage. While laser photocoagulation and/or anti-vascular endothelial growth factor (VEGF) therapies are often effective for limiting the late-stage vascular pathology, we still do not have an effective treatment to limit the neurovascular dysfunction or promote repair during the early stages of DR. This review addresses the role of arginase as a mediator of retinal neurovascular injury and therapeutic target for early stage DR. Arginase is the ureohydrolase enzyme that catalyzes the production of L-ornithine and urea from L-arginine. Arginase upregulation has been associated with inflammation, oxidative stress, and peripheral vascular dysfunction in models of both types of diabetes. The arginase enzyme has been identified as a therapeutic target in cardiovascular disease and central nervous system disease including stroke and ischemic retinopathies. Here, we discuss and review the literature on arginase-induced retinal neurovascular dysfunction in models of DR. We also speculate on the therapeutic potential of arginase in DR and its related underlying mechanisms. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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17 pages, 1293 KiB  
Review
Do Genomic Factors Play a Role in Diabetic Retinopathy?
by Andrea P. Cabrera, Finny Monickaraj, Sampathkumar Rangasamy, Sam Hobbs, Paul McGuire and Arup Das
J. Clin. Med. 2020, 9(1), 216; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010216 - 14 Jan 2020
Cited by 33 | Viewed by 4569
Abstract
Although there is strong clinical evidence that the control of blood glucose, blood pressure, and lipid level can prevent and slow down the progression of diabetic retinopathy (DR) as shown by landmark clinical trials, it has been shown that these factors only account [...] Read more.
Although there is strong clinical evidence that the control of blood glucose, blood pressure, and lipid level can prevent and slow down the progression of diabetic retinopathy (DR) as shown by landmark clinical trials, it has been shown that these factors only account for 10% of the risk for developing this disease. This suggests that other factors, such as genetics, may play a role in the development and progression of DR. Clinical evidence shows that some diabetics, despite the long duration of their diabetes (25 years or more) do not show any sign of DR or show minimal non-proliferative diabetic retinopathy (NPDR). Similarly, not all diabetics develop proliferative diabetic retinopathy (PDR). So far, linkage analysis, candidate gene studies, and genome-wide association studies (GWAS) have not produced any statistically significant results. We recently initiated a genomics study, the Diabetic Retinopathy Genetics (DRGen) Study, to examine the contribution of rare and common variants in the development of different phenotypes of DR, as well as their responsiveness to anti-VEGF treatment in diabetic macular edema (DME). Our preliminary findings reveal a novel set of genetic variants involved in the angiogenesis and inflammatory pathways that contribute to DR progression or protection. Further investigation of variants can help to develop novel biomarkers and lead to new therapeutic targets in DR. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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10 pages, 800 KiB  
Review
Mitochondrial Structural Changes in the Pathogenesis of Diabetic Retinopathy
by Sayon Roy, Dongjoon Kim and Aravind Sankaramoorthy
J. Clin. Med. 2019, 8(9), 1363; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091363 - 01 Sep 2019
Cited by 25 | Viewed by 7725
Abstract
At the core of proper mitochondrial functionality is the maintenance of its structure and morphology. Physical changes in mitochondrial structure alter metabolic pathways inside mitochondria, affect mitochondrial turnover, disturb mitochondrial dynamics, and promote mitochondrial fragmentation, ultimately triggering apoptosis. In high glucose condition, increased [...] Read more.
At the core of proper mitochondrial functionality is the maintenance of its structure and morphology. Physical changes in mitochondrial structure alter metabolic pathways inside mitochondria, affect mitochondrial turnover, disturb mitochondrial dynamics, and promote mitochondrial fragmentation, ultimately triggering apoptosis. In high glucose condition, increased mitochondrial fragmentation contributes to apoptotic death in retinal vascular and Müller cells. Although alterations in mitochondrial morphology have been detected in several diabetic tissues, it remains to be established in the vascular cells of the diabetic retina. From a mechanistic standpoint, our current work supports the notion that increased expression of fission genes and decreased expression of fusion genes are involved in promoting excessive mitochondrial fragmentation. While mechanistic insights are only beginning to reveal how high glucose alters mitochondrial morphology, the consequences are clearly seen as release of cytochrome c from fragmented mitochondria triggers apoptosis. Current findings raise the prospect of targeting excessive mitochondrial fragmentation as a potential therapeutic strategy for treatment of diabetic retinopathy. While biochemical and epigenetic changes have been reported to be associated with mitochondrial dysfunction, this review focuses on alterations in mitochondrial morphology, and their impact on mitochondrial function and pathogenesis of diabetic retinopathy. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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26 pages, 702 KiB  
Review
Diabetic Retinopathy, lncRNAs, and Inflammation: A Dynamic, Interconnected Network
by Saumik Biswas, Marie Sarabusky and Subrata Chakrabarti
J. Clin. Med. 2019, 8(7), 1033; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8071033 - 14 Jul 2019
Cited by 38 | Viewed by 4861
Abstract
Diabetic retinopathy (DR) is reaching epidemic levels globally due to the increase in prevalence of diabetes mellitus (DM). DR also has detrimental effects to quality of life, as it is the leading cause of blindness in the working-age population and the most common [...] Read more.
Diabetic retinopathy (DR) is reaching epidemic levels globally due to the increase in prevalence of diabetes mellitus (DM). DR also has detrimental effects to quality of life, as it is the leading cause of blindness in the working-age population and the most common cause of vision loss in individuals with DM. Over several decades, many studies have recognized the role of inflammation in the development and progression of DR; however, in recent years, accumulating evidence has also suggested that non-coding RNAs, especially long non-coding (lncRNAs), are aberrantly expressed in diabetes and may play a putative role in the development and progression of DR through the modulation of gene expression at the transcriptional, post-transcriptional, or epigenetic level. In this review, we will first highlight some of the key inflammatory mediators and transcription factors involved in DR, and we will then introduce the critical roles of lncRNAs in DR and inflammation. Following this, we will discuss the implications of lncRNAs in other epigenetic mechanisms that may also contribute to the progression of inflammation in DR. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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Review
The Regulatory Role of Rac1, a Small Molecular Weight GTPase, in the Development of Diabetic Retinopathy
by Nikhil Sahajpal, Anjan Kowluru and Renu A. Kowluru
J. Clin. Med. 2019, 8(7), 965; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8070965 - 03 Jul 2019
Cited by 23 | Viewed by 4100
Abstract
Diabetic retinopathy, a microvascular complication of diabetes, remains the leading cause of vision loss in working age adults. Hyperglycemia is considered as the main instigator for its development, around which other molecular pathways orchestrate. Of these multiple pathways, oxidative stress induces many metabolic, [...] Read more.
Diabetic retinopathy, a microvascular complication of diabetes, remains the leading cause of vision loss in working age adults. Hyperglycemia is considered as the main instigator for its development, around which other molecular pathways orchestrate. Of these multiple pathways, oxidative stress induces many metabolic, functional and structural changes in the retinal cells, leading to the development of pathological features characteristic of this blinding disease. An increase in cytosolic reactive oxygen species (ROS), produced by cytosolic NADPH oxidase 2 (Nox2), is an early event in the pathogenesis of diabetic retinopathy, which leads to mitochondrial damage and retinal capillary cell apoptosis. Activation of Nox2 is mediated through an obligatory small molecular weight GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), and subcellular localization of Rac1 and its activation are regulated by several regulators, rendering it a complex biological process. In diabetes, Rac1 is functionally activated in the retina and its vasculature, and, via Nox2-ROS, contributes to mitochondrial damage and the development of retinopathy. In addition, Rac1 is also transcriptionally activated, and epigenetic modifications play a major role in this transcriptional activation. This review focusses on the role of Rac1 and its regulation in the development and progression of diabetic retinopathy, and discusses some possible avenues for therapeutic interventions. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Biomolecules and Pathophysiology)
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