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      Glycyrrhizin Protects the Diabetic Retina against Permeability, Neuronal, and Vascular Damage through Anti-Inflammatory Mechanisms

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          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, 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.

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          A central role for inflammation in the pathogenesis of diabetic retinopathy.

          Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.
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            Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities.

            High-mobility group box 1 protein (HMGB1) is a nuclear component, but extracellularly it serves as a signaling molecule involved in acute and chronic inflammation, for example in sepsis and arthritis. The identification of HMGB1 inhibitors is therefore of significant experimental and clinical interest. We show that glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, inhibits HMGB1 chemoattractant and mitogenic activities, and has a weak inhibitory effect on its intranuclear DNA-binding function. NMR and fluorescence studies indicate that glycyrrhizin binds directly to HMGB1 (K(d) approximately 150 microM), interacting with two shallow concave surfaces formed by the two arms of both HMG boxes. Our results explain in part the anti-inflammatory properties of glycyrrhizin, and might direct the design of new derivatives with improved HMGB1-binding properties.
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              Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia.

              The proinflammatory cytokine, interleukin (IL)-1beta, is known to induce vascular dysfunction and cell death. We investigated the role of IL-1beta and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Caspase-1 activity is increased in retinas of diabetic and galactosemic mice and diabetic patients. First, we investigated the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1beta production and retinal capillary degeneration in diabetic and galactose-fed mice. Second, we examined the effect of genetic deletion of the IL-1beta receptor on diabetes-induced caspase activities and retinal capillary degeneration. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5 mg/kg). At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1beta production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro but not in vivo. Mice deficient in the IL-1beta receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. These results indicate that the caspase-1/IL-1beta signaling pathway plays an important role in diabetes-induced retinal pathology, and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                02 July 2019
                July 2019
                : 8
                : 7
                : 957
                Affiliations
                Visual, and Anatomical Sciences, Department of Ophthalmology, Wayne State University, Detroit, MI 48202, USA
                Author notes
                [* ]Correspondence: jsteinle@ 123456med.wayne.edu ; Tel.: +1-313-577-9731; Fax: +1-313-577-3125
                Author information
                https://orcid.org/0000-0002-7539-2892
                Article
                jcm-08-00957
                10.3390/jcm8070957
                6678129
                31269685
                6629301e-4d57-40ea-9a2f-77dc389d5ada
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 May 2019
                : 29 June 2019
                Categories
                Article

                diabetic retinopathy,inflammation,endothelial cells,glycyrrhizin,high mobility group box 1 (hmgb1)

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