Abstract
High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte activation and migration, tumorigenesis, neoangiogenesis, and the activation of several inflammatory pathways. HMGB1 is, in fact, responsible for the trigger, among others, of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and vascular endothelial growth factor (VEGF) pathways. Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM) that is rapidly growing in number. DR is an inflammatory disease caused by hyperglycemia, which determines the accumulation of oxidative stress and cell damage, which ultimately leads to hypoxia and neovascularization. Recent evidence has shown that hyperglycemia is responsible for the hyperexpression of HMGB1. This protein activates numerous pathways that cause the development of DR, and HMGB1 levels are constantly increased in diabetic retinas in both proliferative and non-proliferative stages of the disease. Several molecules, such as glycyrrhizin (GA), have proven effective in reducing diabetic damage to the retina through the inhibition of HMGB1. The main focus of this review is the growing amount of evidence linking HMGB1 and DR as well as the new therapeutic strategies involving this protein.
Highlights
Introduction to DiabeticRetinopathy (DR)Diabetes mellitus (DM) is a well-known metabolic disease that causes numerous chronic complications
The silencing of High-mobility group box 1 (HMGB1) inhibits the activation of MAPK and nuclear factor-κB (NF-κB) signaling pathway; modulates the levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), influencing endothelial permeability; attenuates cell apoptosis, blood–retinal barrier (BRB) damage, and the inflammatory response induced by high concentration of glucose [83]
hypoxia-induced factor-1α (HIF-1α) is associated with retinal inflammation induced by diabetes, early growth response protein-1 (Egr-1) may play a role in the development of vascular complications of diabetes mellitus (DM), and the CXCL12/CXCR4 chemokine axis contributes to neovascularization
Summary
Information regarding the function of HMGB1 in DR is mostly limited to murine and information in vitro studies. At themodels moment, regarding the function of HMGB1of in DR is mostly limited activation of inflammatory signaling pathways such as the RAGE-mediated activation murine models and in vitro studies. Intravitreal injection of HMGB1 mimics the effects of diabetes and increases RAGE, ERK1/2, NF-κB, These mechanisms decrease TLR-2 and occludin expression, increasing retinal vascular permeability and proinflammatory biomarkers such as ICAM-1 and soluble ICAM-1 (Scheme 2). These mechanisms and disrupting the stability of tight junction complex between adjacent retinal microvascular EC decrease TLR-2 and occludin expression, increasing retinal vascular permeability and disrupting the [66].
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