Diabetic retinopathy, oxidative stress, and sirtuins: an in depth look in enzymatic patterns and new therapeutic horizons.

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. DR represents the most common microvascular complication of diabetes, and its incidence is constantly rising. The complex interactions between inflammation, oxidative stress, and the production of free oxygen radicals caused by prolonged exposure to hyperglycemia determine the development of DR. Sirtuins (SIRTs) are a recently discovered class of 7 histone deacetylases involved in cellular senescence, regulation of cell cycle, metabolic pathways, and DNA repair. SIRTs participate in the progress of several pathologies such as cancer, neurodegeneration, and metabolic diseases. In DR sirtuins 1,3,5, and 6 play an important role as they regulate the activation of the inflammatory response, insulin sensibility, and both glycolysis and gluconeogenesis. A wide spectrum of direct and indirect activators of SIRTs pathways (e.g., antagomiR, resveratrol, or glycyrrhizin) is currently being developed to treat the inflammatory cascade occurring in DR. We focus on the main metabolic and inflammatory pathways involving SIRTs and DR, as well as recent evidence on SIRTs activators that may be employed as novel therapeutic approaches to DR.

The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies.

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.