Together, our data suggest that the TXNIP/NLRP3 pathway is a potential therapeutic target for the treatment of DR, and the use of minocycline specifically for such therapy may be a new avenue of investigation in inflammatory disease.

Purpose This study aimed to evaluate the mechanisms underlying the effects of 1,25-dihydroxyvitamin D (vitamin D3) on diabetes-induced retinal vascular damage and retinal vascular endothelial cell apoptosis. Methods Diabetic and control rats were randomly assigned to receive vitamin D3 or vehicle for 6 months. Additionally, human retinal microvascular endothelial cells (HRMECs) were incubated in normal or high-glucose medium with or without vitamin D3. Morphological changes in retinal tissues and retinal vascular permeability were examined, and cellular apoptosis was detected by fluorescence staining. Intracellular reactive oxygen species (ROS) levels were determined using fluorescent probes. Proteins were examined by Western blotting. Results Vitamin D3 significantly downregulated intracellular ROS and inhibited TRX-interacting protein (TXNIP)/NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation. Additionally, vitamin D3 reduced vascular endothelial growth factor (VEGF) expression and the Bax/Bcl-2 ratio. These changes were associated with retinal recovery and with decreases in retinal vascular permeability and retinal capillary cell apoptosis. Conclusions Vitamin D3 decreases diabetes-induced ROS and exerts protective effects against retinal vascular damage and cell apoptosis in association with inhibition of the ROS/TXNIP/NLRP3 inflammasome pathway. Understanding the mechanisms of action of vitamin D3 has important implications for preventing and treating inflammatory-related illnesses such as diabetic retinopathy.

Aims/hypothesis The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. Methods The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. Results High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. Conclusions/interpretation These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucoseinduced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

This review focuses on the RhoA/mDia-1/profilin-1 signaling pathway that specifically triggers endothelial dysfunction in diabetic patients. Recently, RhoA and profilin-1 signaling has attracted a great deal of attention in the context of diabetes-related research. However, the precise molecular mechanism by which the RhoA/mDia-1/profilin-1 pathway is involved in progression of microvascular endothelial dysfunction (MVED) during DR has not been determined. This review briefly describes each feature of the cascade before exploring the most recent findings on how the pathway may trigger endothelial dysfunction in DR. When the underlying mechanisms are understood, novel therapies seeking to restore the endothelial homeostasis comprised in DR will become possible.