HMGB1 and neuropathy: Numerous studies have shown that ROS generated by NOX2 can lead to microvascular dysfunction in the early stages of DR, possibly through specific mechanisms: (1) Positive feedback between high mobility group box-1 (HMGB1) and NOX-derived ROS mediates the diabetes-induced up-regulation of retinal apoptotic markers (e.g., PARP-1 and caspase-3), which leads to retinal apoptosis, causing vasculopathy and neuropathy [92].