br Experimental section br Acknowledgements This research wa

Experimental section
Acknowledgements This research was supported by the National Natural Science Foundation of China (81402795) and a Grant from the Bureau of Education of Guangzhou Municipality (1201630308).
Introduction Diabetes mellitus is a serious worldwide health problem. The higher prevalence of diabetes seen in recent decades increases the risk of serious diabetes complications. Diabetic retinopathy is one of the major complications of diabetes and the main cause of diabetes-related blindness [1]. It has been estimated that approximately one third of diabetes patients have signs of retinopathy and many of them have vision-threatening risk factors [2]. The retina is a specialized tissue that converts visible light into the neuronal signals which are perceived by the brain. The retina\'s unique vascular system provides nutrients and oxygen to the inner and outer retina, the integrity of which is essential for sensing light. The retinal vascular structure has features similar to the blood EHop-016 receptor barrier and is highly sensitive to the microenvironment. Upon prolonged exposure to chronic hyperglycemia conditions, retinal endothelial cells undergo a range of unique structural changes, such as altered permeability, hyper-proliferation of endothelial cells and edema, and abnormal vascularization of the retina, resulting in loss of vision. Extensive studies have demonstrated that oxidative stress and inflammation are linked to one another and act as significant drivers of these diabetic complications. Recent research has been focused on specific mechanism-based strategies to target both oxidative stress and inflammatory pathways, thereby improving the complication burden of diabetes patients, including retinopathy [3]. Often the early stages of diabetic retinopathy have no visual symptoms, so early detection and treatment is of utmost importance in preventing significant vision loss from diabetic retinopathy. It has been proposed that an efficient early medical treatment would be significant in preventing further vision loss due to diabetic retinopathy. Gliptins have become a part of various therapeutic regimens to treat type 2 diabetics in recent decades. Gliptins were developed to lower the blood glucose in type 2 diabetes patients and have been shown to be effective [4,5]. More than a dozen gliptins have been developed for the treatment of T2DM, including the most commonly used alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin [6]. In this study, we report that linagliptin, a commercially available DPP-4 inhibitor, actually exerts a protective effect in cultured retinal vascular endothelial cells.
Materials and methods
Results
Discussion Like other gliptin compounds, linagliptin acts by inhibiting the enzymatic activity of DPP-4, stabilizing incretins such as GLP-1, and ultimately lowering blood glucose. Linagliptin is unique among the gliptins. Its administration has a mild influence on hepatic function, and it is excreted largely by non-renal routes. Therefore, dose adjustment is not required in patients with renal and hepatic impairment [5]. Aside from its ability to lower blood glucose, linagliptin has been shown to be effective for cardiovascular outcomes [8]. In vascular endothelial cells, recent studies have shown that linagliptin has vascular benefits and these properties are independent of its glucose-lowering property. Multiple separate studies have shown that linagliptin treatment could prevent diabetes condition and generation of ROS and inflammatory genes including RAGE, ICAM-1, SOD2, and PAI-1 expression in endothelial cells induced by its byproducts [[9], [10], [11]]. Vellecco V et al. showed that linagliptin exerts a direct vasodilation activity on vessels from both normal and hyperglycemic mice, suggesting that the vascular effect of linagliptin is independent from its ability to control glucose. Additionally, cell experiments have concluded that linagliptin increases eNOS availability and enhances NO production [12]. Romacho T et al. found that linagliptin helps to preserve microvascular endothelial function by suppressing PAR2 activation and thromboxane A2 release [13].