Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and angiogenesis through regulating Sestrin2/Nrf2 signaling

Abstract

To explore the potential function of tricin in diabetic retinopathy (DR) and investigate whether Sestrin2 is closely involved in DR. A single intraperitoneal injection of streptozotocin-induced diabetes model in Sprague-Dawley rats and a high glucose-induced retinal epithelial cell model in ARPE-19 cells were established. The retinas were removed and examined by hematoxylin-eosin (HE) staining and dihydroethidium (DHE) staining. The proliferation ability and reactive oxygen species (ROS) level of ARPE-19 cells were detected by 5-ethynyl-2′-deoxyuridine (EdU) and flow cytometry. Then, the content of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione peroxidase (GSH-Px) in serum or cell supernatant was tested using enzyme linked immunosorbent assay (ELISA). In addition, the expression of Sestrin2, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), platelet endothelial cell adhesion molecule-1 (CD31), and vascular endothelial growth factor receptor 2 (VEGFR2) in retina tissue or ARPE-19 cells were validated through western blot and immunofluorescence assays. With the increase of MDA and ROS concentration, Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in retina tissue or ARPE-19 cells of model group, whereas CD31 and VEGFR2 expression was upregulated. However, tricin ameliorated the oxidative stress and angiogenesis and rectified the abnormal expression of Sestrin2/Nrf2 in diabetic retinopathy. Further mechanistic studies showed that silence Sestrin2 reduced the protective effect of tricin on ARPE-19 cells, as well as abolished its regulating effect on the Nrf2 pathway. These results suggested that tricin inhibits oxidative stress and angiogenesis in retinal epithelial cells of DR rats via reinforcing Sestrin2/Nrf2 signaling.

Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis

“…Sestrin2 alleviates the development of sepsis by inhibiting ferroptosis of dendritic cells in sepsis (Li et al 2021 ). In addition, research has found that Tricin alleviates DR by regulating Sestrin2/Nrf2 signaling to inhibit oxidative stress and angiogenesis (Yang and Li 2023 ). In addition, Sestrin2 has important clinical functions in a variety of metabolic diseases, such as diabetes and its complications, which can reduce insulin resistance by regulating glucose and lipid homeostasis, and studies have shown that serum Sestrin2 levels are significantly reduced in obese children and diabetic nephropathy patients (Lee et al 2012 ; Mohany and Al Rugaie 2020 ; Nourbakhsh et al 2017 ).…”

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

“…However, it has been systematically shown, in in vitro and in vivo studies, that exposure to a high level of glucose induces a decrease in Nrf2 levels, particularly in the nucleus, but also total Nrf2 in all types of retinal cells: RPE cells, mainly investigated in ARPE-19 cells [392][393][394], endothelial cells, mainly HREC cells [395], Müller cells [23,396], and ganglion cells [397]. In vivo experiments also showed that diabetes decreases Nrf2 retinal content even during the early periods of diabetes before vascular alterations occur [378,379,398,399]. As mentioned earlier, Nrf2 controls the gene transcription of several antioxidant signals, some of them crucial to glutathione (GSH) generation, such as glutathione peroxidase and the catalytic subunit (xCT) of the cystine/glutamate antiporter X c − system (see [23] for a review).…”

Alleviate oxidative stress in diabetic retinopathy: antioxidant therapeutic strategies

“…Tricin reduces ROS production in endothelial cells, leading to downregulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling and inhibition of HIF-1α accumulation in tumor cells, resulting in decreased expression of VEGF [ 71 ]. Yang et al discovered that tricin inhibit angiogenesis and oxidative stress in retinal epithelial cells of DR rats by reinforces the Sestrin2/Nrf2 signaling pathway [ 72 ].…”

“…Due to its high capacity for oxygen uptake, the retina is particularly vulnerable to oxidative stress in diabetes. The diabetic environment promotes oxidative stress, and molecules or medicines with antioxidant properties could be suitable candidates for attenuating DR [ 72 ].…”