Diabetic retinopathy (DR) is a progressive microvascular complication of diabetes mellitus and is characterised by excessive inflammation and oxidative stress. Urolithin A (UA), a major metabolite of ellagic acid, exerts anti-inflammatory and antioxidant functions in various human diseases. This study, for the first time, uncovered the role of UA in DR pathogenesis. Streptozotocin-induced diabetic rats were used to determine the effects of UA on blood glucose levels, retinal structures, inflammation, and oxidative stress. High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to elucidate the anti-inflammatory and antioxidant mechanisms of UA in DR in vitro. The in vivo experiments demonstrated that UA injection reduced blood glucose levels, decreased albumin and vascular endothelial growth factor concentrations, and ameliorated the injured retinal structures caused by DR. UA administration also inhibited inflammation and oxidative damage in the retinal tissues of diabetic rats. Similar anti-inflammatory and antioxidant effects of UA were observed in HRECs induced by HG. Furthermore, we found that UA elevated the levels of nuclear Nrf2 and HO-1 both in vivo and in vitro. Nrf2 silencing reversed the inhibitory effects of UA on inflammation and oxidative stress during DR progression. Together, our findings indicate that UA can ameliorate DR by repressing inflammation and oxidative stress via the Nrf2/HO-1 pathway, which suggests that UA could be an effective drug for clinical DR treatment.
Objective: To investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic retinopathy (DR) in diabetic rats, and to study the mechanism of hUCMSCs in treating diabetic retinopathy by tert-butylhydroquinone (tBHQ) regulation of the Nrf2/HO-1 pathway.Methods: The diabetic rat model was induced by intraperitoneal injection of streptozotocin (STZ). The experimental animals were divided into six groups: Normal, diabetes mellitus (DM), hUCMSCs, tBHQ, combined tBHQ-hUCMSCs, and all-trans-retinoid acid (ATRA)-hUCMSCs combined group. Visual function experiments and histological analyses were performed eight weeks post intravitreal injection. Biochemical and molecular analyses were used to assess the hUCMSCs composition and its biological effects.Results: Improvements in systemic oxidative stress and inflammation were found in the tBHQ group. Although hUCMSCs had no significant effect on oxidative stress, retinal structure was improved, visual defects reduced and expression of local retinal inflammatory factors were inhibited following its application. The effect of combined therapy was better than that of single therapy. Inhibition of the Nrf2/HO-1 pathway can promote the expression of systemic inflammatory factors and inhibit the therapeutic effect of hUCMSCs in the retina.Conclusions: Intravitreal administration of hUCMSCs triggers an effective cytoprotective microenvironment in the retina of diabetic mice. Alone, however, it may not significantly improve the systemic inflammatory response of diabetes. In combination with tBHQ it may promote Nrf2expression, systemic antioxidant stress and therapeutic effects of hUCMSCs.
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