Background
As one of the major microvascular complication of diabetes mellitus (DM), diabetic retinopathy (DR) is considered as the leading cause of visual impairment and blindness worldwide (Stitt, Curtis, 2016). It is estimated that 2.4 million cases of blindness globally are resulted from DR (Dow, Mancini, 2018). Accompanied by the annual incidence of 2·2% to 12·7%, the progression of DR ranged from 3·4% to 12·3% (Sabanayagam, Banu, 2019). As a sight-threatening disorder, DR is characterized by neuronal and vascular dysfunction in the retina at early stages, and subsequently further impairment of visual acuity through neovascularization (Wang, Ling, 2017). The pathogenesis of DR is closely related to angiogenesis, oxidative stress, as well as chronic inflammation (Maghbooli, Emamgholipour, 2018). Multiple risk factors including hyperglycaemia, hypertension, advanced age, insulin treatment, induced fasting blood glucose level, longer DM duration, higher haemoglobin A1c concentration, and diet have close links with the occurrence and progression of DR (Dow, Mancini, 2018, Nawaz, Rezzola, 2019, Song, Yu, 2018). Although progress has been made in improving the vascular alterations, DR remains a major challenge in clinical therapy (Rubsam, Parikh, 2018). Thus, new and more accurate predictors to help provide better therapeutic strategies of DR are necessary.
Phytoestrogens, as natural chemicals, possess important modulatory activities on estrogen receptors, therefore affecting glucose homeostasis, and preventing DM among women (Glisic, Kastrati, 2018, Ye, Yang, 2019). For example, daidzein has been reported to be a potential candidate for the treatment of DM (Das, Sarkar, 2018). Coumestrol (CMS), as a coumestan isoflavone, exerts paramount roles in the treatment of estrogen-linked pathologies, such as DM (Li, Zhang, 2019). Besides, it was reported that 10-hydroxy-coumestrol showed strong activity working as antihyperlipidemic agent in streptozotocin (STZ) induced diabetes (Seida, El-Hefnawy, 2015). Furthermore, CMS was found to promote mitochondrial biogenesis through the activation of Sirtuin 1 (SIRT1) in the skeletal muscle cells (Seo, Jeong, 2014). More importantly, activated SIRT1 has been used for treating DR with good outcomes. For example, a recent study has pointed out that down-regulating microRNA-377 inhibited high glucose and hypoxia-induced angiogenic functions and suppressed pro-inflammatory cytokines release via enhancing SIRT1, thereby attenuating DR (Maghbooli, Emamgholipour, 2018). In addition, a previous study demonstrated that formononetin treatment together with induced SIRT1 in kidney tissues of diabetic rats contributed to reduction of oxidative stress burden (Oza and Kulkarni, 2018). From aforementioned reports, we can make the speculation that a potential regulatory relationship among CMS, SIRT1, and DR might exist. Thus, the aim of the present study was to investigate the effects of CMS on oxidative stress, inflammatory response, and cell apoptosis of DR in relation to SIRT1.