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.