Abstract
The current study was designed to investigate the protective role of diosmin against cyclophosphamide-induced premature ovarian insufficiency (POI). Female Swiss albino rats received a single intraperitoneal dose of cyclophosphamide (200 mg/kg) followed by 8 mg/kg/day for the next 15 consecutive days either alone or in combination with oral diosmin at 50 or 100 mg/kg. Histopathological examination of ovarian tissues, hormonal assays for follicle stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH), assessment of the oxidative stress status, as well as measurement of the relative expression of miRNA-145 and its target genes [vascular endothelial growth factor B (VEGF-B) and regulator of cell cycle (RGC32)] were performed. Diosmin treatment ameliorated the levels of E2, AMH, and oxidative stress markers. Additionally, both low and high diosmin doses significantly reduced the histopathological alterations and nearly preserved the normal ovarian reserve. MiRNA-145 expression was upregulated after treatment with diosmin high dose. miRNA-145 target genes were over-expressed after both low and high diosmin administration. Based on our findings, diosmin has a dose-dependent protective effect against cyclophosphamide-induced ovarian toxicity in rats.
Highlights
Ovarian folliculogenesis is a dynamic and highly regulated process that determines female reproduction [1]
MiRNA-145 was markedly under-expressed in the ovaries from the premature ovarian insufficiency (POI) (G II) group and both of low and high diosmin-treated (G II and G IV) groups compared to the control (G I) group (p < 0.0001)
Gene expression profiling for the miRNA-145 target genes showed significant under-expression of RGC32 in the POI (G II) group compared to the control (G I) group (p = 0.006), and over-expression in the low diosmin-treated (G III) group compared to that of the POI (G II) group (p = 0.038)
Summary
Ovarian folliculogenesis (comprising primordial follicle assembly, follicle growth, ovulation, and formation of the corpus luteum) is a dynamic and highly regulated process that determines female reproduction [1]. Abnormalities in folliculogenesis result in serious ovarian pathological conditions such as premature ovarian insufficiency (POI) and polycystic ovary syndrome [2,3]. Most follicles undergo degeneration during growth and development in a process known as follicular atresia. Abnormal follicular atresia may accelerate follicular depletion and lead to ovarian insufficiency. Recent studies have suggested that granulosa cell (GC) apoptosis is the main cause of follicular atresia [4,5,6]. Oxidative stress, which arises as a consequence of the excessive production of reactive oxygen species (ROS) and/or impaired antioxidant defense mechanisms, is believed to be the major causes of GC apoptosis [7]
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