Ellagic acid improved diabetes mellitus-induced testicular damage and sperm abnormalities by activation of Nrf2

Abstract

Diabetes mellitus induces testicular damage, increases sperm abnormalities, and impairs reproductive dysfunction due to induction of endocrine disturbance and testicular oxidative stress. This study evaluated the reproductive protective effect of ellagic acid (EA) against testicular damage and abnormalities in sperm parameters in Streptozotocin (STZ)-induced diabetic rats (T1DM) and examined some possible mechanisms of protection. Adult male rats were segregated into 5 groups (n = 12 rat/each) as control, control + EA (50 mg/kg/day), T1DM, T1DM + EA, and T1DM + EA + brusatol (an Nrf-2 inhibitor) (2 mg/twice/week). All treatments were conducted for 12 weeks, daily. EA preserved the structure of the seminiferous tubules, prevented the reduction in sperm count, motility, and viability, reduced sperm abnormalities, and downregulated testicular levels of cleaved caspase-3 and Bax in diabetic rats. In the control and diabetic rats, EA significantly increased the circulatory levels of testosterone, reduced serum levels of FSH and LH, and upregulated Bcl-2 and all steroidogenic genes (StAr, 3β-HSD1, and 11β-HSD1). Besides, it reduced levels of ROS and MDA but increased levels of GSH and MnSOD and the transactivation of Nrf2. All these biochemical alterations induced by EA were associated with increased activity and nuclear accumulation of Nrf2. However, all these effects afforded by EA were weakened in the presence of brusatol. In conclusion, EA could be an effective therapy to alleviated DM-induced reproductive toxicity and dysfunction in rats by a potent antioxidant potential mediated by the upregulation of Nrf2.

Esculeoside A Decreases Diabetic Cardiomyopathy in Streptozotocin-Treated Rats by Attenuating Oxidative Stress, Inflammation, Fibrosis, and Apoptosis: Impressive Role of Nrf2

“…In addition, the data of this study also confirmed inflammation in the LVs of these rats by the significant upregulation in the mRNA levels and nuclear levels of NF-κB and higher levels of ICAM-1, TNF-α, IL-6, and IL-1β. These data follow many other studies that have also shown similar results on the reduction in these antioxidant levels and in the elevation of MDA, TNF-α, IL-6, and collagen levels, as well as the of NF-κB in the hearts of STZ-diabetic rats [32,[50][51][52][53][54][55][56][57]. However, restoring all of these biochemical endpoints in the LVs of these rats was our strongest evidence that the cardioprotective effect of ESA is mediated by suppressing oxidative stress, inflammation, and fibrosis.…”

“…The utilized dose of ESA showed hypoglycemic and hypolipidemic effects in mice and rats [28,31]. We previously tested and used brusatol to suppress Nrf2 activities in vivo in rats [32]. Treatment with ESA was administered orally via a gavage feeding needle daily.…”

“…Treatment with ESA was administered orally via a gavage feeding needle daily. Two doses of brusatol were given per week [32]. All treatments were terminated after 84 days, the time at which diabetic cardiomyopathy was induced in the rats at the selected dose of STZ [30].…”

“…The assessment of the left ventricular (LV) function was carried out as previously shown in our prior studies [32]. During week 12, the rats were anesthetized as described by Rakhshandeh et al [33] using ketamine (85 mg), acepromazine (3 mg/kg), and xylazine (8 mg/kg, v/v) [34].…”

Dietary Fibre Supplementation Improves Semen Production by Increasing Leydig Cells and Testosterone Synthesis in a Growing Boar Model

“…Both StAR and CYP11A1 play critical roles in testicular development and spermatogenesis by regulating androgen production and are the rate-limiting factors of steroidogenesis ( 42 ), while SOCS3 is related to androgen production and sperm production in rats ( 43 ). Research has shown that diets supplemented with fruit pulp ( 44 ) or ellagic acid ( 45 ) improve reproductive function in male rats by increasing the circulatory levels of testosterone and up-regulating steroidogenic gene expression. Furthermore, dietary fibre intake up-regulated the expression of AMH and AMHR2 .…”