Abstract
Leydig cell injury has been described as a primary driver of testicular dysfunction and is affected by oxidative stress. Dioscorea polystachya (Chinese yam) is used to improve testicular dysfunction in clinical and pharmacological research via its antioxidative activity, but the mechanisms underlying the beneficial effect of Chinese yam on testicular dysfunction and its suppression of Leydig cell oxidative damage remain unclear. In this study, we obtained a Chinese yam protein (DP1) and explored its effectiveness and possible mechanism in improving testicular dysfunction in vivo and in vitro. We established a testicular dysfunction model in rats using hydrocortisone (HCT). DP1 increased body weight and organ index, improved the deterioration in testicular morphology (including increasing the diameter of seminiferous tubules and thickness of germinal cell layers, inhibiting testicular cell apoptosis by increasing the Bcl-2/Bax ratio, and impeding collagen leakage by downregulating TGF-β1 and p-SMAD2/3 expression), and restored the testosterone content. In addition, DP1 enhanced the number of Leydig cells in rats and H2O2-induced TM3 Leydig cells, and the effect of DP1 on the apoptosis, fibrosis, and testosterone content of TM3 cells was similar to that observed in vivo. These changes were dependent on the regulation of oxidative stress, including significantly reduced intracellular 8-hydroxy-2-deoxyguanosine levels, enhanced superoxide dismutase activities, and decreased superoxide anion levels, which were confirmed via a superoxide overexpression system. Furthermore, we observed that DP1 promoted Nrf2 nuclear import and upregulated antioxidant factor expression in vivo and in vitro. However, Nrf2 silencing eliminated the ability of DP1 to increase the Bcl-2/Bax ratio, reduce the expression levels of TGF-β1 and p-SMAD2/3, and increase testosterone contents in H2O2-induced TM3 cells. In conclusion, DP1 reversed the HCT-induced testicular apoptosis and fibrosis and decreased testosterone contents by alleviating Leydig cell oxidative damage via upregulation of the Nrf2 pathway.
Highlights
Leydig cells, the primary site of androgen synthesis and secretion, are essential in establishing and maintaining the male testicular microenvironment [1, 2]
We found that the ability of DP1 to increase nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 protein expression and inhibit superoxide anion was significantly reduced after Nrf2 silencing (Figures 6(b)–6(d))
A previous study revealed that Chinese yam protein extract enhanced testosterone levels and attenuated testicular fibrosis and oxidative stress in HCT-induced erectile dysfunction rats and H2O2-treated TM3 cells, suggesting that Chinese yam protein is potentially effective for the treatment of testicular dysfunction via the inhibition of oxidative stress [9]
Summary
The primary site of androgen synthesis and secretion, are essential in establishing and maintaining the male testicular microenvironment [1, 2]. Leydig cell injury is a vital factor contributing to testicular dysfunction and is accompanied by diminished fertility and erectile ability [3, 4]. Glucocorticoids, such as hydrocortisone (HCT), are widely used for the treatment of multiple diseases because of their strong anti-inflammatory and immunosuppressive effects [5, 6]. Inhibition of apoptosis and fibrosis would hinder Leydig cell injury, which can in turn effectively delay the initiation and progression of glucocorticoids-induced testicular dysfunction.
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