Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, the Republic of Korea.
Department of Animal Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, the Republic of Korea.
Reprod Toxicol. 2023 Sep;120:108426. doi: 10.1016/j.reprotox.2023.108426. Epub 2023 Jun 21.
Deguelin is a natural flavonoid extracted from plants belonging to the Lonchocarpus, Derris, or Tephrosia genera. It inhibits AKT activity in tumors and has the potential to be used as a treatment for malignant tumors. However, the risks associated with the use of deguelin on male fertility have not yet been explained in detail. Therefore, this study was conducted to investigate the effects of deguelin on sperm functions during capacitation. First, boar spermatozoa were exposed to different concentrations of deguelin (0.1, 1, 10, 50, and 100 μM). Next, sperm functional assessments, such as sperm motility, capacitation status, intracellular ATP level, and cell viability, were performed. The expression levels of PI3K/AKT-related proteins and the phosphorylation of their tyrosine residues were also evaluated by western blotting. No significant difference was observed in cell viability; however, deguelin considerably decreased sperm motility and motion kinematics in a dose-dependent manner. Although no significant difference was observed in the capacitation status, acrosome reaction decreased at high concentrations of deguelin (50 and 100 μM). Furthermore, intracellular ATP levels were significantly decreased in all deguelin treatment groups compared with those in the control group. Results of western blotting revealed that deguelin substantially diminished tyrosine phosphorylation. Interestingly, in contrast to previous studies showing that deguelin inhibits AKT activity, our results showed that it increased the expression of PI3K/AKT pathway-related proteins. Collectively, these findings indicate that deguelin exerts negative effects on sperm functions due to abnormal PI3K/AKT signaling activation. We believe that this is the first study to provide evidence that deguelin can regulate sperm functions independent of PI3K/AKT pathway inhibition. Furthermore, its detrimental effects on male fertility should be considered while developing or using deguelin as a therapeutic agent.
格尔德霉素是一种从 Lonchocarpus、Derris 或 Tephrosia 属植物中提取的天然黄酮类化合物。它能抑制肿瘤中的 AKT 活性，有可能被用于恶性肿瘤的治疗。然而，格尔德霉素对男性生育力的潜在风险尚未得到详细解释。因此，本研究旨在探讨格尔德霉素在精子获能过程中对精子功能的影响。首先，将猪精子暴露于不同浓度的格尔德霉素（0.1、1、10、50 和 100μM）中。然后，进行精子功能评估，如精子活力、获能状态、细胞内 ATP 水平和细胞活力。通过 Western blot 评估 PI3K/AKT 相关蛋白的表达水平及其酪氨酸残基的磷酸化水平。细胞活力无显著差异；然而，格尔德霉素以剂量依赖性方式显著降低精子活力和运动学。虽然获能状态无显著差异，但顶体反应在高浓度格尔德霉素（50 和 100μM）时降低。此外，与对照组相比，所有格尔德霉素处理组的细胞内 ATP 水平均显著降低。Western blot 结果表明，格尔德霉素显著降低了酪氨酸磷酸化。有趣的是，与先前研究表明格尔德霉素抑制 AKT 活性的结果相反，我们的结果表明，它增加了 PI3K/AKT 通路相关蛋白的表达。综上所述，这些发现表明，由于 PI3K/AKT 信号通路的异常激活，格尔德霉素对精子功能产生负面影响。我们认为，这是首次提供证据表明格尔德霉素可以独立于 PI3K/AKT 通路抑制来调节精子功能。此外，在开发或使用格尔德霉素作为治疗剂时，应考虑其对男性生育力的有害影响。
