Chang Xuhong, Tian Minmin, Zhang Qiong, Liu Fangfang, Gao Jinxia, Li Sheng, Liu Han, Hou Xiangbo, Li Lei, Li Chengyun, Sun Yingbiao
Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China.
Department of Occupational Diseases, Lanzhou Municipal Center for Disease Control, Lanzhou, China.
J Food Biochem. 2021 Jun 21:e13825. doi: 10.1111/jfbc.13825.
Testicular toxicity is an adverse reaction of the effective chemotherapy drug cisplatin (CIS). Our previous study found that grape seed proanthocyanidin extract (GSPE) had a protective effect on CIS-induced testicular toxicity. However, the protective mechanism of GSPE against CIS-induced testicular toxicity remains unknown. In this study, we aimed to investigate whether GSPE can reduce CIS-induced testicular toxicity and its potential mechanism in rats. The results showed that GSPE ameliorated CIS-induced the apoptosis of testicular cells and inhibited the protein levels of Bad, Cyt c, caspase-9, caspase-3, caspase-12, GRP78, CHOP, IRE1α, p-IRE1α, XBP-1S, PERK, p-PERK, eIF2α, and p-eIF2α. Besides, GSPE reversed the downregulation of PI3K, p-PI3K, Akt, p-Akt, mTOR, and p-mTOR protein expression induced by CIS. These results indicated that GSPE can improve CIS-induced testicular cells apoptosis via activating PI3K/Akt/mTOR and inhibiting Bad/Cyt c/caspase-9/caspase-3 pathways. And GSPE relieved endoplasmic reticulum stress-mediated apoptosis via inhibiting PREK/eIF2α and IRE1α/XBP-1S/caspase-12 pathways. In conclusion, the evidence suggested that GSPE can act as a protective agent against testicular toxicity induced by CIS. PRACTICAL APPLICATIONS: Testicular toxicity was a well-known adverse effect of cisplatin (CIS) in cancer treatment. Grape seed proanthocyanidin extract (GSPE) has been reported to serve as one of the most therapeutic potentials agents. In present study, we explored the regulatory effects of GSPE on the apoptosis induced by CIS, which involved testicular apoptosis mechanisms in rats. Our results indicated that CIS caused testicular toxicity via PI3K/AKT/mTOR and ERS mediated apoptosis pathway in rats. This toxicity was attenuated by GSPE treatment via activated PI3K/Akt/mTOR pathway, and inhibiting Bad/CytC/caspase-9/caspase-3 as well as PREK/eIF2α, IRE1α/XBP-1S/caspase-12 pathways. Our findings suggest that GSPE may be a novel protective agent against testicular toxicity induced by CIS.
睾丸毒性是有效化疗药物顺铂（CIS）的一种不良反应。我们之前的研究发现葡萄籽原花青素提取物（GSPE）对CIS诱导的睾丸毒性具有保护作用。然而，GSPE对抗CIS诱导的睾丸毒性的保护机制仍不清楚。在本研究中，我们旨在探讨GSPE是否能减轻CIS诱导的大鼠睾丸毒性及其潜在机制。结果表明，GSPE改善了CIS诱导的睾丸细胞凋亡，并抑制了Bad、Cyt c、caspase-9、caspase-3、caspase-12、GRP78、CHOP、IRE1α、p-IRE1α、XBP-1S、PERK、p-PERK、eIF2α和p-eIF2α的蛋白水平。此外，GSPE逆转了CIS诱导的PI3K、p-PI3K、Akt、p-Akt、mTOR和p-mTOR蛋白表达下调。这些结果表明，GSPE可通过激活PI3K/Akt/mTOR和抑制Bad/Cyt c/caspase-9/caspase-3途径改善CIS诱导的睾丸细胞凋亡。并且GSPE通过抑制PREK/eIF2α和IRE1α/XBP-1S/caspase-12途径减轻内质网应激介导的凋亡。总之，证据表明GSPE可作为对抗CIS诱导的睾丸毒性的保护剂。实际应用：睾丸毒性是顺铂（CIS）在癌症治疗中众所周知的不良反应。葡萄籽原花青素提取物（GSPE）已被报道为最具治疗潜力的药物之一。在本研究中，我们探讨了GSPE对CIS诱导的凋亡的调节作用，其中涉及大鼠睾丸凋亡机制。我们的结果表明，CIS通过PI3K/AKT/mTOR和内质网应激介导的凋亡途径在大鼠中引起睾丸毒性。GSPE通过激活PI3K/Akt/mTOR途径、抑制Bad/CytC/caspase-9/caspase-3以及PREK/eIF2α、IRE1α/XBP-1S/caspase-12途径减轻这种毒性。我们的研究结果表明，GSPE可能是一种对抗CIS诱导的睾丸毒性的新型保护剂。
