Grape seed proanthocyanidin extract ameliorates cisplatin‐induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

Abstract

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.

Grape seed proanthocyanidin extract alleviates inflammation in experimental colitis mice by inhibiting NF‐κB signaling pathway

“…PAC extract from grape seeds has been shown the therapeutic effects on inflammatory and metabolism‐related diseases. GSPE can ameliorate cisplatin‐induced apoptosis in testicular cells by modulating the PI3K/AKT/mTOR pathway and the Bad/Cyt c/Caspase9/Caspase3 pathway, 33 and it can also attenuate concomitant bladder dysfunction by activating the Nrf2/HO‐1 pathway to inhibit oxidative damage in diabetes mellitus 34 . Additionally, both short‐term and long‐term GSPE administration have exhibited no obvious toxic effect on organs such as heart, liver, testis, lung, and kidney, as shown by tissue sections 13,14,35–37 .…”

Tempol improves optic nerve histopathology and ultrastructures in cisplatin-induced optic neuropathy in rats by targeting oxidative stress—Endoplasmic reticulum stress—Autophagy signaling pathways

“…Our study's result showed that cisplatin upregulated the mRNA expression levels of Bip, ATF6, and XBP1 besides the proteins of ER stress-induced apoptosis—CHOP and JNK. Former studies demonstrated that ER stress and its mediated apoptosis were linked to cisplatin-induced cytotoxicity in various tissues (Sahu et al, 2019 ; Huang et al, 2020 ; Chang et al, 2021 ). According to Foufelle and Fromenty ( 2016 ), ER stress and oxidative stress form a viscous circle.…”

Grape Seed Proanthocyanidins Improve the Quality of Fresh and Cryopreserved Semen in Bulls

“…Several studies have shown that GSPs inhibit oxidative stress damage through the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling [35], while mammalian target of rapamycin (mTOR) is necessary for both the proliferation and differentiation of progenitor spermatogonia during spermatogenesis [44,45]. A previous study indicated that GSPs can improve chemotherapy drug cisplatin (CIS)-induced testicular cell apoptosis via activating the phosphatidylinositol 3-kinase (PI3K)/V-akt murine thymoma viral oncogene homolog (Akt)/mTOR signaling pathway [46]. Although the in vitro experiments of this study have different triggers for oxidative damage compared to previous studies, we suspect that the antioxidant effect of GSPs may be through the activation of the MAPK, NF-κB, and PI3K/Akt/mTOR signaling pathways.…”