College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
Int Immunopharmacol. 2022 Oct;111:109111. doi: 10.1016/j.intimp.2022.109111. Epub 2022 Aug 4.
Cisplatin is the most widely prescribed drug in chemotherapy, but its gastrointestinal toxicity reduces therapeutic efficacy. Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin-induced intestinal toxicity. Dioscin is a steroidal saponin with potential anti-cancer, antioxidant, and anti-inflammatory activities. In this study, we established a rat model of intestinal injury by tail vein injection of cisplatin, and intragastrically administered dioscin to evaluate its effect on intestinal injury. Biochemical markers, western blotting, qRT-PCR and histopathological staining were used to analyze intestinal injury according to various molecular mechanisms. The results revealed that dioscin significantly inhibited cisplatin-induced intestinal mucosal damage and decreased DAO levels in rats. Furthermore, dioscin activated the Nrf2/HO-1 pathway to increase the level of antioxidant enzymes and reduce the levels of MDA and HO. In addition, dioscin pretreatment significantly reduced ileum epithelial NLRP3 inflammasome formation and decreased the levels of inflammatory factors compared with the cisplatin group. In parallel, Nrf2 inhibitor ML385 blocked the therapeutic effect of dioscin in rat with cisplatin-induced intestinal toxicity. In terms of mechanisms, dioscin reversed cisplatin-induced up-regulation of MAPKs and up-regulated p-PI3K and p-AKT levels. Meanwhile, dioscin potently promoted Wnt3A/β-catenin signaling to relieve cisplatin-induced proliferation inhibition. In conclusion, our study suggests that dioscin could ameliorate the cisplatin-induced intestinal toxicity by reducing oxidative stress and inflammation.
顺铂是化疗中最广泛应用的药物，但它的胃肠道毒性会降低治疗效果。氧化应激和炎症被认为是顺铂诱导的肠道毒性的主要发病机制。薯蓣皂苷元是一种具有潜在抗癌、抗氧化和抗炎活性的甾体皂苷。在本研究中，我们通过尾静脉注射顺铂建立了大鼠肠道损伤模型，并通过灌胃给予薯蓣皂苷元，评估其对肠道损伤的作用。根据各种分子机制，采用生化标志物、western blot、qRT-PCR 和组织病理学染色来分析肠道损伤。结果表明，薯蓣皂苷元显著抑制顺铂诱导的大鼠肠道黏膜损伤，降低 DAO 水平。此外，薯蓣皂苷元激活 Nrf2/HO-1 通路，增加抗氧化酶水平，降低 MDA 和 HO 的水平。此外，薯蓣皂苷元预处理可显著减少回肠上皮 NLRP3 炎性小体的形成，并降低与顺铂组相比的炎症因子水平。平行地，Nrf2 抑制剂 ML385 阻断了薯蓣皂苷元在顺铂诱导的大鼠肠道毒性中的治疗作用。在机制方面，薯蓣皂苷元逆转了顺铂诱导的 MAPKs 上调，并上调了 p-PI3K 和 p-AKT 水平。同时，薯蓣皂苷元强烈促进 Wnt3A/β-连环蛋白信号通路，缓解顺铂诱导的增殖抑制。总之，我们的研究表明，薯蓣皂苷元通过减轻氧化应激和炎症来改善顺铂诱导的肠道毒性。
