OBJECTIVE: This study was conducted to demonstrate the pathogenetic, morphologic, and toxicologic effects of doxorubicin on the heart and to investigate how the MAPK /TNF-α pathway can be modulated to improve doxorubicin-Induced cardiac lesions using bone marrow-derived mesenchymal stem cells (BM-MSCs) and olive leaf extract (OLE).
METHODS: During the study, 40 adult male rats were used. Ten were used to donate MSCs, and the other 30 were split into 5 equal groups: Group I was the negative control, Group II obtained oral OLE, Group III obtained an intraperitoneal cumulative dose of DOX (12 mg/kg) in 6 equal doses of 2 mg/kg every 48 h for 12 days, Group IV obtained intraperitoneal DOX and oral OLE at the same time, and Group V obtained intraperitoneal DOX and BM-MSCs through the tail vein at the same time for 12 days. Four weeks after their last dose of DOX, the rats were euthanized. By checking the bioinformatic databases, a molecularly targeted path was selected. Then the histological, immunohistochemistry, and gene expression of ERK, JNK, NF-κB, IL-6, and TNF-α were done.
RESULTS: Myocardial immunohistochemistry revealed severe fibrosis, cell degeneration, increased vimentin, and decreased CD-31 expression in the DOX-treated group, along with a marked shift in morphometric measurements, a disordered ultrastructure, and overexpression of inflammatory genes (ERK, NF-κB, IL-6, and TNF-α), oxidative stress markers, and cardiac biomarkers. Both groups IV and V displayed reduced cardiac fibrosis or inflammation, restoration of the microstructure and ultrastructure of the myocardium, downregulation of inflammatory genes, markers of oxidative stress, and cardiac biomarkers, a notable decline in vimentin, and an uptick in CD-31 expression. In contrast to group IV, group V showed a considerable beneficial effect.
CONCLUSIONS: Both OLE and BM-MSCs showed an ameliorating effect in rat models of DOX-induced cardiotoxicity, with BM-MSCs showing a greater influence than OLE.
目的:本研究的目的是,形态学,和多柔比星对心脏的毒理学作用,并研究如何使用骨髓间充质干细胞(BM-MSCs)和橄榄叶提取物(OLE)调节MAPK/TNF-α途径以改善多柔比星诱导的心脏损伤。
方法:在研究期间,使用40只成年雄性大鼠。十个被用来捐赠MSC,其余30只分为5组:第一组为阴性对照,II组获得口服OLE,第III组获得腹膜内累积剂量的DOX(12mg/kg),每48小时6个相等剂量的2mg/kg,持续12天,IV组同时获得腹腔DOX和口服OLE,第五组同时通过尾静脉获得腹腔DOX和BM-MSCs,持续12天。在他们最后一次服用DOX后四周,对大鼠实施安乐死。通过检查生物信息学数据库,选择分子靶向路径。然后组织学,免疫组织化学,和ERK的基因表达,JNK,NF-κB,进行IL-6和TNF-α。
结果:心肌免疫组化显示严重纤维化,细胞变性,增加波形蛋白,和减少CD-31表达在DOX处理组,随着形态测量的明显变化,无序的超微结构,和炎症基因的过度表达(ERK,NF-κB,IL-6和TNF-α),氧化应激标志物,和心脏生物标志物。IV组和V组均显示心脏纤维化或炎症减少,心肌的微观结构和超微结构的恢复,炎症基因的下调,氧化应激的标志物,和心脏生物标志物,波形蛋白的显著下降,和CD-31表达的上升。与IV组相比,组V表现出相当的有益效果。
结论:OLE和BM-MSCs在DOX诱导的大鼠心脏毒性模型中均有改善作用,BM-MSCs显示出比OLE更大的影响。