骨髓间充质干细胞和橄榄油叶提取物通过 MAPK/TNF-α 通路减轻大鼠多柔比星诱导的心脏毒性：临床前、实验和生物信息学富集研究。

Alleviation of doxorubicin-induced cardiotoxicity in rat by mesenchymal stem cells and olive leaf extract via MAPK/ TNF-α pathway: Preclinical, experimental and bioinformatics enrichment study.

机构信息

Department of Internal Medicine (Forensic Medicine and Clinical Toxicology division), College of Medicine, Jouf University, Aljouf 72341, Saudi Arabia.

Pathology Department, College of Medicine, Jouf University, Aljouf, Saudi Arabia.

出版信息

Tissue Cell. 2023 Dec;85:102239. doi: 10.1016/j.tice.2023.102239. Epub 2023 Oct 10.

DOI:10.1016/j.tice.2023.102239

PMID:37865037

Abstract

BACKGROUND

Toxic cardiomyopathies were a potentially fatal adverse effect of anthracycline therapy.

AIM

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.

CONCLUSION

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.

摘要

背景

蒽环类药物治疗的潜在致命不良反应是中毒性心肌病。

目的

本研究旨在展示多柔比星对心脏的发病机制、形态和毒理学影响，并研究 MAPK/TNF-α 途径如何被调节，以使用骨髓间充质干细胞 (BM-MSCs) 和橄榄油叶提取物 (OLE) 改善多柔比星诱导的心脏病变。

方法

在研究过程中，使用了 40 只成年雄性大鼠。其中 10 只为 MSC 供体，其余 30 只大鼠分为 5 个相等的组：第 I 组为阴性对照组，第 II 组口服 OLE，第 III 组腹腔内累积剂量的 DOX(12mg/kg)，分 6 次给予，每次 2mg/kg，每 48 小时给予一次，共 12 天，第 IV 组同时腹腔内给予 DOX 和口服 OLE，第 V 组同时通过尾静脉给予腹腔内 DOX 和 BM-MSCs，共 12 天。DOX 最后一次给药后 4 周，处死大鼠。通过检查生物信息学数据库，选择了一个分子靶向途径。然后进行 ERK、JNK、NF-κB、IL-6 和 TNF-α 的组织化学、免疫组织化学和基因表达。

结果

心肌免疫组织化学显示，多柔比星治疗组心肌纤维化严重，细胞变性，波形蛋白增加，CD-31 表达减少，形态测量指标明显改变，超微结构紊乱，炎症基因 (ERK、NF-κB、IL-6 和 TNF-α)、氧化应激标志物和心脏生物标志物过度表达。第 IV 组和第 V 组均显示心脏纤维化或炎症减少，心肌微观结构和超微结构恢复，炎症基因、氧化应激标志物和心脏生物标志物下调，波形蛋白显著减少，CD-31 表达增加。与第 IV 组相比，第 V 组显示出显著的有益效果。