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

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.

Keywords: Apoptosis; Bioinformatics; Cardiotoxicity; MSCs; Oxidative stress; PCR.