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

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 BMMSCs
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.