Protective Effects of Propolis against Metaflumizone Induced Cardiotoxicity through Modulation of Oxidative Stress, Inflammation, and the PI3K/Akt/mTOR Pathway

Abstract

This study aimed to evaluate the cardiotoxic effects of metaflumizone (MTF), a commonly used pesticide, and the potential protective role of propolis (PROP) against MTF-induced cardiac damage. Twenty-eight male Wistar albino rats were randomly divided into four groups: Control, PROP (200 mg/kg), MTF (500 mg/kg), and MTF + PROP. All treatments were administered orally for 21 days. Biochemical, molecular (RT-qPCR), histopathological, and UHPLC-Orbitrap (R)-HRMS analyses were performed to assess the outcomes. MTF administration significantly increased malondialdehyde (MDA) levels in whole blood and decreased glutathione (GSH) levels, indicating elevated oxidative stress. Additionally, superoxide dismutase (SOD) and catalase (CAT) activities were reduced in erythrocyte packs, further confirming systemic oxidative imbalance. At the molecular level, MTF suppressed the activities of PI3K, Akt, and mTOR in cardiac tissue and significantly upregulated the mRNA expression of TNF-alpha, IL-1 beta, IL-6, NF-kappa B, and Cyt-c. Histopathological evaluation revealed pronounced myocardial degeneration in the MTF group. In contrast, PROP supplementation effectively reversed these pathological alterations by restoring PI3K/Akt/mTOR pathway activity, attenuating oxidative and inflammatory responses, and preserving histological integrity. Collectively, the findings suggest that propolis exerts significant cardioprotective effects against MTF induced toxicity by modulating oxidative stress, inflammation, and apoptosis. These results provide the first in vivo evidence that propolis may mitigate MTF induced cardiotoxicity through regulation of oxidative stress, inflammation, and apoptosis.