Targeting mitochondrial dysfunction and apoptosis in 5-fluorouracil-induced cardiotoxicity using kaempferol-mediated...

5-Flurouracil (5-FU) is still considered as one of the most popular antimetabolite chemotherapy drugs to treat a wide variety of solid tumors. Dose limiting toxicity on major organs, especially cardiovascular system limits the therapeutic use of 5-FU. The current paper addresses the cardioprotective effect of green synthesized selenium nanoparticles through kaempferol (KMP-SeNPs) on the cardiotoxicity induced by 5-FU in a rat model. 35 male Wistar rats were divided equally into five groups, namely control, 5-FU, Na₂SeO₃&5-FU, KMP&5-FU, and KMP-SeNPs&5-FU. The 5-FU consumed 5 days induced cardiotoxicity and there were 21 days of oral treatment. The levels of cardiac injury markers, oxidative stress indices, antioxidant enzymes, inflammatory/anti-inflammatory cytokines and apoptotic markers were measured by ELISA, gene expression and immunohistochemistry. The evaluation of cardiac tissue was done by using histopathology. 5-FU caused significant cardiotoxicity detected by increased cardiac enzymes, oxidative stress, inflammatory cytokines, apoptosis, and extensive histopathologic damage. KMP-SeNPs treatment had a great impact on reducing myocardial injury, normalizing cardiac enzymes, decreasing lipid peroxidation and NO generation, reestablishing antioxidant defenses, and increasing Nrf2 signaling and inhibiting Keap-1 expression. The expression of TNF-α, IL-6, NF-κB, Bax, and caspase-3, were significantly decreased, whereas IL-10, FOXP3, and Bcl-2 showed a significant increase, which is evidence of the great anti-inflammatory, as well as anti-apoptotic effect of KMP-SeNPs. Immunohistochemical and histopathology results supported these molecular and biochemical findings to show approximately normal cardiac architecture. KMP-SeNPs are more effective in protecting against 5-FU-induced cardiotoxicity using antioxidant, anti-inflammatory, immunoregulatory, and anti-apoptotic activities.