Mokko Lactone Attenuates Doxorubicin-Induced Hepatotoxicity in Rats: Emphasis on Sirt-1/FOXO1/NF-κB Axis

Area of Science:

• Pharmacology
• Toxicology
• Hepatology

Background:

• Doxorubicin (DOX) is a widely used chemotherapy agent with significant hepatotoxicity.
• Mokko lactone (ML), a guainolide sesquiterpene, possesses various biological activities.
• Hepatotoxicity induced by DOX necessitates the search for protective agents.

Purpose of the Study:

• To investigate the protective effects of ML against DOX-induced hepatotoxicity in a rat model.
• To elucidate the underlying mechanisms of ML's hepatoprotective action.

Main Methods:

• Rats were administered DOX to induce hepatotoxicity, with ML given as a potential protective agent.
• Serum liver enzymes (ALT, AST, ALP), liver histology, oxidative stress markers (MDA, GSH, SOD, CAT), and gene/protein expression (Nrf2, FOXO1, IL-6, TNF-α, NF-κB, Bax, Bcl-2, Sirt-1) were assessed.
• Western blot and RT-PCR were used to evaluate protein and mRNA expression.

Main Results:

• ML significantly ameliorated DOX-induced increases in serum liver enzymes and prevented pathological liver alterations.
• ML reduced oxidative stress by preventing malondialdehyde accumulation and glutathione depletion, while restoring antioxidant enzyme activity.
• ML exhibited anti-inflammatory and anti-apoptotic effects, evidenced by modulation of key signaling pathways (Nrf2, FOXO1, NF-κB) and apoptosis-related genes (Bax, Bcl-2).
• ML upregulated silent information regulator 1 (Sirt-1) expression.

Conclusions:

• Mokko lactone (ML) effectively prevents Doxorubicin (DOX)-induced hepatotoxicity in rats.
• ML's protective mechanisms involve antioxidant, anti-inflammatory, and anti-apoptotic activities, potentially through the regulation of the Sirt-1/FOXO1/NF-κB axis.
• ML shows promise as a therapeutic agent to mitigate DOX-induced liver injury.