Diosmetin alleviates S. aureus-induced mastitis by inhibiting SIRT1/GPX4 mediated ferroptosis

Area of Science:

• Biomedical Science
• Pharmacology
• Immunology

Background:

• Mastitis, a common mammary gland infection, is primarily caused by microbial pathogens.
• Staphylococcus aureus (S. aureus) is a significant pathogen responsible for inducing mastitis.
• Understanding therapeutic interventions for S. aureus-induced mastitis is crucial for animal and human health.

Purpose of the Study:

• To investigate the therapeutic potential of diosmetin against Staphylococcus aureus-induced mastitis.
• To elucidate the underlying mechanisms by which diosmetin exerts its anti-mastitis effects.

Main Methods:

• A mouse model of S. aureus-induced mastitis was established.
• Mice were treated with varying doses of diosmetin (12.5, 25, 50 mg/kg) or a combination of diosmetin and EX-527 (a SIRT1 inhibitor).
• Pathological changes, inflammatory markers (MPO, TNF-α, IL-1β, NF-κB), oxidative stress markers (MDA, Fe2+), antioxidant levels (ATP, GSH), and key protein expressions (GPX4, SIRT1, Nrf2, HO-1) were assessed.

Main Results:

• Diosmetin significantly reduced mammary gland pathological damage caused by S. aureus.
• Treatment with diosmetin decreased myeloperoxidase activity, pro-inflammatory cytokines (TNF-α, IL-1β), NF-κB activation, and malondialdehyde levels.
• Diosmetin upregulated antioxidant defenses, including ATP and glutathione (GSH) production, and increased the expression of GPX4, SIRT1, Nrf2, and HO-1.
• The protective effects of diosmetin were diminished by the SIRT1 inhibitor EX-527, indicating SIRT1's involvement.

Conclusions:

• Diosmetin effectively suppresses S. aureus-induced mastitis.
• The anti-mastitis effects of diosmetin are mediated through the attenuation of inflammation and ferroptosis.
• SIRT1 signaling pathway plays a critical role in the protective mechanisms of diosmetin against mastitis.