(±)-Agrimonolide

Microglial and astrocytic activation is the main reason for the neuroinflammatory responses, which damages neurons resulting in neurological disorders. Currently, there are few drugs that directly target neuroinflammation in clinical practice, which highlights the urgent need for effective inhibitors. In this study, we identified agrimonolide, from a screen of 40 compounds, as an inhibitor of glia activation, and further confirmed its efficacy in vitro and in vivo. In cellular models, agrimonolide significantly reduced the expression levels of proinflammatory cytokines (IL-1β, IL-6 and TNFα) in LPS stimulated BV2 cells and primary astrocytes. Mechanistic investigation revealed that agrimonolide suppresses the activation of both NF-κB and MAPK signaling pathways, combined the molecular docking results, it is suggested that agrimonolide may have multiple targets. In ICR mice, our measurements showed that agrimonolide treatment decreased LPS-induced glial activation, as evidenced by the protein levels of IBA-1 and GFAP. Additionally, it significantly inhibited the activation of TLR4-mediated signaling pathways. Our findings suggest that agrimonolide suppresses neuroinflammatory responses by inhibiting microglial and astrocytic activation, providing insight into potential treatment strategies for neuroinflammation-related diseases.

Drug-resistant C. albicans infection is difficult to treat, and many studies have shown that energy metabolism disorder caused by glycolysis pathway can be an important research field of antifungal drugs. In present work, in vitro and in vivo antifungal activities of agrimonolide-based compounds combined with FLC. The results indicated that (±)-methylagrimonolide (1) combined with FLC showed good synergistic inhibition against FLC-resistant ATCC14053-FR with MIC₅₀ of 8 μM and FICI of 0.08. In addition, the combined drugs could also improve the survival status and pathological damage of different organs in immunodeficient mice. Further mechanistic studies showed that the combined drugs could reduce the glycolytic products of C. albicans such as ATP and pyruvate by more than 50 % and promote the death of C. albicans. Therefore, (±)-methylagrimonolide acts as a glycolytic-targeting synergetic agent to significantly enhance the antifungal activity of FLC against resistant C. albicans.