Unprecedented Meroterpenoids Exert Anti-inflammatory Activity by Targeting NF-κB and PI3K Signaling Pathways.

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Fungal Biotechnology

Background:

• Meroterpenoids are complex natural products derived from both mevalonate and shikimate pathways.
• Fungal biotransformation is a powerful tool for generating structurally diverse secondary metabolites.
• Understanding the anti-inflammatory potential of novel natural products is crucial for drug discovery.

Purpose of the Study:

• To isolate and characterize unprecedented meroterpenoids from symbiotic fungi.
• To investigate the anti-inflammatory activities of these novel compounds.
• To elucidate the molecular mechanisms underlying their anti-inflammatory effects.

Main Methods:

• Isolation and structure elucidation of meroterpenoids using chromatographic and spectroscopic techniques.
• In vitro anti-inflammatory assays using RAW 264.7 macrophage cell lines.
• Western blot analysis to assess the expression of inflammatory markers and signaling proteins.

Main Results:

• Four novel classes of meroterpenoids (1-10) with unique fused carbon ring systems were identified.
• Compounds 1-3 featured a 5/3/6/6/6 system, 4-5 a 6/6/6/6 tetracyclic skeleton, 6 a 5/3/6/6/5 pentacyclic framework, and 7-10 a 6/6/6/5 architecture.
• Compounds 1 and 6 exhibited significant inhibition of nitric oxide (NO) production, surpassing the positive control indomethacin.
• Compounds 1 and 6 downregulated inducible nitric oxide synthase (iNOS) and inhibited NF-κB, PI3K, and IκB-α phosphorylation.

Conclusions:

• The symbiotic fungi yielded structurally diverse and unprecedented meroterpenoids.
• Compounds 1 and 6 possess potent anti-inflammatory properties.
• The anti-inflammatory effects are mediated through the inhibition of iNOS expression and modulation of key inflammatory signaling pathways like NF-κB and PI3K/Akt.