Abstract
BACKGROUND: Marine-derived microorganisms are renowned for producing structurally diverse secondary metabolites with notable biological activities, serving as a promising reservoir for pharmaceutical development. In this study, the fungal strain Westerdykella dispersa Ca4-13, isolated from the edible oyster Crassostrea angulata, was investigated for its potential anti-inflammatory and cytoprotective properties using BV-2 microglial cells as a model system. RESULTS: Metabolite profiling of the solid-state fermented products of W. dispersa Ca4-13 yielded seven compounds 1-7. Their structures were elucidated using NMR and MS techniques, revealing three previously undescribed cytochalasins, namely westerchalasin A (1), westerchalasin B (2), and westerchalasin C (3), along with four known compounds 4-7. Among these, westerchalasin B (2) and westerchalasin C (3) significantly exhibited nitric oxide (NO) production production in LPS-stimulated BV-2 microglial cells, with IC₅₀ values of 11.1 ± 0.4 and 9.9 ± 0.4 µM, respectively. Western blot analysis demonstrated that compounds 2 and 3 significantly downregulated inducible nitric oxide synthase (iNOS) expression at a concentration of 20 µM. Moreover, molecular docking analysis revealed that compound 3 exhibited a high binding affinity for iNOS synthase (ΔG = -18.8104 kcal/mol). The strong interaction was attributed to of hydrogen bonds between the catalytic residue Arg375 and the C-18 carbonyl group of the cycloundecene moiety, as well as Pi-alkyl interactions with Trp367, which contributed to enhanced stability of the complex. CONCLUSIONS: This study reported the isolation and structural elucidation of three novel cytochalasins 1-3 from W. dispersa Ca4-13. Notably, compounds 2 and 3 demonstrated anti-inflammatory activity by inhibiting NO production and iNOS expression in LPS-stimulated BV-2 microglial cells. Molecular docking analysis further confirmed strong interactions between compound 3 and key iNOS residues. Given the crucial role of neuroinflammation in neurodegenerative disorders, these findings suggested that compounds 2 and 3 may possess dual neuroprotective properties, warranting further exploration for therapeutic applications.