Abstract
A chemical investigation of the marine-derived fungal strain Penicillium glabrum (SF-7123) revealed a new citromycetin (polyketide) derivative (1) and four known secondary fungal metabolites, i.e, neuchromenin (2), asterric acid (3), myxotrichin C (4), and deoxyfunicone (5). The structures of these metabolites were identified primarily by extensive analysis of their spectroscopic data, including NMR and MS data. Results from the initial screening of anti-inflammatory effects showed that 2, 4, and 5 possessed inhibitory activity against the excessive production of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values of 2.7 µM, 28.1 µM, and 10.6 µM, respectively. Compounds 2, 4, and 5 also inhibited the excessive production of NO, with IC50 values of 4.7 µM, 41.5 µM, and 40.1 µM, respectively, in LPS-stimulated RAW264.7 macrophage cells. In addition, these compounds inhibited LPS-induced overproduction of prostaglandin E2 in both cellular models. Further investigation of the most active compound (2) revealed that these anti-inflammatory effects were associated with a suppressive effect on the over-expression of inducible nitric oxide synthase and cyclooxygenase-2. Finally, we showed that the anti-inflammatory effects of compound 2 were mediated via the downregulation of inflammation-related pathways such as those dependent on nuclear factor kappa B and p38 mitogen-activated protein kinase in LPS-stimulated BV2 and RAW264.7 cells. In the evaluation of the inhibitory effects of the isolated compounds on protein tyrosine phosphate 1B (PTP1B) activity, compound 4 was identified as a noncompetitive inhibitor of PTP1B, with an IC50 value of 19.2 µM, and compound 5 was shown to inhibit the activity of PTP1B, with an IC50 value of 24.3 µM, by binding to the active site of the enzyme. Taken together, this study demonstrates the potential value of marine-derived fungal isolates as a bioresource for bioactive compounds.
Highlights
Marine-derived fungi have been suggested as a unique source of bioactive secondary metabolites [1,2]
In the evaluation of the inhibitory effects of the isolated compounds on protein tyrosine phosphate 1B (PTP1B) activity, compound 4 was identified as a noncompetitive inhibitor of PTP1B, with an IC50 value of 19.2 μM, and compound 5 was shown to inhibit the activity of PTP1B, with an IC50 value of 24.3 μM, by binding to the active site of the enzyme
Our chemical investigation of the marine-derived fungal isolate P. glabrum SF-7123 resulted in the isolation and identification of five secondary metabolites, including one new fungal metabolite named 9-O-methylneuchromenin (1)
Summary
Marine-derived fungi have been suggested as a unique source of bioactive secondary metabolites [1,2]. Macrophages and microglia (the resident macrophage-like cells of the central nervous system) have been repeatedly reported to exert a key role in the immune system [4,5] They are activated in response to various stimuli and lead to phagocytosis of damaged macrophages and neuronal cells to protect tissues and prevent damage to the brain and body. Their sustained activation leads to the release of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NO, and prostaglandin E2 (PGE2 ), as well as of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12. PTP1B expression is increased under many pathophysiological conditions such as inflammation, cancer, and diabetes, suggesting novel therapeutic implications for these PTP1B inhibitors in the treatment of such diseases [12]
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