Context:Paramignya trimera (Oliv.) Burkill (Rutaceae) has been used to treat liver diseases and cancer. However, the anti-inflammatory effects of this medicinal plant and its components have not been elucidated.Objective: This study investigated chemical constituents of the P. trimera stems and evaluated anti-inflammatory effects of isolated compounds.Materials and methods: Cytotoxicity of isolated compounds (5–40 μM) toward BV2 cells was tested using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) for 24 h. Inhibitory effects of isolated compounds (5-40 μM) on nitrite and PGE2 concentrations were determined using Griess reaction and PGE2 ELISA kit, respectively (pretreated with the compounds for 3 h and then stimulated for 18 h with LPS). Inhibitory effects of compounds (5-40 μM) on iNOS and COX-2 protein expression were evaluated by Western blot analysis (pretreated with the compounds for 3 h and then stimulated for 24 h with LPS).Results: Seven coumarins were isolated and identified as: ostruthin (1), ninhvanin (2), 8-geranyl-7-hydroxycoumarin (3), 6-(6′,7′-dihydroxy-3′,7′-dimethylocta-2′-enyl)-7-hydroxycoumarin (4), 6-(7-hydroperoxy-3,7-dimethylocta-2,5-dienyl)-7-hydroxycoumarin (5), 6-(2-hydroxyethyl)-2,2-dimethyl-2H-1-benzopyran (6), and luvangetin (7). Compounds 1–4 and 7 inhibited NO and PGE2 production in LPS-stimulated BV2 cells, with IC50 values ranging from 9.8 to 46.8 and from 9.4 to 52.8 μM, respectively. Ostruthin (1) and ninhvanin (2) were shown to suppress LPS-induced iNOS and COX-2 protein expression.Discussion and conclusion: The present study provides a scientific rationale for the use of P. trimera in the prevention and treatment of neuroinflammatory diseases. Ostruthin and ninhvanin might have potential therapeutic effects and should be considered for further development as new anti-neuroinflammatory agents.

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.

Chemical study on the extract of a marine-derived fungal strain Penicillium sp. SF-5859 yielded a new curvularin derivative (1), along with eight known curvularin-type polyketides (2–9). The structures of these metabolites (1–9) were established by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). In vitro anti-inflammatory effects of these metabolites were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Among these metabolites, 3–9 were shown to strongly inhibit LPS-induced overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) with IC50 values ranging from 1.9 μM to 18.1 μM, and from 2.8 μM to 18.7 μM, respectively. In the further evaluation of signal pathways involved in these effects, the most active compound, (10E,15S)-10,11-dehydrocurvularin (8) attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages. Furthermore, compound 8 was shown to suppress the upregulation of pro-inflammatory mediators and cytokines via the inhibition of the nuclear factor-κB (NF-κB) signaling pathway, but not through the mitogen-activated protein kinase (MAPK) pathway. Based on the comparisons of the different magnitude of the anti-inflammatory effects of these structurally-related metabolites, it was suggested that the opening of the 12-membered lactone ring in curvularin-type metabolites and blocking the phenol functionality led to the significant decrease in their anti-inflammatory activity.

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