Abstract
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.
Highlights
Inflammation is a vital part of the body’s immune response
This study describes the isolation curvularin derivative (1), along with their anti‐inflammatory effects in LPS‐stimulated RAW264.7 and structural elucidation of these curvularin-type metabolites (1–9), including a new curvularin macrophages
The structures of known polyketides (2–9) were determined by the analysis of their nuclear magnetic resonance (NMR), mass spectrometry (MS), and specific rotation data, along with comparisons of these data with those of the and specific rotation data, along with comparisons of these data with those of the previously-published previously‐published values in the literature. They were identified as curvulone B (2) [10], values in the (3)
Summary
Inflammation is a vital part of the body’s immune response. There are two types of signals in the inflammatory process: the signals that initiate and maintain inflammation and the other signals that cease the process. Macrophages are innate immune cells that play a critical role in the initiation, maintenance, and resolution of inflammation. These cells participate in tissue homeostasis, immune responses, and inflammations in lymphoid organs, liver, lung, and the central nervous system [2]. Cytokines and enzymes as interleukins (ILs), tumor factor-α (TNF-α), inducibleand nitric oxide synthase (iNOS),such and cyclooxygenase‐2. EtOAc extract obtained from the culture of a marine‐derived search for bioactive secondary metabolites from marine-derived fungi [7,8,9], we investigated the fungal strain. This study describes the isolation curvularin derivative (1), along with their anti‐inflammatory effects in LPS‐stimulated RAW264.7 and structural elucidation of these curvularin-type metabolites (1–9), including a new curvularin macrophages. Derivative (1), along with their anti-inflammatory effects in LPS-stimulated RAW264.7 macrophages
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