Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages

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.

Classification of Aspergillus, Penicillium, Talaromyces and related genera (Eurotiales): An overview of families, genera, subgenera, sections, series and species

“…Extrolites : Penicillium sumatraense produces curvularins such as curvularin, dehydrocurvularin, sumalactone A-D, sumalarins and citridones E-G ( Vesonder et al., 1976 , Malmstrom et al., 2000 , Meng et al., 2013 , de Castro et al., 2016 , Ha et al., 2017 , Wu et al., 2017 , Xu et al., 2019b ). This species has been reported to produce a blue mould rot of Vitus vinifera and Sparassis crispa ( Mahdian and Zafari, 2016 , Liu et al., 2018b ).…”

The Anti-Inflammatory and Cytoprotective Efficiency of Curvularin, a Fungal Macrolactone against Lipopolysaccharide-Induced Inflammatory Response in Nucleus Pulposus Cells: An In Vitro Study

“…Cur is a novel bioactive fungal macrolactone (secondary metabolite) that can effect potent anti-inflammatory action; hence, it indicates importance for medicine and agriculture [22]. Schmidt et al [17] in 2012 investigated the anti-inflammatory activity of (S)-Cur in mice and conducted microarray analyses of human C28/I2 chon- drocyte cells, by which they reduced the expression of pro-inflammatory genes.…”

“…Schmidt et al [17] in 2012 investigated the anti-inflammatory activity of (S)-Cur in mice and conducted microarray analyses of human C28/I2 chon- drocyte cells, by which they reduced the expression of pro-inflammatory genes. Nitric oxide (NO) plays a pivotal role in osteoarthritis and rheumatoid arthritis; (S)-Cur inhibited the production of NO by downregulating inducible NO synthase [22]. Rudolph et al [16] in 2012 found that (S)-Cur and dehydrocurvularin can be used as anticancer drugs as they are able to hinder the cellular effects of transforming growth factor-beta, which is a key mediator in the cell cycle process.…”

“…In the current study, we used LPS to induce inflammation in NPCs. Our study aims to evaluate the anti-inflammatory and regenerative efficiency of curvularin (Cur), a known natural fungal macrolactone [16,21,22], against LPS-induced inflammation in primary human NPCs, by altering the expression profiles of proinflammatory and metalloprotease genes in vitro. To our knowledge, no studies have been published on Cur that show it as having anti-inflammatory and cytoprotective properties for NPCs; hence, our study will be the first to evaluate Cur in this context.…”

“…Overview of inflammatory mediators used for inducing inflammation in varied NPCs and expression profile of cytokines, metalloproteases, etc [6,9,[12][13][14][15][19][20][21][22]. …”