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Anti-Inflammatory Effects of Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 in HaCaT Human Keratinocytes.

ABSTRACT: Chemical investigation of the Antarctic fungi Pleosporales sp. SF-7343 revealed four known secondary fungal metabolites: alternate C (1), altenusin (2), alternariol (3), and altenuene (4). The compound structures were identified primarily by NMR and MS analyses. Atopic dermatitis, an inflammatory disease, is driven by the abnormal activation of T helper (Th) 2 cells and barrier dysfunction. We attempted to identify the anti-inflammatory components of SF-7343. Initial screening showed that compounds 1 and 3 inhibited the secretion of interleukin-8 and -6 in tumor necrosis factor-α/interferon-γ-treated HaCaT cells, and these compounds also showed inhibitory effects on CCL5 and CCL22. Compounds 1 and 3 also downregulated the protein expression levels of intercellular adhesion molecule-1 and upregulated the expression of filaggrin and involcurin. The mechanism study results showed that compounds 1 and 3 inhibited nuclear translocation of nuclear factor-kappa B p65 and the phosphorylation of STAT1 and STAT3. Compound 1, but not compound 3, significantly promoted the expression of heme oxygenase (HO)-1. The effects of compound 1 were partly reversed by co-treatment with a HO-1 inhibitor, tin protoporphyrin IX. Taken together, this study demonstrates the potential value of Antarctic fungal strain SF-7343 isolates as a bioresource for bioactive compounds to prevent skin inflammation.

SUBMITTER: Dong L

PROVIDER: S-EPMC8468741 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:BackgroundKeratinocytes constitute a major part of the melanoma microenvironment, considering their protective role towards melanocytes in physiological conditions. However, their interactions with tumor cells following melanomagenesis are still unclear.MethodsWe used two in vitro models (melanoma-conditioned media and indirect co-culture of keratinocytes with melanoma cells on Transwell inserts) to activate immortalized keratinocytes towards cancer-associated ones. Western Blotting and qPCR were used to evaluate keratinocyte markers and mediators of cell invasiveness on protein and mRNA expression level respectively. The levels and activity of proteases and cytokines were analysed using gelatin-FITC staining, gelatin zymography, chemiluminescent enzymatic test, as well as protein arrays. Finally, to further study the functional changes influenced by melanoma we assessed the rate of proliferation of keratinocytes and their invasive abilities by employing wound healing assay and the Transwell filter invasion method.ResultsHaCaT keratinocytes activated through incubation with melanoma-conditioned medium or indirect co-culture exhibit properties of less differentiated cells (downregulation of cytokeratin 10), which also prefer to form connections with cancer cells rather than adjacent keratinocytes (decreased level of E-cadherin). While they express only a small number of cytokines, the variety of secreted proteases is quite prominent especially considering that several of them were never reported as a part of secretome of activated keratinocytes' (e.g., matrix metalloproteinase 3 (MMP3), ADAM metallopeptidase with thrombospondin type 1 motif 1). Activated keratinocytes also seem to exhibit a high level of proteolytic activity mediated by MMP9 and MMP14, reduced expression of TIMPs (tissue inhibitor of metalloproteinases), upregulation of ERK activity and increased levels of MMP expression regulators-RUNX2 and galectin 3. Moreover, cancer-associated keratinocytes show slightly elevated migratory and invasive abilities, however only following co-culture with melanoma cells on Transwell inserts.ConclusionsOur study offers a more in-depth view of keratinocytes residing in the melanoma niche, drawing attention to their unique secretome and mediators of invasive abilities, factors which could be used by cancer cells to support their invasion of surrounding tissues. Video abstract.

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Anti-Inflammatory Effects of Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 in HaCaT Human Keratinocytes.

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