6-Pentyl-α-Pyrone from Trichoderma gamsii Exert Antioxidant and Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Mouse Macrophages

Abstract

Filamentous fungi produce several beneficial secondary metabolites, including bioactive compounds, food additives, and biofuels. Trichoderma, which is a teleomorphic Hypocrea that falls under the taxonomic groups Ascomycota and Dikarya, is an extensively studied fungal genus. In an ongoing study that seeks to discover bioactive natural products, we investigated potential bioactive metabolites from the methanolic extract of cultured Trichoderma gamsii. Using liquid chromatography–mass spectrometry (LC–MS), one major compound was isolated and structurally identified as 6-pentyl-α-pyrone (6PP) based on nuclear magnetic resonance data and LC–MS analysis. To determine its antioxidant and anti-inflammatory activity, as well as the underlying mechanisms, we treated lipopolysaccharide (LPS)-stimulated Raw264.7 mouse macrophages with 6PP. We found that 6PP suppresses LPS-induced increase in the levels of nitric oxide, a mediator of oxidative stress and inflammation, and restores LPS-mediated depletion of total glutathione by stabilizing nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidative factor, and elevating heme oxygenase-1 levels. Furthermore, 6PP inhibited LPS-induced production of proinflammatory cytokines, which are, at least in part, regulated by heme oxygenase-1 (HO-1). 6PP suppressed proinflammatory responses by inhibiting the nuclear localization of nuclear factor kappa B (NF-κB), as well as by dephosphorylating the mitogen-activated protein kinases (MAPKs). These results indicate that 6PP can protect macrophages against oxidative stress and LPS-induced excessive inflammatory responses by activating the Nrf2/HO-1 pathway while inhibiting the proinflammatory, NF-κB, and MAPK pathways.

Impact of S100A4 Deletion on the Macrophage Metabolome and Differentiation

“…Metabolomic ngerprinting indicates that Leishmania infection alters Larginine/polyamines/trypanothione metabolism inside the host cell, and the parasite arginase impacts Larginine metabolism and polyamine production, acting as a determination of infection progression (49). In addition, 6-pentyl-α-pyrone is a natural metabolite that has been con rmed to inhibit the LPS-induced in ammatory response in mouse macrophages in vitro (50). These results suggest that targeting macrophage metabolism is feasible for regulating the occurrence and development of diseases.…”

Uncovering the multifaceted properties of 6-pentyl-alpha-pyrone for control of plant pathogens

“…Trichoderma produces 6-PP when grown in different solid and liquid media, such as minimal medium supplemented with various carbon and nitrogen sources ( Moss et al., 1975 ; Yong et al., 1985 ; Serrano-Carreon et al., 1993 ; Bonnarme et al., 1997 ), malt extract ( Claydon et al., 1987 ), Sabouraud dextrose ( Bello et al., 2022 ), and potato dextrose broth/agar (PDB/PDA) ( Collins and Halim, 1972 ; Simon et al., 1988 ; Prapulla et al., 1992 ; Scarselletti and Faull, 1994 ; Worasatit et al., 1994 ; Reithner et al., 2005 ; Lim et al., 2023 ). In PDB and PDA, Trichoderma produces higher 6-PP concentrations ( Bello et al., 2022 ), suggesting that media-rich nutrients promote the primary production of 6-PP.…”

“…In fungi, the proteins equivalent to Na+, K+ATPases are the proton-ATPases involved in regulation of hypersensitivity to osmotic stresses, cell wall stressors and oxidative stress ( Mou et al., 2020 ; Deng et al., 2023 ). In fungi, 6-PP may also target other enzymes involved in critical metabolic pathways, such as glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid biosynthesis as well as key components associated with nutrients sensing such as TOR kinase signaling ( Jin et al., 2020 ; Lim et al., 2023 ; Liu et al., 2023 ; Wu et al., 2023 ). By inhibiting enzymes within these pathways, 6-PP disrupts the production of essential metabolites and intermediates, impairing the pathogen’s ability to generate energy and synthesize macromolecules necessary for growth and replication ( Jin et al., 2020 ).…”