Disulfides from the Brown Alga Dictyopteris membranacea Suppress M1 Macrophage Activation by Inducing AKT and Suppressing MAPK/ERK Signaling Pathways

Abstract

Inflammation is part of the organism’s response to deleterious stimuli, such as pathogens, damaged cells, or irritants. Macrophages orchestrate the inflammatory response obtaining different activation phenotypes broadly defined as M1 (pro-inflammatory) or M2 (homeostatic) phenotypes, which contribute to pathogen elimination or disease pathogenesis. The type and magnitude of the response of macrophages are shaped by endogenous and exogenous factors and can be affected by nutrients or therapeutic agents. Multiple studies have shown that natural products possess immunomodulatory properties and that marine algae contain products with such action. We have previously shown that disulfides isolated from Dictyopteris membranacea suppress nitric oxide (NO) production from activated macrophages, suggesting potential anti-inflammatory actions. In this study, we investigated the anti-inflammatory mechanism of action of bis(5-methylthio-3-oxo-undecyl) disulfide (1), 5-methylthio-1-(3-oxo-undecyl) disulfanylundecan-3-one (2) and 3-hexyl-4,5-dithiocycloheptanone (3). Our results showed that all three compounds inhibited M1 activation of macrophages by down regulating the production of pro-inflammatory cytokines TNFα, IL-6 and IL-12, suppressed the expression of the NO converting enzyme iNOS, and enhanced expression of the M2 activation markers Arginase1 and MRC1. Moreover, disulfides 1 and 2 suppressed the expression of glucose transporters GLUT1 and GLUT3, suggesting that compounds 1 and 2 may affect cell metabolism. We showed that this was due to AKT/MAPK/ERK signaling pathway modulation and specifically by elevated AKT phosphorylation and MAPK/ERK signal transduction reduction. Hence, disulfides 1–3 can be considered as potent candidates for the development of novel anti-inflammatory molecules with homeostatic properties.

Purification, Structural Characterization and Immunomodulatory Effects of Polysaccharides from Amomumvillosum Lour. on RAW 264.7 Macrophages

“…To further investigate which subtypes are activated in response to AVPG-2 treatment, the transcription of CD86 and CD206, two commonly used markers of M1 macrophages and M2 macrophages were investigated [ 56 ]. LPS and IL-4 are the M1 and M2 polarization agents, respectively [ 57 , 58 ]. As shown in Figure 7 H, LPS and IL-4 upregulated the mRNA expression of CD86 and CD206, respectively.…”

Collagen-Containing Fish Sidestream-Derived Protein Hydrolysates Support Skin Repair via Chemokine Induction

“…Over the past decades, peptides and proteins from different marine sources have been shown to possess immunomodulatory activities. We have previously reported that compounds isolated from marine algae present strong anti-inflammatory action [ 53 , 54 ]. It is therefore evident that multiple studies have explored the role of different marine-derived extracts in the context of wound healing.…”

The Natural Products and Pharmacological Biodiversity of Brown Algae from the Genus Dictyopteris

“…Disulfide metabolites were inactive as antibacterial while metabolite (97) was able to cause strong inhibition of NO production (IC50= 3.8 μM) [81]. 5-methylthio-1-(3-oxo-undecyl) disulfanylundecan-3-one (97), bis(5-methylthio-3-oxo-undecyl) disulfide (100) and 3-hexyl-4,5dithiocycloheptanone (101) were detected in CH2Cl2-MeOH (1:1, v/v) extract of D. memberanacea, collected from Tinos island, Greece, inhibited activation of macrophages M1 by down regulating the production of proinflammatory cytokines such as TNFα, IL-6 and IL-12, suppressed the expression of iNOS, and enhanced expression of the macrophages M2 activation markers Arginase1 and MRC1 [82]. 4-Acetoxycrenulide (102), 18, 19-epoxyxenic-19-one-6,9,13-triene (103), dictyolactone (104), cholesterol (105) and diisooctyl phthalate (106) were detected in ethanol extract of D. memberanacea collected from the Mediterranean coast of Egypt (Fig.…”