Searching for immunomodulatory compounds from Icelandic marine invertebrates
Year: 2019
Type: dissertation
Abstract: A substantial diversity of secondary metabolites from marine invertebrates has been described; however, only a few studies have investigated secondary metabolites of marine invertebrates collected in Icelandic waters. The unique marine environment around Iceland, in terms of temperature and underwater geothermal activity, has forced the living marine organisms to survive in the surroundings by developing unique biomolecules. The marine invertebrates are therefore an excellent starting point for searching for new bioactive compounds. The aim of this thesis was to isolate and identify new compounds, and known, with immunomodulatory activity from marine invertebrates collected in Icelandic waters. \nSeven crude extracts from Icelandic marine sponges were screened for immunomodulatory activities using an in vitro dendritic cell (DC) model. The bioactive extracts were then fractionated by column chromatographic technique with the help of bioassay-guided isolation approach to isolate the active constituents. Five pure known polyunsaturated fatty acids (PUFAs) from unidentified marine sponges and several lipophilic fractions from Halichondria sitiens were obtained and they showed immunomodulatory activity, demonstrated by their ability to reduce DC secretion of the pro-inflammatory cytokine IL-12p40 and the anti-inflammatory cytokine IL-10. Maturing DCs in the presence of selected fractions before co-culturing them with allogeneic CD4+ T cells mainly led to a decrease in T cell secretion of IFN-y, indicating a reduction in Th1 immune response. In addition, one new glycerol ester featuring methyl branched fatty acid chain was obtained but it did not have immunomodulatory activity using the DC model. \nCrude extracts from the marine sponge Geodia barretti and the bryozoan Flustra foliacea were chemically profiled by UPLC-qTOF-MS. Both previously known and unknown compounds were characterized by comparing the obtained molecular (precursor) ions and fragmentation patterns from obtained MS/MS data with data from the literature and databases. The crude extracts were subjected to various chromatographic techniques that yielded nineteen new alkaloids and sixteen known alkaloids. The structures of the isolated new compounds were elucidated by detailed spectroscopic analysis, including 1H NMR, 13C NMR, 1H-1H COSY, HSQC, HMBC, NOESY, 1H-15N HSQC, 1H-15N HMBC, and HRESIMS. The stereochemistry was assigned by combination of \niii \nNMR spectroscopic data, optical rotation, ECD analysis and application of a Marfey’s-type method employing the new reagent ʟ-ND-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (ʟ-FDTA). The absolute stereochemistry of one known compound was re-evaluated. All the isolated compounds were screened for immunomodulatory activity using the DC model. Twelve of the compounds decreased DC secretion of IL-12p40 and two of them increased secretion of IL-10. Three of the compounds were chosen for further investigation of dose-dependency of their activity and subsequently their ability to induce a Th1 or a Treg immune response in T cells co-cultured with DCs previously incubated with the compounds. Overall, G. barretti and F. foliacea contain a variety of alkaloids, several of which have anti-inflammatory activity, some of them warranting further investigation into their potential as a candidate for relieving inflammatory diseases. \nThe results demonstrate that marine invertebrates collected from the marine environment around Iceland contain a number of secondary metabolites some of which have immunomodulatory effects. These studies indicate that the marine environment around Iceland may be a plentiful source of biological compounds with the potential of becoming a drug lead for treatment of inflammatory related diseases.
Source: Opin vísindi (Opin vísindi)
Author: Xiaxia Di
Language: English
Subfield: Biotechnology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2913362708