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Mar. Drugs 2019, 17(2), 97; https://doi.org/10.3390/md17020097

Neorogioltriol and Related Diterpenes from the Red Alga Laurencia Inhibit Inflammatory Bowel Disease in Mice by Suppressing M1 and Promoting M2-Like Macrophage Responses

1
Laboratory of Biochemistry, School of Medicine, University of Crete, Heraklion 70013, Greece
2
Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 70013, Greece
3
Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece
4
Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece
5
Present address: Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
6
Present address: Section of Plant Biochemistry, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark
*
Authors to whom correspondence should be addressed.
Received: 24 December 2018 / Revised: 21 January 2019 / Accepted: 24 January 2019 / Published: 2 February 2019
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Abstract

Macrophages are central mediators of inflammation, orchestrating the inflammatory response through the production of cytokines and nitric oxide. Macrophages obtain pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, which can be modulated by soluble factors, including natural products. Despite the crucial protective role of inflammation, chronic or deregulated inflammation can lead to pathological states, such as autoimmune diseases, metabolic disorders, cardiovascular diseases, and cancer. In this case, we studied the anti-inflammatory activity of neorogioltriol (1) in depth and identified two structurally related diterpenes, neorogioldiol (2), and O11,15-cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (3), with equally potent activity. We investigated the mechanism of action of metabolites 13 and found that all three suppressed macrophage activation and promoted an M2-like anti-inflammatory phenotype by inducing expression of Arginase1, MRC1, IRAK-M, the transcription factor C/EBPβ, and the miRNA miR-146a. In addition, they suppressed iNOS induction and nitric oxide production. Importantly, treatment of mice with 2 or 3 suppressed DSS-induced colitis by reducing tissue damage and pro-inflammatory cytokine production. Thus, all these three diterpenes are promising lead molecules for the development of anti-inflammatory agents targeting macrophage polarization mechanisms. View Full-Text
Keywords: Laurencia; halogenated diterpenes; neorogioltriol; cytokine; nitric oxide; TNF-alpha; colitis Laurencia; halogenated diterpenes; neorogioltriol; cytokine; nitric oxide; TNF-alpha; colitis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Daskalaki, M.G.; Vyrla, D.; Harizani, M.; Doxaki, C.; Eliopoulos, A.G.; Roussis, V.; Ioannou, E.; Tsatsanis, C.; Kampranis, S.C. Neorogioltriol and Related Diterpenes from the Red Alga Laurencia Inhibit Inflammatory Bowel Disease in Mice by Suppressing M1 and Promoting M2-Like Macrophage Responses. Mar. Drugs 2019, 17, 97.

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