| Autor: |
Daskalaki MG; Laboratory of Biochemistry, School of Medicine, University of Crete, Heraklion 70013, Greece. m.daskalaki@med.uoc.gr.; Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 70013, Greece. m.daskalaki@med.uoc.gr.; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece. m.daskalaki@med.uoc.gr., Vyrla D; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece. di_micro@hotmail.com., Harizani M; Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece. mariachariz@pharm.uoa.gr., Doxaki C; Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 70013, Greece. cdoxaki@med.uoc.gr.; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece. cdoxaki@med.uoc.gr., Eliopoulos AG; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece. eliopag@med.uoa.gr.; Present address: Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece. eliopag@med.uoa.gr., Roussis V; Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece. roussis@pharm.uoa.gr., Ioannou E; Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece. eioannou@pharm.uoa.gr., Tsatsanis C; Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 70013, Greece. tsatsani@uoc.gr.; Institute of Molecular Biology and Biotechnology, FORTH, Heraklion, Crete 71110, Greece. tsatsani@uoc.gr., Kampranis SC; Laboratory of Biochemistry, School of Medicine, University of Crete, Heraklion 70013, Greece. soka@plen.ku.dk.; Present address: Section of Plant Biochemistry, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark. soka@plen.ku.dk. |
| Abstrakt: |
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 O 11 ,15-cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol ( 3 ), with equally potent activity. We investigated the mechanism of action of metabolites 1 ⁻ 3 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. |
