RT journal article
T1 Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages
A1 Kretzer, Christian
A1 Jordan, Paul Mike
A1 Meyer, Katharina Paula Lydia
A1 Hoff, Daniel
A1 Werner, Markus
A1 Hofstetter, Robert Klaus
A1 Koeberle, Andreas
A1 Cala Peralta, Antonio
A1 Viault, Guillaume
A1 Seraphin, Denis
A1 Richomme, Pascal
A1 Helesbeux, Jean-Jacques
A1 Stuppner, Hermann
A1 Temml, Veronika
A1 Schuster, Daniela
A1 Werz, Oliver
A2 Química Orgánica
K1 chalcones
K1 15-lipoxygenase
K1 lipid mediators
K1 specialized pro-resolving mediators
K1 macrophages
K1 inflammation resolution
AB Specialized pro-resolving mediators (SPMs) comprise lipid mediators (LMs) produced from polyunsaturated fatty acids (PUFAs) via stereoselective oxygenation particularly involving 12/15-lipoxygenases (LOXs). In contrast to pro-inflammatory LMs such as leukotrienes formed by 5-LOX and prostaglandins formed by cyclooxygenases, the SPMs have anti-inflammatory and inflammation-resolving properties. Although glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin production are still prime therapeutics for inflammation-related diseases despite severe side effects, novel concepts focus on SPMs as immunoresolvents for anti-inflammatory pharmacotherapy. Here, we studied the natural chalcone MF-14 and the corresponding dihydrochalcone MF-15 from Melodorum fruticosum, for modulating the biosynthesis of LM including leukotrienes, prostaglandins, SPM and their 12/15-LOX-derived precursors in human monocyte-derived macrophage (MDM) M1- and M2-like phenotypes. In MDM challenged with Staphylococcus aureus-derived exotoxins both compounds (10 µM) significantly suppressed 5-LOX product formation but increased the biosynthesis of 12/15-LOX products, especially in M2-MDM. Intriguingly, in resting M2-MDM, MF-14 and MF-15 strikingly evoked generation of 12/15-LOX products and of SPMs from liberated PUFAs, along with translocation of 15-LOX-1 to membranous compartments. Enhanced 12/15-LOX product formation by the chalcones was evident also when exogenous PUFAs were supplied, excluding increased substrate supply as sole underlying mechanism. Rather, MF-14 and MF-15 stimulate the activity of 15-LOX-1, supported by experiments with HEK293 cells transfected with either 5-LOX, 15-LOX-1 or 15-LOX-2. Together, the natural chalcone MF-14 and the dihydrochalcone MF-15 favorably modulate LM biosynthesis in human macrophages by suppressing pro-inflammatory leukotrienes but stimulating formation of SPMs by differential interference with 5-LOX and 15-LOX-1.
PB Elsevier
SN 1873-2968
YR 2021
FD 2021-12-23
LK http://hdl.handle.net/10498/33390
UL http://hdl.handle.net/10498/33390
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 07-nov-2026