@misc{10498/33390,
year = {2021},
month = {12},
url = {http://hdl.handle.net/10498/33390},
abstract = {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.},
publisher = {Elsevier},
keywords = {chalcones},
keywords = {15-lipoxygenase},
keywords = {lipid mediators},
keywords = {specialized pro-resolving mediators},
keywords = {macrophages},
keywords = {inflammation resolution},
title = {Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages},
doi = {10.1016/j.bcp.2021.114825},
author = {Kretzer, Christian and Jordan, Paul Mike and Meyer, Katharina Paula Lydia and Hoff, Daniel and Werner, Markus and Hofstetter, Robert Klaus and Koeberle, Andreas and Cala Peralta, Antonio and Viault, Guillaume and Seraphin, Denis and Richomme, Pascal and Helesbeux, Jean-Jacques and Stuppner, Hermann and Temml, Veronika and Schuster, Daniela and Werz, Oliver},
}