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  • In the present studies we found that

    2021-10-13

    In the present studies, we found that genistein did not antagonize fMLF-induced Ca2+ mobilization in FPR1-HL60 gyy and human neutrophils. Thus, the previously reported inhibitory effect of genistein on fMLF-stimulated degranulation, aggregation, and reactive oxygen species (ROS) production in human neutrophils [47], [72], [73] may be related to pathways downstream of Ca2+-mobilization, such as tyrosine kinase-dependent signaling [46], [47] and ROS scavenger activity [74]. Indeed, the broad modulatory activity of genistein on neutrophil activity suggests a non-receptor mode of action. For example, genistein inhibited neutrophil adhesion/adherence activated by agonists of protease-activated receptor 2 (PAR2) [75] or TNF [76]. Moreover, pretreatment of neutrophils with genistein potentiated fMLF-induced cell transmigration [77]. Another isoflavone, afrormosin, inhibited fMLF-stimulated neutrophil degranulation at very high concentrations only (IC50 ∼67μM) [78]. Thus, our current studies suggest that FPR1-independent molecular mechanisms could play a role in the previously reported inhibition of fMLF-induced neutrophil responses by genistein and afrormosin. Although isoflavones are abundant in the members of the Fabaceae (i.e., Leguminosae) [79], these compounds were also isolated from species belonging to other families. Dozens of novel isoflavonoids are discovered every year (for review, see [79]) and further broad screening of natural isoflavones for FPR antagonist activity and ant-inflammatory activity should now be considered. Furthermore, previously reported inhibitory effects of 4H-chromen-4-ones and related flavonoids (e.g., [80]) on fMLF-induced neutrophil responses should be reevaluated in light of our current findings because their biological effects may involve FPR1 antagonist activity. In conclusion, we have identified a number of specific, competitive FPR1 antagonists with isoflavone backbones. Several of these 4H-chromen-4-one derivatives could represent important leads for therapeutic development focused on FPR1 function and attenuation of neutrophil-mediated inflammatory diseases. These compounds can also serve as scaffolds for the development of additional potent and selective FPR1 antagonists. Furthermore, characterization of this class of antagonists and analysis of additional derivatives should provide important clues to understanding the molecular structural requirements of FPR1 antagonists.
    Acknowledgements This work was supported in part by National Institutes of Health IDeA Program COBRE grant GM110732 and grant AI033503, an equipment grant from the M.J. Murdock Charitable Trust, a USDA National Institute of Food and Agriculture Hatch project, and the Montana State University Agricultural Experiment Station.
    The human formyl-peptide receptor (FPR) and its variant FPRL1 (FPR-like 1) belong to the seven transmembrane domain Gi-protein-coupled receptor (GPCR) family. Both receptors are expressed at high levels on neutrophils and monocytes, and both mediate cell chemotaxis in a pertussis toxin-sensitive manner, indicating coupling to one or more members of the Gi (inhibitory G) subfamily of G proteins. Classic studies suggested that the N-formyl group was a crucial determinant of ligand binding to FPR , and because bacterial , and mitochondrial proteins are the only sources of N-formyl peptides in nature, it has been widely thought that these receptors evolved to mediate trafficking of phagocytes to sites of bacterial invasion or tissue damage. This is supported by the ability of N-formyl peptides to induce the release of anti-microbial peptides and oxidants from phagocytes (reviewed in , , , ) and by the reduced resistance of FPR knockout mice to infection by . Nevertheless, over the past five years, data from several groups have indicated that these receptors might act in a more complex manner. A large number of non-formylated peptide ligands for FPR and FPRL1 and a lipid ligand for FPRL1 have now been identified (). Some have prominent anti-inflammatory actions and formyl peptides have themselves been proposed to have anti-inflammatory effects by cross-desensitizing receptors for other classical chemoattractants and chemokines (reviewed in ). In addition to several synthetic small peptide agonists originating from random peptide libraries, some of the new ligands are endogenous in origin, some come from pathogens and several are associated with human diseases, including HIV, Alzheimer's disease (AD), amyloidosis and prion disease (). Another recent development is the identification of novel, host-derived receptor antagonists, that join an older group of FPR antagonists which include small synthetic peptides with a t-butyloxycarbonyl (tBOC) or isopropylureido group at the N-termini, and the fungus product Cyclosporine H (CsH) , . New antagonists include the bile products deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) (reviewed in ), as well as spinorphin , which is a peptide of the opioid hemorphin family that might help to limit inflammatory responses associated with FPR activation. These newly identified ligand–receptor interactions and their implications in the pathogenesis of infectious and immunologically mediated diseases are the subject of this review.