A novel immunomodulatory effect of ugonin U in human neutrophils via stimulation of phospholipase C

Chen, Chun-Yu; Liaw, Chih‐Chuang; Chen, Yi‐Hsuan; Chang, Wen-Yi; Chung, Pei-Jen; Hwang, Tsong‐Long

doi:10.1016/j.freeradbiomed.2014.04.018

Cited by 32 publications

(36 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, compounds 94 and 95 may activate Ca 2+ flux via FPR-independent pathways, which leads to cross-desensensitization of FPR1 and/or cross-talk with the receptor. Indeed, several other synthetic and natural flavonoids (wogonin, apigenin, genistein, kazinol B, and ugonin U) have been reported to activate intracellular Ca 2+ flux in various cell lines [68, 69] or neutrophils [70, 71]. Clearly, additional research is required to define the mechanisms of biochanin A action on neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Schepetkin

Kirpotina

Khlebnikov

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki~100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists.

show abstract

Section: Discussionmentioning

confidence: 99%

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Schepetkin

Kirpotina

Khlebnikov

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…Thus, biochanin A and its synthetic derivative may activate Ca 2+ flux via pathways that lead to cross-desensensitization of FPR1 and/or cross-talk with the receptor. Indeed, several other synthetic and natural flavonoids, including apigenin, wogonin, genistein, kazinol B, and ugonin U, have been reported to stimulate a Ca 2+ flux in various cell lines [80, 81] and neutrophils [82, 83]. …”

Section: Small-molecule Non-peptide Fpr1 Antagonists and Their Synmentioning

confidence: 99%

“…Likewise, the isoprenylated flavonoid ugonin 3 (Table 1) isolated from Helminthostachys zeylanica and several related ugonins potently inhibited similar f MLF-induced functional responses [95, 96]. However, a related ugonin (ugonin U) was found to directly activate PLC and Ca 2+ flux in human neutrophils [97], suggesting possible receptor desensitization rather than antagonism. Binding of these compounds to FPR1 and effects on Ca 2+ mobilization were not reported.…”

Section: Small-molecule Non-peptide Fpr1 Antagonists and Their Synmentioning

confidence: 99%

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

Schepetkin

Khlebnikov

Kirpotina

et al. 2016

International Immunopharmacology

View full text Add to dashboard Cite

Formyl peptide receptor 1 (FPR1) regulates a wide variety of neutrophil functional responses and plays an important role in inflammation and the pathogenesis of various diseases. To date, a variety of natural and synthetic molecules have been identified as FPR1 ligands. Here, we review current knowledge on natural products and natural product-inspired small-molecules reported to antagonize and/or inhibit the FPR1-mediated responses. Based on this literature, additional screening of selected commercially available natural compounds for their ability to inhibit fMLF-induced Ca2+ mobilization in human neutrophils and FPR1 transfected HL-60 cells, and pharmacophore modeling, natural products with potential as FPR1 antagonists are considered and discussed in this review. The identification and characterization of natural products that antagonize FPR1 activity may have potential for the development of novel therapeutics to limit or alter the outcome of inflammatory processes.

show abstract

“…1A) was extracted from rhizomes of H. zeylanica (L) Hook as previously described in detail [31]. In brief, the dried rhizomes of H. zeylanica (L) Hook were extracted with methanol (MeOH).…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that ugonin U (UgU, 4′′a,5′′,6′′,7′′,8′′,8′′a-hexahydro-5,3′,4′-trihydroxy-5′′,5′′,8′′a-trimethyl-4H-chromeno [2′′,3′′:7,6]flavone, Fig. 1A) is the first identified natural flavonoid that directly stimulates phospholipase C (PLC) and induces a respiratory burst in human neutrophils [31]. UgU is isolated from Helminthostachys zeylanica (L) Hook, a pteridophyte with several medicinal properties including pain relief, detoxification, germ killing, and wound healing [32], [33].…”

Section: Introductionmentioning

confidence: 99%

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

et al. 2017

Self Cite

View full text Add to dashboard Cite

The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.

show abstract

A novel immunomodulatory effect of ugonin U in human neutrophils via stimulation of phospholipase C

Cited by 32 publications

References 43 publications

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

Contact Info

Product

Resources

About