The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation

Hwang, Tsong‐Long; Wang, Chien Chiao; Kuo, Yao Haur; Huang, Hui; Wu, Yang Chang; Kuo, Liang Mou; Wu, Yuan-Hua

doi:10.1016/j.bcp.2010.06.028

Cited by 61 publications

(39 citation statements)

References 51 publications

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“…Receptor binding was assayed by the FACScan analysis of the binding of FNLFNYK, a fluorescent analog of fMLF, as described previously (27,28). Neutrophils (2 3 10 6 cells/ml), differentiated THP-1 (2 3 10 6 cells/ml), or FPR1-transfected HEK-293 (2.5 3 10 5 cells/ml) were incubated with propofol for 5 min at 4˚C and labeled with FNLFNYK.…”

Section: Receptor-binding Assaymentioning

confidence: 99%

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

Yang

Chung

et al. 2013

The Journal of Immunology

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Neutrophils play a critical role in acute and chronic inflammatory processes, including myocardial ischemia/reperfusion injury, sepsis, and adult respiratory distress syndrome. Binding of formyl peptide receptor 1 (FPR1) by N-formyl peptides can activate neutrophils and may represent a new therapeutic target in either sterile or septic inflammation. Propofol, a widely used i.v. anesthetic, has been shown to modulate immunoinflammatory responses. However, the mechanism of propofol remains to be established. In this study, we showed that propofol significantly reduced superoxide generation, elastase release, and chemotaxis in human neutrophils activated by fMLF. Propofol did not alter superoxide generation or elastase release in a cell-free system. Neither inhibitors of γ-aminobutyric acid receptors nor an inhibitor of protein kinase A reversed the inhibitory effects of propofol. In addition, propofol showed less inhibitory effects in non-FPR1–induced cell responses. The signaling pathways downstream from FPR1, involving calcium, AKT, and ERK1/2, were also competitively inhibited by propofol. These results show that propofol selectively and competitively inhibits the FPR1-induced human neutrophil activation. Consistent with the hypothesis, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils, differentiated THP-1 cells, and FPR1-transfected human embryonic kidney-293 cells. To our knowledge, our results identify, for the first time, a novel anti-inflammatory mechanism of propofol by competitively blocking FPR1 in human neutrophils. Considering the importance of N-formyl peptides in inflammatory processes, our data indicate that propofol may have therapeutic potential to attenuate neutrophil-mediated inflammatory diseases by blocking FPR1.

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Section: Receptor-binding Assaymentioning

confidence: 99%

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

Yang

Chung

et al. 2013

The Journal of Immunology

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174

200

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“…Although none of these triterpenes and their saponins have been evaluated for direct FPR1 binding activity, SMG-1 (hederagenin 3- O -(3,4- O -di-acetyl-α-L-arabinopyranoside)-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside) blocked binding of fluorescent FPR1 ligand in human neutrophils and inhibited f MLF-induced O 2 −· production and HNE release by these cells [161]. Because the saponinogen of SMG-1 was not studied, we evaluated the effect of hederagenin and found that this compound inhibited f MLF-induced Ca 2+ flux in human neutrophils and FPR1 HL-60 cells.…”

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

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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.

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“…However, activated human neutrophils are known to cause tissue damage and to play a critical role in a variety of acute and chronic inflammatory diseases [14,15]. For example, high concentrations of reactive oxygen species and elastase produced by activated neutrophils in the sputum of patients with airway mucus hypersecretion has been implicated in the pathogenesis of many pulmonary diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis and acute respiratory distress syndrome [16][17][18][19]. In a search for suitable new anti-neutrophilic inflammatory agents from natural sources, the inhibition of O 2…”

Section: Introductionmentioning

confidence: 99%

A New Hydroxychavicol Dimer from the Roots of Piper betle

et al. 2013

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Abstract:A new hydroxychavicol dimer, 2-('-hydroxychavicol)-hydroxychavicol (1), was isolated from the roots of Piper betle Linn. along with five known compounds, hydroxychavicol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6). The structures of these isolated compounds were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils.

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The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation

Cited by 61 publications

References 51 publications

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

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

A New Hydroxychavicol Dimer from the Roots of Piper betle

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