scholarly journals Chemical Composition and Immunomodulatory Activity of Essential Oils from Rhododendron albiflorum

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3652
Author(s):  
Igor A. Schepetkin ◽  
Gulmira Özek ◽  
Temel Özek ◽  
Liliya N. Kirpotina ◽  
Andrei I. Khlebnikov ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Essential Oils ◽  
Neutrophil Migration ◽  
Compositional Analysis ◽  
Microglial Cells ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Immunomodulatory Activity ◽  
Hl60 Cells ◽  
Formyl Peptide

Rhododendron (Ericaceae) extracts contain flavonoids, chromones, terpenoids, steroids, and essential oils and are used in traditional ethnobotanical medicine. However, little is known about the immunomodulatory activity of essential oils isolated from these plants. Thus, we isolated essential oils from the flowers and leaves of R. albiflorum (cascade azalea) and analyzed their chemical composition and innate immunomodulatory activity. Compositional analysis of flower (REOFl) versus leaf (REOLv) essential oils revealed significant differences. REOFl was comprised mainly of monoterpenes (92%), whereas sesquiterpenes were found in relatively low amounts. In contrast, REOLv was primarily composed of sesquiterpenes (90.9%), with a small number of monoterpenes. REOLv and its primary sesquiterpenes (viridiflorol, spathulenol, curzerene, and germacrone) induced intracellular Ca2+ mobilization in human neutrophils, C20 microglial cells, and HL60 cells transfected with N-formyl peptide receptor 1 (FPR1) or FPR2. On the other hand, pretreatment with these essential oils or component compounds inhibited agonist-induced Ca2+ mobilization and chemotaxis in human neutrophils and agonist-induced Ca2+ mobilization in microglial cells and FPR-transfected HL60 cells, indicating that the direct effect of these compounds on [Ca2+]i desensitized the cells to subsequent agonist activation. Reverse pharmacophore mapping suggested several potential kinase targets for these compounds; however, these targets were not supported by kinase binding assays. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the R. albiflorum essential oils and suggest that essential oils from leaves of this plant may be effective in modulating some innate immune responses, possibly by inhibition of neutrophil migration.

scholarly journals Innate Immunomodulatory Activity of Cedrol, a Component of Essential Oils Isolated from Juniperus Species

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7644
Author(s):  
Gulmira Özek ◽  
Igor A. Schepetkin ◽  
Moldir Yermagambetova ◽  
Temel Özek ◽  
Liliya N. Kirpotina ◽  
...  
Keyword(s):  
Essential Oils ◽  
Compositional Analysis ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Immunomodulatory Activity ◽  
Neutrophil Chemotaxis ◽  
Pharmacophore Mapping ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Similarities And Differences

Little is known about the immunomodulatory activity of essential oils isolated from Juniperus species. Thus, we isolated essential oils from the cones and leaves of eight juniper species found in Montana and in Kazakhstan, including J. horizontalis, J. scopolorum, J. communis, J. seravschanica, J. sabina, J. pseudosabina, J. pseudosabina subsp. turkestanica, and J. sibirica. We report here the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of the 16 samples of Juniper essential oils revealed similarities and differences between our analyses and those previously reported for essential oils from this species. Our studies represent the first analysis of essential oils isolated from the cones of four of these Juniper species. Several essential oil samples contained high levels of cedrol, which was fairly unique to three Juniper species from Kazakhstan. We found that these essential oils and pure (+)-cedrol induced intracellular Ca2+ mobilization in human neutrophils. Furthermore, pretreatment of human neutrophils and N-formyl peptide receptor 1 and 2 (FPR1 and FPR2) transfected HL60 cells with these essential oils or (+)-cedrol inhibited agonist-induced Ca2+ mobilization, suggesting these responses were desensitized by this pretreatment. In support of this conclusion, pretreatment with essential oils from J. seravschanica cones (containing 16.8% cedrol) or pure (+)-cedrol inhibited human neutrophil chemotaxis to N-formyl peptide. Finally, reverse pharmacophore mapping predicted several potential kinase targets for cedrol. Thus, our studies have identified cedrol as a novel neutrophil agonist that can desensitize cells to subsequent stimulation by N-formyl peptide.

scholarly journals Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

2020 ◽  
Author(s):  
Martina Sundqvist ◽  
André Holdfeldt ◽  
Shane C. Wright ◽  
Thor C. Møller ◽  
Esther Siaw ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Neutrophil Migration ◽  
Adaptor Protein ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Ros Production ◽  
Receptor Endocytosis ◽  
Formyl Peptide ◽  
Clathrin Adaptor ◽  
Nadph Oxidase Activation

AbstractFormyl peptide receptor 2 (FPR2), a member of the family of G protein-coupled receptors (GPCRs), mediates neutrophil migration, a response that has been linked to β-arrestin recruitment. β-Arrestin regulates GPCR endocytosis and can also elicit non-canonical receptor signaling. To determine the poorly understood role of β-arrestin in FPR2 endocytosis and in NADPH-oxidase activation in neutrophils, Barbadin was used as a research tool in this study. Barbadin has been shown to bind the clathrin adaptor protein (AP2) and thereby prevent β- arrestin/AP2 interaction and β-arrestin-mediated GPCR endocytosis. In agreement with this, AP2/β-arrestin interaction induced by an FPR2-specific agonist was inhibited by Barbadin. Unexpectedly, however, Barbadin did not inhibit FPR2 endocytosis, indicating that a mechanism independent of β-arrestin/AP2 interaction may sustain FPR2 endocytosis. This was confirmed by the fact, that FPR2 also underwent agonist-promoted endocytosis in β-arrestin deficient cells, albeit at a diminished level as compared to wild type cells. Dissection of the Barbadin effects on FPR2-mediated neutrophil functions including NADPH-oxidase activation mediated release of reactive oxygen species (ROS) and chemotaxis reveled that Barbadin had no effect on chemotactic migration whereas the release of ROS was potentiated/primed. The effect of Barbadin on ROS production was reversible, independent of β-arrestin recruitment, and similar to that induced by latrunculin A. Taken together, our data demonstrate that endocytic uptake of FPR2 occurs independently of β-arrestin, while Barbadin selectively augments FPR2-mediated neutrophil ROS production independently of receptor endocytosis. Given that Barbadin binds to AP2 and prevents the AP2/β-arrestin interaction, our results indicate a role for AP2 in FPR2-mediated ROS release from human neutrophils.

scholarly journals Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

2019 ◽  
Vol 116 (37) ◽  
pp. 18561-18570 ◽  
Author(s):  
Alan Y. Hsu ◽  
Decheng Wang ◽  
Sheng Liu ◽  
Justice Lu ◽  
Ramizah Syahirah ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Systemic Inflammation ◽  
Human Neutrophil ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Neutrophil Migration ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Formyl Peptide

Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those,miR-199decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils,miR-199alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore,miR-199overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions ofmiR-199and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.

scholarly journals Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils.

1993 ◽  
Vol 123 (4) ◽  
pp. 895-907 ◽  
Author(s):  
B A McCormick ◽  
S P Colgan ◽  
C Delp-Archer ◽  
S I Miller ◽  
J L Madara
Keyword(s):  
Epithelial Cells ◽  
Salmonella Typhimurium ◽  
Apical Membrane ◽  
Coli Strain ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Classical Pathway ◽  
Intestinal Epithelial ◽  
Formyl Peptide

In human intestinal disease induced by Salmonella typhimurium, transepithelial migration of neutrophils (PMN) rapidly follows attachment of the bacteria to the epithelial apical membrane. In this report, we model those interactions in vitro, using polarized monolayers of the human intestinal epithelial cell, T84, isolated human PMN, and S. typhimurium. We show that Salmonella attachment to T84 cell apical membranes did not alter monolayer integrity as assessed by transepithelial resistance and measurements of ion transport. However, when human neutrophils were subsequently placed on the basolateral surface of monolayers apically colonized by Salmonella, physiologically directed transepithelial PMN migration ensued. In contrast, attachment of a non-pathogenic Escherichia coli strain to the apical membrane of epithelial cells at comparable densities failed to stimulate a directed PMN transepithelial migration. Use of the n-formyl-peptide receptor antagonist N-t-BOC-1-methionyl-1-leucyl-1- phenylalanine (tBOC-MLP) indicated that the Salmonella-induced PMN transepithelial migration response was not attributable to the classical pathway by which bacteria induce directed migration of PMN. Moreover, the PMN transmigration response required Salmonella adhesion to the epithelial apical membrane and subsequent reciprocal protein synthesis in both bacteria and epithelial cells. Among the events stimulated by this interaction was the epithelial synthesis and polarized release of the potent PMN chemotactic peptide interleukin-8 (IL-8). However, IL-8 neutralization, transfer, and induction experiments indicated that this cytokine was not responsible for the elicited PMN transmigration. These data indicate that a novel transcellular pathway exists in which subepithelial PMN respond to lumenal pathogens across a functionally intact epithelium. Based on the known unique characteristics of the intestinal mucosa, we speculate that IL-8 may act in concert with an as yet unidentified transcellular chemotactic factor(s) (TCF) which directs PMN migration across the intestinal epithelium.

scholarly journals Influence of botulinum C2 toxin on F-actin and N-formyl peptide receptor dynamics in human neutrophils.

1989 ◽  
Vol 109 (3) ◽  
pp. 1133-1140 ◽  
Author(s):  
J Norgauer ◽  
I Just ◽  
K Aktories ◽  
L A Sklar
Keyword(s):  
Actin Polymerization ◽  
Response Characteristic ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Peptide Ligand ◽  
Light Scatter ◽  
Binding Studies ◽  
Rhodamine Phalloidin ◽  
Formyl Peptide ◽  
C2 Toxin

Stimulation of human neutrophils with the chemotactic N-formyl peptide causes production of oxygen radicals and conversion of monomeric actin (G-actin) to polymeric actin (F-actin). The effects of the binary botulinum C2 toxin on the amount of F-actin and on neutrophil cell responses were studied. Two different methods for analyzing the actin response were used in formyl peptide-stimulated cells: staining of F-actin with rhodamine-phalloidin and a transient right angle light scatter. Preincubation of neutrophils with 400 ng/ml component I and 1,600 ng/ml component II of botulinum C2 toxin for 30 min almost completely inhibited the formyl peptide-stimulated polymerization of G-actin and at the same time decreased the amount of F-actin in unstimulated neutrophils by an average of approximately 30%. Botulinum C2 toxin preincubation for 60 min destroyed approximately 75% of the F-actin in unstimulated neutrophils. Right angle light scatter analysis showed that control neutrophils exhibited the transient response characteristic of actin polymerization; however, after botulinum C2 toxin treatment, degranulation was detected. Single components of the binary botulinum C2 toxin were without effect on the actin polymerization response. Fluorescence flow cytometry and fluorospectrometric binding studies showed little alteration in N-formyl peptide binding or dissociation dynamics in the toxin-treated cells. However, endocytosis of the fluorescent N-formyl peptide ligand-receptor complex was slower but still possible in degranulating neutrophils treated with botulinum C2 toxin for 60 min. The half-time of endocytosis, estimated from initial rates, was 4 and 8 min in control and botulinum C2 toxin-treated neutrophils, respectively.

Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils

Gene ◽  
1992 ◽  
Vol 118 (2) ◽  
pp. 303-304 ◽  
Author(s):  
H.Daniel Perez ◽  
Richard Holmes ◽  
Edward Kelly ◽  
John McClary ◽  
William H. Andrews
Keyword(s):  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Peptide Receptor ◽  
Formyl Peptide

scholarly journals N-Formyl peptide receptor subtypes in human neutrophils activate l-plastin phosphorylation through different signal transduction intermediates

2004 ◽  
Vol 377 (2) ◽  
pp. 469-477 ◽  
Author(s):  
Marie-Hélène PACLET ◽  
Clare DAVIS ◽  
Peter KOTSONIS ◽  
Jasminka GODOVAC-ZIMMERMANN ◽  
Anthony W. SEGAL ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Formyl Peptide Receptor ◽  
Actin Binding ◽  
Human Neutrophils ◽  
Receptor Subtypes ◽  
Peptide Receptor ◽  
High Affinity ◽  
Formyl Peptide ◽  
Fmlp Receptor ◽  
Phosphoinositide 3 Kinase

We investigated the coupling of the fMLP (N-formyl-l-methionyl-l-leucyl-l-phenylalanine; ‘chemotactic peptide’) receptor with phosphorylation of the actin-binding protein l-plastin in neutrophils. Using two-dimensional IEF (isoelectric focusing)/PAGE and MALDI–TOF (matrix-assisted laser desorption ionization–time-of-flight)-MS, l-plastin was identified as a major phosphoprotein in fMLP-stimulated neutrophils whose phosphorylation was dependent on phosphoinositide 3-kinase, PLD (phospholipase D) and PKC (protein kinase C) activity. Two fMLP receptor subtypes were identified in neutrophils, characterized by a distinct sensitivity to fMLP and antagonistic peptides. Both receptor subtypes induced the phosphorylation of l-plastin. l-plastin phosphorylation induced by low-affinity fMLP receptors involves an action of phosphoinositide 3-kinase, PLD and PKC isotypes. In contrast, none of these intermediates are utilized by high-affinity fMLP receptors in the phosphorylation of l-plastin. However, the PKC inhibitor Ro-31-8220 inhibits l-plastin phosphorylation induced by the high-affinity fMLP receptor. Thus, an as yet unknown Ro-31-8220-sensitive kinase regulates l-plastin phosphorylation in response to the high-affinity fMLP receptor. The results suggest a model in which receptor subtypes induce a similar endpoint event through different signal-transduction intermediates. This may be relevant in the context of cell migration in which one receptor subpopulation may become desensitized in a concentration gradient of chemoattractant.

scholarly journals Development, characterisation and in vitro evaluation of lanthanide-based FPR2/ALX-targeted imaging probes

2019 ◽  
Vol 48 (44) ◽  
pp. 16764-16775 ◽  
Author(s):  
Tamara Boltersdorf ◽  
Junaid Ansari ◽  
Elena Y. Senchenkova ◽  
Lijun Jiang ◽  
Andrew J. P. White ◽  
...  
Keyword(s):  
Lanthanide Complexes ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Targeted Imaging ◽  
In Vitro Evaluation ◽  
Peptide Receptor ◽  
Imaging Probes ◽  
Formyl Peptide

Formyl Peptide Receptor (FPR)-targeted lanthanide complexes with long-lived emission in stimulated human neutrophils.

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