Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R related Ca2+ fluctuations

Ding, Yuanyuan; Che, Delu; Li, Chaomei; Cao, Jiao; Wang, Jue; Ma, Pengyu; Zhao, Tingting; An, Hongli; Zhang, Tao

doi:10.1016/j.intimp.2018.11.025

Cited by 57 publications

(40 citation statements)

References 32 publications

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“…Therefore, antagonizing MRGPRX2 is a rational therapeutic strategy for the prevention and treatment of anaphylactoid reactions. In recent years, several attempts have been made to target MRGPRX2 for screening antiallergic and anti-anaphylactoid molecules [36][37][38]. Recently some natural compounds such as quercetin [38], saikosaponin A [36], and shikonin [39] have been reported to inhibit mast cell degranulation and inhibit MRGPRX2-induced pseudo allergic reactions.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

et al. 2020

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Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

et al. 2020

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“…While pretreated with EPF, the Ca 2+ mobilization was suppressed dose‐dependently. Since it is reported that C48/80‐induced mast cell activation is MRGPRX2 mediated, the results suggested the inhibition of EPF on mast cell activation may related to MRGPRX2.…”

Section: Resultsmentioning

confidence: 46%

Discovery and analysis the anti-pseudo-allergic components from Perilla frutescens leaves by overexpressed MRGPRX2 cell membrane chromatography coupled with HPLC-ESI-IT-TOF system

Yang

Zeng

Wang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Screen and identify the anti-pseudo-allergic activity components of Perilla frutescens leaves that interacted with MRGPRX2 (a new reported pseudoallergic reaction-related receptor). Methods An overexpressed MRGPRX2 cell membrane chromatography (CMC) coupled with HPLC-ESI-IT-TOF system has been established to screen and identify the effective components from P. frutescens leaves. A frontal analysis method was performed to investigate the binding affinity between ligands and MRGPRX2. Their activity of relieving pseudo-allergic reaction was evaluated in vitro by histamine release assay, β-hexosaminidase release assay and intracellular Ca 2+ mobilization assay. Key findings Extract of P. frutescens leaves was proved to be effective in antipseudo-allergic reaction by inhibiting MRGPRX2. Apigenin (API) and rosmarinic acid (ROS) were confirmed to be the potential anti-allergy compounds that could bind with MRGPRX2. The binding affinity (K D ) of ROS and API with MRGPRX2 was (8.79 ± 0.13) 9 10 −8 M and (6.54 ± 1.69) 9 10 −8 M, respectively. The IC 50 of API inhibiting laboratory of allergic disease 2 cells degranulation was also determined to be (51.96 ± 0.18) μM. Conclusions A MRGPRX2/CMC coupled with HPLC-ESI-IT-TOF system was successfully established and applied to discover the effective components from P. frutescens leaves.

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“…While it is still unclear whether MRGPRX2 responses in mast cells function via the T-and L-type or TRPV channels, it is plausible that osthole inhibits mast cell activation by blocking these channels resulting in reduced downstream responses such as degranulation and cytokine production. Intracellular signaling events activated by MRGPRX2 are not well characterized; although, the MAP kinase pathway has been shown to be activated in previous studies (45,46). Our results demonstrated the phosphorylation of ERK1/2 was significantly reduced in the presence of osthole.…”

Section: Discussionmentioning

confidence: 50%

“…To test whether osthole regulated the delayed response of mast cell activation, we exposed LAD2 cells to osthole and assessed for chemokine and cytokine generation by ELISA. We specifically chose to examine the production of MCP-1 and IL-8 since LAD2 cells release these effectors upon on MRGPRX2 stimulation (45). LAD2 cells produced both MCP-1 and IL-8 on stimulation with compound 48/80 ( Figures 3A,B), substance P (Figures 3C,D) and LL-37 ( Figures 3E,F).…”

Section: Osthole Inhibits Chemokine/cytokine Production and Mitogen-amentioning

confidence: 99%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

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Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca 2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2-(mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.

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Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R related Ca2+ fluctuations

Cited by 57 publications

References 32 publications

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

Discovery and analysis the anti-pseudo-allergic components from Perilla frutescens leaves by overexpressed MRGPRX2 cell membrane chromatography coupled with HPLC-ESI-IT-TOF system

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

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