The anti‐anaphylactoid effects of Piperine through regulating MAS‐related G protein‐coupled receptor X2 activation

Qiao, Chuchu; Hu, Shiling; Che, Delu; Wang, Jue; Gao, Jiapan; Ma, Ruiping; Jiang, Wenjun; Zhang, Tao; Liu, Rui

doi:10.1002/ptr.6615

Cited by 17 publications

(18 citation statements)

References 33 publications

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“…However, compounds 1 and 2 did not show any inhibitory effect on SP-induced mouse MC activation [ 42 ]. The alkaloid compound piperine, reported as a small molecule MRGPRX2 antagonist, has a cross-inhibitory effect with mice and ameliorates mouse anaphylactic reactions [ 141 ]. In addition, naturally occurring compounds such as isoliquiritigenin (a component of licorice), shikonin (a component of Lithospermum erythrorhizon), imperatorin (an active furocumarin in Angelica Dahurica radix ), and roxithromysin (a derivative of erythromycin) were shown to bind to MRGPRX2 in molecular docking studies and surface plasmon resonance (SPR) and inhibit C48/80 or SP-induced passive cutaneous anaphylaxis (PCA) in mice [ 50 , 142 , 143 , 144 ].…”

Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

“…Paeoniflorin (a component of Paeonia Lactiflora ), quercetin (a plant flavonoid), and genistein (a non-steroidal polyphenol), which were found to bind MRGPRX2 only in the docking model, also suppressed C48/80-induced PCA in mice [ 145 , 146 , 147 ]. On the other hand, naturally occurring components such as piperine, isoliquiritigenin, and shikonin are also known to act on various enzymes [ 141 , 160 , 161 ]. These compounds are low-affinity antagonists with inhibitory concentrations on the order of μM.…”

Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

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Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

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Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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“…Saikosaponin A might act as an inhibitor of MRGPRX2 (Wang et al, 2018), but no direct experiments have confirmed the interaction between saikosaponin A and MRGPRX2. Furthermore, quercetin (Ding et al, 2019), shikonin (Wang, Zhang, Li, et al, 2020; Wang, Zhang, Wang, et al, 2020), piperine (Qiao et al, 2020), and other compounds have been shown to inhibit MRGPRX2‐mediated pseudo‐allergic reactions by inhibiting calcium ion signaling pathway activation. Because of the lack of specificity, these herbal extracts, such as quercetin (Ding et al, 2019, Ding et al, 2020) and paeoniflorin (Wang, Zhang, Li, et al, 2020; Wang, Zhang, Wang, et al, 2020; Zhang, Hu, Ge, Wang, & He, 2020), also showed an inhibitory effect on IgE‐induced Type Ι hypersensitivity reactions, which are considered antagonists of key kinases in the calcium ion signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Dehydroandrographolide targets CD300f and negatively regulated MRGPRX2‐induced pseudo‐allergic reaction

Che

Zheng

Hou³

et al. 2022

Phytotherapy Research

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Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates mast cells (MCs) activation, which is a key target for the treatment of allergic diseases. However, there are few drugs targeting MRGPRX2. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) is a negative regulator of FcεRΙ-mediated MC activation. However, the regulatory effect of CD300f on MRGPRX2 remains unclear. Dehydroandrographolide (DA) is a main contributor of Andrographis paniculata (Burm.f.) Nees (family: Acanthaceae) have been shown to inhibit type I hypersensitivity. The aim of this study was to determine whether DA negatively regulated MRGPRX2-mediated MC activation via CD300f and showed therapeutic effect on pseudo-allergic reactions. Mouse allergic models and MC degranulation were detected in vivo and in vitro, and inflammatory mediators were detected. siRNA interference and Biacore were used to verify the target. DA inhibited pseudo-allergic reactions by reducing vasodilation and serum cytokine levels in mice and inhibited MRGPRX2-mediated MC activation. The regulatory effect of DA was significantly decreased after the knockdown of CD300f expression. Moreover, DA upregulated the phosphorylation level of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2, which are key kinases in the negative regulatory signaling pathways associated with CD300f. In conclusion, DA negatively regulates MRGPRX2-mediated MC activation via CD300f to inhibit pseudo-allergic reactions.

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“…Piperine attenuated hind paw swelling and reversed hypothermia in a systemic anaphylaxis mouse model. Furthermore, piperine was tested for its binding affinity to MRGPRX2 via a chromatography method; piperine showed a competitive binding affinity with sinomenine hydrochloride (a plant-based agonist) [ 177 ].…”

Section: Development Of Mrgprx2 Antagonistsmentioning

confidence: 99%

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Kumar

Duraisamy

Chow

2021

Cells

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Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

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The anti‐anaphylactoid effects of Piperine through regulating MAS‐related G protein‐coupled receptor X2 activation

Cited by 17 publications

References 33 publications

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Dehydroandrographolide targets CD300f and negatively regulated MRGPRX2‐induced pseudo‐allergic reaction

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

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