{"id":3252,"date":"2024-09-27T10:20:23","date_gmt":"2024-09-27T01:20:23","guid":{"rendered":"https:\/\/misterx95.myds.me\/wordpress\/?p=3252"},"modified":"2024-10-31T10:25:46","modified_gmt":"2024-10-31T01:25:46","slug":"journal-club-2024-09-27","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=3252","title":{"rendered":"Journal club : 2024.09.27"},"content":{"rendered":"\n

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists<\/strong><\/h2>\n\n\n\n

[The journal of allergy and clinical immunology] July 2, 2024<\/p>\n\n\n\n

Background: Mas-related G protein\u2013coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell\u2013mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identi\ufb01ed, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo.
Objective: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell\u2013mediated disease.<\/p>\n\n\n\n


Methods: Antagonists were identi\ufb01ed using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell\u2013derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-\/-) knockout and Mrgprb2em(MRGPRX2)
transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. <\/p>\n\n\n\n

Results: MRGPRX2 antagonists potently inhibited agonist- induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist- induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin.<\/p>\n\n\n\n


Conclusions: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.<\/p>\n\n\n\n

<\/object>Inhibition-of-mast-cell-degranulation-by-novel-small-molecule-MRGPRX2-antagonists<\/a>Download<\/a><\/div>\n","protected":false},"excerpt":{"rendered":"

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists [The journal of allergy and clinical immunology] July 2, 2024 Background: Mas-related G protein\u2013coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell\u2013mediated disorders, including chronic urticaria, atopic dermatitis, and pain […]<\/p>\n","protected":false},"author":16,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3252"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/16"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3252"}],"version-history":[{"count":3,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3252\/revisions"}],"predecessor-version":[{"id":3258,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3252\/revisions\/3258"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3252"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3252"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3252"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}