Abstract
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.
Highlights
Anaphylaxis is a type-I IgE mediated allergic reaction caused by the activation of mast cells, whereas anaphylactoid reactions or pseudo-allergic reactions are non-immunologic sudden onset reactions mediated through the non-IgE pathway
After assuring that Genistein possesses no toxicity in these cells, we have evaluated its inhibitory actions on the mast cell degranulation and Mas related GPCRX2 (MRGPRX2) activation by β-hexosaminidase and PRESTO-Tango as well as Ca2+ flux assays respectively
The Ca2+ flux was measured in human Laboratory Allergic Disease 2 (LAD-2) mast cells by using the Fluo-4 NW calcium assay kit and the protocol according to the manufacturer
Summary
Anaphylaxis is a type-I IgE mediated allergic reaction caused by the activation of mast cells, whereas anaphylactoid reactions or pseudo-allergic reactions are non-immunologic sudden onset reactions mediated through the non-IgE pathway. The clinical symptoms of anaphylactoid shock, are similar to anaphylaxis [1]. Activation of mast cells by allergen or drugs causes a profound release of inflammatory mediators, which leads to anaphylactoid shock [2]. The clinical manifestations of anaphylactoid reaction are similar and indistinguishable from anaphylaxis, and sometimes even more severe, leading to cardiovascular collapse and death [1,3]. The exact incident rate of anaphylactoid reaction is difficult to be established, as many of them are not diagnosed or reported. The estimated frequency varies considerably between epidemiological studies from different countries [4,5,6], while studies conducted over the last years provided an incident rate in the range of 40–500 per million persons per year [7,8,9,10,11]
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