Forsythoside A and Forsythoside B Contribute to Shuanghuanglian Injection-Induced Pseudoallergic Reactions through the RhoA/ROCK Signaling Pathway.
In recent years, hypersensitivity reactions to the Shuanghuanglian injection have attracted broad attention. However, the componential chief culprits inducing the reactions and the underlying mechanisms involved have not been completely defined. In this study, we used a combination of approaches based on the mouse model, human umbilical vein endothelial cell monolayer, real-time cellular monitoring, immunoblot analysis, pharmacological inhibition, and molecular docking. We demonstrated that forsythoside A and forsythoside B contributed to Shuanghuanglian injection-induced pseudoallergic reactions through activation of the RhoA/ROCK signaling pathway. Forsythoside A and forsythoside B could trigger dose-dependent vascular leakage in mice. Moreover, forsythoside A and forsythoside B slightly elicited mast cell degranulation. Correspondingly, treatment with forsythoside A and forsythoside B disrupted the endothelial barrier and augmented the expression of GTP-RhoA, p-MYPT1, and p-MLC2 in a concentration-dependent manner. Additionally, the ROCK inhibitor effectively alleviated forsythoside A/forsythoside B-induced hyperpermeability in both the endothelial cells and mice. Similar responses were not observed in the forsythoside E-treated animals and cells. These differences may be related to the potential of the tested compounds to react with RhoA-GTPγS and form stable interactions. This study innovatively revealed that some forsythosides may cause vascular leakage, and therefore, limiting their contents in injections should be considered.
['Han|Jiayin|J|', 'Zhang|Yushi|Y|0000-0002-3268-0421', 'Pan|Chen|C|', 'Xian|Zhong|Z|', 'Pan|Chenling|C|0000-0001-8510-9344', 'Zhao|Yong|Y|', 'Li|Chunying|C|', 'Yi|Yan|Y|', 'Wang|Lianmei|L|', 'Tian|Jingzhuo|J|', 'Liu|Suyan|S|', 'Wang|Dunfang|D|', 'Meng|Jing|J|', 'Liang|Aihua|A|']
D000818:Animals D002109:Caffeic Acids D002199:Capillary Permeability D015550:Cell Degranulation D004365:Drugs, Chinese Herbal D042783:Endothelial Cells D005960:Glucosides D006027:Glycosides D006801:Humans D008407:Mast Cells D051379:Mice D008958:Models, Molecular D008968:Molecular Conformation D015394:Molecular Structure D015398:Signal Transduction D013329:Structure-Activity Relationship D054460:rho-Associated Kinases D020742:rhoA GTP-Binding Protein
forsythoside A forsythoside B RhoA/ROCK signaling pathway Shuanghuanglian injection forsythoside E pseudo-allergic reactions