Forsythoside A and Forsythoside B Contribute to Shuanghuanglian Injection-Induced Pseudoallergic Reactions through the RhoA/ROCK Signaling Pathway.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Caffeic Acids/*pharmacology ; Drugs, Chinese Herbal/*chemistry ; Glucosides/*pharmacology ; Glycosides/*pharmacology ; Signal Transduction/*drug effects ; rho-Associated Kinases/*metabolism ; rhoA GTP-Binding Protein/*metabolism; Animals ; Caffeic Acids/chemistry ; Capillary Permeability/drug effects ; Capillary Permeability/immunology ; Cell Degranulation ; Drugs, Chinese Herbal/administration & dosage ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Glucosides/chemistry ; Glycosides/chemistry ; Humans ; Mast Cells/immunology ; Mast Cells/metabolism ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Structure-Activity Relationship ; rho-Associated Kinases/chemistry ; rhoA GTP-Binding Protein/chemistry

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.

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Keywords: RhoA/ROCK signaling pathway; Shuanghuanglian injection; forsythoside A; forsythoside B; forsythoside E; pseudo-allergic reactions

0 (Caffeic Acids)
0 (Drugs, Chinese Herbal)
0 (Glucosides)
0 (Glycosides)
0 (forsythoside B)
0 (shuang-huang-lian)
124671-05-2 (RHOA protein, human)
EC 2.7.11.1 (rho-Associated Kinases)
EC 3.6.5.2 (rhoA GTP-Binding Protein)
OUH5BQ893P (forsythiaside)

Date Created: 20191218 Date Completed: 20200430 Latest Revision: 20200430

20221213

PMC6940901

10.3390/ijms20246266

31842335