1. Berbamine ameliorates DSS-induced colitis by inhibiting peptidyl-arginine deiminase 4-dependent neutrophil extracellular traps formation.
- Author
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Tang W, Ma J, Chen K, Wang K, Chen Z, Chen C, Li X, Wang Y, Shu Y, Zhang W, Yuan X, Shi G, Chen T, Wang P, and Chen Y
- Subjects
- Animals, Mice, Male, Colitis drug therapy, Colitis chemically induced, Colitis pathology, Colitis metabolism, Neutrophils drug effects, Neutrophils metabolism, Neutrophils immunology, Colon drug effects, Colon pathology, Colon metabolism, Mice, Inbred C57BL, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Anti-Inflammatory Agents chemistry, Disease Models, Animal, Extracellular Traps drug effects, Extracellular Traps metabolism, Protein-Arginine Deiminase Type 4 metabolism, Protein-Arginine Deiminase Type 4 antagonists & inhibitors, Dextran Sulfate, Molecular Docking Simulation, Benzylisoquinolines pharmacology, Benzylisoquinolines therapeutic use, Benzylisoquinolines chemistry
- Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships in this publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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