Systems pharmacology approach reveals protective mechanisms of Jian-Pi Qing-Chang decoction on ulcerative colitis

BACKGROUND Given the complex pathogenesis of ulcerative colitis (UC), the conventional therapeutic methods are not fully curative. As a sort of systematic complementary and alternative medicine, traditional Chinese medicine (TCM) provides new options for the standard therapy. Nevertheless, there are still numerous problems with the promotion of TCM attributed to its complexity, and consequently, new research approaches are urgently needed. Thus, we explored the protective effects of Jian-Pi Qing-Chang (JPQC) decoction on UC based on systems pharmacology approach, which might fill the current innovation gap in drug discovery and clinical practice pertaining to TCM. AIM To investigate the protective mechanisms of JPQC decoction on UC based on systems pharmacology approach. METHODS We performed systems pharmacology to predict the active ingredients, the matched targets, and the potential pharmacological mechanism of JPQC on UC. In vivo, we explored the effects of JPQC in a colitis model induced by dextran sulfate sodium. In vitro, we adopted the bone marrow-derived macrophages (BMDMs) as well as BMDMs co-cultured with Caco2 cells to verify the underlying mechanisms and effects of JPQC on UC under TNF-alpha stimulation. RESULTS Systems pharmacology revealed 170 targets for the 107 active ingredients of JPQC and 112 candidate targets of UC. Protein-protein interaction networks were established to identify the underlying therapeutic targets of JPQC on UC. Based on enrichment analyses, we proposed our hypothesis that JPQC might have a protective effect on UC via the NF-kappa B/HIF-1 alpha signalling pathway. Subsequent experimental validation revealed that treatment with TNF alpha activated the NF-kappa B/HIF-1 alpha signalling pathway in BMDMs, thereby damaging the epithelial barrier permeability in co-cultured Caco2 cells, while JPQC rescued this situation. The findings were also confirmed in a dextran sulfate sodium-induced colitis model. CONCLUSION JPQC could improve the mucosal inflammatory response and intestinal epithelial barrier function via the NF-kappa B/HIF-1 alpha signalling pathway, which provides new perspectives on the pharmaceutical development and clinical practice of TCM.