Glycyrrhizic acid and patchouli alcohol in Huoxiang Zhengqi attenuate intestinal inflammation and barrier injury via regulating endogenous corticosterone metabolism mediated by 11β-HSD1

• Published in: Journal of ethnopharmacology 2025-02, Vol.338 (Pt 1), p.119025, Article 119025
• Main Authors: Wang, Yangyang, Sun, Chuying, Cao, Yutang, Jiao, Tingying, Wang, Kanglong, Li, Jiaqi, Zhang, Mengjiao, Jiang, Jie, Zhong, Xianchun, Yu, Shuwu, Xu, Hualing, Wang, Jiawen, Yi, Tong, Tian, Xiaoting, Zhu, Haiyan, Zhou, Haifeng, Huang, Chenggang, Wu, Tong, Guo, Xiaozhen, Xie, Cen
• Format: Article
• Language: English
• Subjects: 11β-hydroxysteroid dehydrogenase 1; Animals; Anti-Inflammatory Agents - pharmacology; Caco-2 Cells; Colitis - chemically induced; Colitis - drug therapy; Colitis - metabolism; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Corticosterone; Dextran Sulfate - toxicity; Disease Models, Animal; Drugs, Chinese Herbal - pharmacology; Glycyrrhizic acid; Glycyrrhizic Acid - pharmacology; Glycyrrhizic Acid - therapeutic use; Humans; Huoxiang Zhengqi; Inflammation; Intestinal barrier injury; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Mice; Mice, Inbred C57BL; Patchouli alcohol; Sesquiterpenes - pharmacology
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.119025

Ulcerative colitis (UC), a chronic inflammatory bowel disease, has become a significant public health challenge due to the limited effectiveness of available therapies. Huoxiang Zhengqi (HXZQ), a well-established traditional Chinese formula, shows potential in managing UC, as suggested by clinical and pharmacological studies. However, the active components and mechanisms responsible for its effects remain unclear. This study aimed to identify the bioactive components of HXZQ responsible for its therapeutic effects on UC and to elucidate their underlying mechanisms. The effect of HXZQ against dextran sodium sulfate (DSS)-induced colitis was investigated. Ingredients in HXZQ were characterized and analyzed in colitic mice using liquid chromatography–mass spectrometry (LC-MS) and gas chromatography–mass spectrometry (GC-MS). In vitro, biological activity of compounds was assessed using lipopolysaccharide (LPS)-induced Ana-1 cells and bone marrow-derived macrophages (BMDMs), tumor necrosis factor-alpha (TNF-α)-induced Caco-2 cells, and isolated intestinal crypts from colitic mice. These results were confirmed in vivo. The targets of the components were identified through bioinformatics analysis and validated via molecular docking, enzyme inhibition assays, and in vivo experiments. Hematoxylin and eosin (HE) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative real-time polymerase chain reaction (qPCR) were employed to confirm the pharmaceutical effects. A clinical equivalent dose of HXZQ (2.5 mL/kg) effectively treated DSS-induced colitis. A total of 113 compounds were identified in HXZQ, with 35 compounds detected in colitic mice. Glycyrrhizic acid (GA) and patchouli alcohol (PA) emerged as key contributors to the anti-colitic effects of HXZQ. Further investigation revealed that HXZQ and its active components decreased the levels of pro-inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) in colon, likely by inhibiting nuclear factor kappa-B (NF-κB) signaling pathway. This inhibition indirectly activated the intestinal farnesoid X receptor (FXR) signaling pathway, correcting bile acid imbalances caused by colitis. Additionally, these components significantly enhanced the expression of tight junction proteins ZO-1 and Occludin, as well as the adhesion protein E-cadherin, and reduced goblet cell loss, thereby repairing intestinal barrier injur