Guohui Zhang1, Meijing Liu2, Meng Song3, Jueyu Wang3, Jiazhong Cai4, Chuanquan Lin4, Yanwu Li4, Xin Jin5, Chuangpeng Shen5, Zhao Chen6, Dake Cai6, Yong Gao7, Chenchen Zhu3, Chaozhan Lin8, Changhui Liu9. 1. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Zhuhai Precision Medicine Center, Zhuhai People(')s Hospital, Zhuhai, China. 2. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China. 3. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. 4. Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. 5. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. 6. The Fifth Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 500095, China. 7. Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: gaoyong@gzucm.edu.cn. 8. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: linchaozhan@gzucm.edu.cn. 9. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: liuchanghui@gzucm.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: The pregnane-X-receptor (PXR) is involved in inflammatory bowel disease (IBD). Patchouli alcohol (PA) has anti-inflammatory effects; however, the effect of PA on IBD pathogenesis remains largely unknown. AIM OF THE STUDY: The aim of the present study was to investigate the anti-inflammatory effect of PA, primarily focused on crosstalk between PA-mediated PXR activation and NF-κB inhibition. MATERIALS AND METHODS: We evaluated the anti-inflammatory effect of PA with respect to PXR/NF-κB signalling using in vitro and in vivo models. In vitro, PA, identified as a PXR agonist, was evaluated by hPXR transactivation assays and through assessing for CYP3A4 expression and activity. NF-κB inhibition was analysed based on NF-κB luciferase assays, NF-κB-mediated pro-inflammatory gene expression, and NF-κB nuclear translocation after activation of PXR by PA. In vivo, colonic mPXR and NF-κB signalling were analysed to assess PA-mediated the protective effect against dextran sulphate sodium (DSS)-induced colitis. Furthermore, pharmacological inhibition of PXR was further evaluated by examining PA protection against DSS-induced colitis. RESULTS: PA induced CYP3A4 expression and activity via an hPXR-dependent mechanism. PA-mediated PXR activation attenuated inflammation by inhibiting NF-κB activity and nuclear translocation. The anti-inflammatory effect of PA on NF-κB was abolished by PXR knockdown. PA prevented DSS-induced inflammation by regulating PXR/NF-κB signalling, whereas pharmacological PXR inhibition abated PA-mediated suppressive effects on NF-κB inflammation signalling. CONCLUSIONS: PA activates PXR signalling and suppresses NF-κB signalling, consequently causing amelioration of inflammation. Our results highlight the importance of PXR-NF-κB crosstalk in colitis and suggest a novel therapeutic reagent.
ETHNOPHARMACOLOGICAL RELEVANCE: The pregnane-X-receptor (PXR) is involved in inflammatory bowel disease (IBD). Patchoulialcohol (PA) has anti-inflammatory effects; however, the effect of PA on IBD pathogenesis remains largely unknown. AIM OF THE STUDY: The aim of the present study was to investigate the anti-inflammatory effect of PA, primarily focused on crosstalk between PA-mediated PXR activation and NF-κB inhibition. MATERIALS AND METHODS: We evaluated the anti-inflammatory effect of PA with respect to PXR/NF-κB signalling using in vitro and in vivo models. In vitro, PA, identified as a PXR agonist, was evaluated by hPXR transactivation assays and through assessing for CYP3A4 expression and activity. NF-κB inhibition was analysed based on NF-κB luciferase assays, NF-κB-mediated pro-inflammatory gene expression, and NF-κB nuclear translocation after activation of PXR by PA. In vivo, colonic mPXR and NF-κB signalling were analysed to assess PA-mediated the protective effect against dextran sulphate sodium (DSS)-induced colitis. Furthermore, pharmacological inhibition of PXR was further evaluated by examining PA protection against DSS-induced colitis. RESULTS: PA induced CYP3A4 expression and activity via an hPXR-dependent mechanism. PA-mediated PXR activation attenuated inflammation by inhibiting NF-κB activity and nuclear translocation. The anti-inflammatory effect of PA on NF-κB was abolished by PXR knockdown. PA prevented DSS-induced inflammation by regulating PXR/NF-κB signalling, whereas pharmacological PXR inhibition abated PA-mediated suppressive effects on NF-κB inflammation signalling. CONCLUSIONS: PA activates PXR signalling and suppresses NF-κB signalling, consequently causing amelioration of inflammation. Our results highlight the importance of PXR-NF-κB crosstalk in colitis and suggest a novel therapeutic reagent.