Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function.

Autor: Liang QH; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Li QR; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Chen Z; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Lv LJ; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Lin Y; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Jiang HL; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Wang KX; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Xiao MY; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Kang NX; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China., Tu PF; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China., Ji SL; Department of Pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, 215163, Jiangsu, China., Deng KJ; School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, China., Gao HW; College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, Guangxi, China.; Guangxi Xinhai Pharmaceutical Technology Co.,Ltd, , Liuzhou, 545025, Guangxi, China., Zhang L; Instrumental Analysis Center, Shanghai JiaoTong University, 800 Dongchuan Road, Shanghai, 200240, China., Li K; Hai'an Traditional Chinese Medicine Hospital, Nantong, 226600, Jiangsu, China., Ge F; Hai'an Traditional Chinese Medicine Hospital, Nantong, 226600, Jiangsu, China., Xu GQ; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, Jiangsu, China., Yang SL; College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, Guangxi, China.; Guangxi Xinhai Pharmaceutical Technology Co.,Ltd, , Liuzhou, 545025, Guangxi, China., Liu YL; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China. liuyanli@suda.edu.cn., Xu QM; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China. xuqiongming@suda.edu.cn.; Guangxi Xinhai Pharmaceutical Technology Co.,Ltd, , Liuzhou, 545025, Guangxi, China. xuqiongming@suda.edu.cn.
Jazyk: angličtina
Zdroj: Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2024 Mar; Vol. 73 (3), pp. 345-362. Date of Electronic Publication: 2023 Dec 29.
DOI: 10.1007/s00011-023-01840-x
Abstrakt: Objectives: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered.
Methods: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo.
Results: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice.
Conclusion: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
Externí odkaz: