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

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Abstract

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.

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Data availability

The authors will supply the relevant data in response to reasonable requests.

Abbreviations

AB4:

Anemoside B4

BC:

Biotin carboxylase domain

BCCP:

Biotin carboxyl carrier protein domain

BSA:

Bovine serum albumin

CD:

Crohn's disease

CETSA:

Cellular thermal shift assay

CT:

Carboxyl transferase domain

DADA:

Diisopropylamine dichloroacetate

DAI:

Disease activity index

DARTS:

Drug affinity-responsive target stability

DSS:

Dextran sulfate sodium

IBD:

Inflammatory bowel disease

LPS:

Lipopolysaccharide

PA:

Palmitic acid

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase

OAA:

Oxaloacetate

UC:

Ulcerative colitis

SDS-PAGE:

Sodium dodecyl sulfate PAGE

SPR:

Surface plasmon resonance

TCA:

Tricarboxylic acid

TNBS:

2, 4, 6-Trinitrobenzene sulfonic acid

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82073912, 82341087), the State Key Laboratory of Natural and Biomimetic Drugs, Traditional Chinese Medicine Technology Project of Jiangsu Province (No YB2020064), and a project funded by Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

Funding

National Natural Science Foundation of China (No. 82073912, 82341087), the state key Laboratory of Natural Biomimetic Drugs, Traditional Chinese Medicine Technology Project of Jiangsu Province (No. YB2020064), PAPD.

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Author notes

  1. Qing-hua Liang and Qiu-rong Li equal contributions to this work.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China

    Qing-hua Liang, Qiu-rong Li, Zhong Chen, Li-juan Lv, Yu Lin, Hong-lv Jiang, Ke-xin Wang, Ming-yue Xiao, Nai-xin Kang, Yan-li Liu & Qiong-ming Xu

  2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Peng-fei Tu

  3. Department of Pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, 215163, Jiangsu, China

    Shi-liang Ji

  4. School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, China

    Ke-jun Deng

  5. College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530000, Guangxi, China

    Hong-wei Gao & Shi-lin Yang

  6. Guangxi Xinhai Pharmaceutical Technology Co.,Ltd, , Liuzhou, 545025, Guangxi, China

    Hong-wei Gao, Shi-lin Yang & Qiong-ming Xu

  7. Instrumental Analysis Center, Shanghai JiaoTong University, 800 Dongchuan Road, Shanghai, 200240, China

    Li Zhang

  8. Hai’an Traditional Chinese Medicine Hospital, Nantong, 226600, Jiangsu, China

    Kun Li & Fei Ge

  9. 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

    Guo-qiang Xu

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Contributions

QHL and QRL conducted most experiments and wrote the manuscript; YLL and QMX designed the research, secured funding to support this project, and reviewed the manuscript; ZC, LJL, YL, HLJ, KXW, and MYX performed the experiments and interpreted the results; NXK, KJD, LK, GF, and HWG assisted with statistical analysis, interpreted the results, and consulted the related authors; SLJ, PFT, LZ, GQX, and SLY provided the technical support and partial funding support. All authors reviewed the manuscript.

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Correspondence to Yan-li Liu or Qiong-ming Xu.

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Liang, Qh., Li, Qr., Chen, Z. et al. Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function. Inflamm. Res. 73, 345–362 (2024). https://doi.org/10.1007/s00011-023-01840-x

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