Chaiqin chengqi decoction alleviates acute pancreatitis by targeting gasdermin D-mediated pyroptosis

Fei Cao; Jie Xiang; Yaodong Wang; Xijie Chen; Xirong Lu; Xingmeng Xu; Lin Chen; Yinghong Fan; Chenchen Yuan; Xiaowu Dong; Qingtian Zhu; Chenxia Han; Guotao Lu; Qing Xia; Weiwei Chen

doi:10.1016/j.jep.2023.116920

Chaiqin chengqi decoction alleviates acute pancreatitis by targeting gasdermin D-mediated pyroptosis

J Ethnopharmacol. 2024 Jan 10;318(Pt A):116920. doi: 10.1016/j.jep.2023.116920. Epub 2023 Jul 21.

Authors

Fei Cao¹, Jie Xiang², Yaodong Wang³, Xijie Chen¹, Xirong Lu³, Xingmeng Xu⁴, Lin Chen⁴, Yinghong Fan⁴, Chenchen Yuan⁴, Xiaowu Dong⁴, Qingtian Zhu⁴, Chenxia Han⁵, Guotao Lu⁴, Qing Xia⁶, Weiwei Chen⁷

Affiliations

¹ Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China.
² Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
³ Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu, China.
⁴ Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225100, Jiangsu, China.
⁵ West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
⁶ West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: xiaqing@medmail.com.cn.
⁷ Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China. Electronic address: cww1984@126.com.

PMID: 37480969
DOI: 10.1016/j.jep.2023.116920

Abstract

Ethnopharmacological relevance: Acute pancreatitis (AP) is an acute inflammatory condition of pancreas with high morbidity and mortality, which has no effective medical treatment. Chaiqin chengqi decoction (CQCQD) has been clinically used for AP for many years in China. However, the underlying mechanisms are still unknown.

Aim of the study: To investigate the mechanism of CQCQD on gasdermin D (GSDMD) -mediated pyroptosis in AP.

Materials and methods: In this study, network pharmacology was used to screen the potential mechanism of CQCQD protecting against AP and then we focused to investigate the mechanism of CQCQD on GSDMD mediated pyroptosis. Mouse models of AP were conducted by caerulein and L-arginine. In order to clarify the mechanism of CQCQD, two kinds of GSDMD gene knockout mice (Gsdmd^-/- and Pdx1^creGsdmd^fl/fl) were applied. And the potential interaction between the main components of CQCQD and GSDMD was explored by molecular docking.

Results: In the caerulein-induced AP model, CQCQD ameliorated pancreatic pathological injury, attenuated systemic inflammation and serum enzymatic levers. Moreover, network pharmacology analysis showed GSDMD mediated pyroptosis was one of the core targets of CQCQD protecting against AP. Additionally, CQCQD appreciably decreased the levels of pyroptosis-related proteins N-terminal GSDMD, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3, and cleaved Caspase-1. Furthermore, the protective effect of CQCQD was neutralized in Gsdmd^-/- and Pdx1^creGsdmd^fl/fl mice in caerulein-induced AP. In addition, we found that CQCQD protects pancreatic tissue from damage and pancreatitis-associated lung injury in the L-arginine-induced mouse model. Moreover, all of the main components of CQCQD possessed binding activity with GSDMD by molecular docking. Seventeen components bound with the human GSDMD Cys191 successfully, which is important for GSDMD pore formation. Among the components, rhein possessed the highest binding activity.

Conclusion: CQCQD could reduce pancreatic necrosis and inflammatory response via inhibiting GSDMD-mediated pyroptosis in acinar cells of AP. Rhein may be the key active ingredient of CQCQD in suppressing pyroptosis.

Keywords: Active ingredients; Acute pancreatitis; Chaiqin chengqi decoction; Gasdermin D; Pyroptosis.

MeSH terms

Acute Disease
Animals
Ceruletide / metabolism
Ceruletide / toxicity
Gasdermins
Humans
Mice
Molecular Docking Simulation
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Pancreatitis* / chemically induced
Pancreatitis* / drug therapy
Pancreatitis* / metabolism
Pyroptosis

Substances

chaiqin chengqi
rhein
Gasdermins
Ceruletide
NLR Family, Pyrin Domain-Containing 3 Protein