AKBA alleviates experimental pancreatitis by inhibiting oxidative stress in Macrophages through the Nrf2/HO-1 pathway

Chenchen Yuan; Xiaowu Dong; Songxin Xu; Qingtian Zhu; Xingmeng Xu; Junxian Zhang; Weijuan Gong; Yanbing Ding; Jiajia Pan; Guotao Lu; Weiwei Chen; Ting Xie; Baiqiang Li; Weiming Xiao

doi:10.1016/j.intimp.2023.110501

AKBA alleviates experimental pancreatitis by inhibiting oxidative stress in Macrophages through the Nrf2/HO-1 pathway

Int Immunopharmacol. 2023 Aug:121:110501. doi: 10.1016/j.intimp.2023.110501. Epub 2023 Jun 24.

Authors

Chenchen Yuan¹, Xiaowu Dong¹, Songxin Xu¹, Qingtian Zhu¹, Xingmeng Xu¹, Junxian Zhang¹, Weijuan Gong¹, Yanbing Ding¹, Jiajia Pan², Guotao Lu¹, Weiwei Chen³, Ting Xie⁴, Baiqiang Li⁵, Weiming Xiao⁶

Affiliations

¹ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, China.
² Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, China; Department of Intensive Care Unit, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
³ Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, China.
⁴ Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China. Electronic address: tingxie1981@126.com.
⁵ Department of Critical Care Medicine, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address: li_baiqiang@aliyun.com.
⁶ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Yangzhou Key Laboratory of Pancreatic Disease, Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, China. Electronic address: wmxiao@yzu.edu.cn.

PMID: 37364326
DOI: 10.1016/j.intimp.2023.110501

Abstract

Background: Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology. Acetyl-11-keto-β-boswellic acid (AKBA) is an active triterpenoid with antioxidant activity. This article seeks to assess the impact of AKBA on AP and investigate its underlying mechanisms.

Methods: AP was induced in wild-type, Lyz2^+/cre Nrf2^fl/fl mice and Pdx1^+/cre Nrf2^fl/fl mice by caerulein. Serum amylase and lipase levels, along with histological grading, were utilized to evaluate the severity of AP. Murine bone marrow-derived macrophages (BMDMs) were isolated, cultured, and polarized to the M1 subtype. Flow cytometry and ELISA were utilized to identify the macrophage phenotype. Alterations in oxidative stress damage and intracellular ROS were observed. Nrf2/HO-1 signaling pathways were also evaluated.

Results: In a caerulein-induced mouse model of AP, treatment with AKBA reduced blood amylase and lipase activity and ameliorated pancreatic tissue histological and pathological features. Furthermore, AKBA significantly mitigated oxidative stress-induced damage and induced the expression of Nrf2 and HO-1 protein. Additionally, by using conditional knockout mice (Lyz2^+/cre Nrf2^fl/fl and Pdx1^+/cre Nrf2^fl/fl mice), we verified that Nrf2 primarily functions in macrophages rather than acinar cells. In vitro, AKBA inhibits pro-inflammatory M1-subtype macrophage polarization and reduces ROS generation through Nrf2/HO-1 oxidative stress pathway. Moreover, the protective effects of AKBA against AP were abolished in myeloid-specific Nrf2-deficient mice and BMDMs. Molecular docking results revealed interactions between AKBA and Nrf2.

Conclusion: Our results confirm that AKBA exerts protective effects against AP in mice by inhibiting oxidative stress in macrophages through the Nrf2/HO-1 Pathway.

Keywords: AKBA; Acute pancreatitis; Macrophages; Nrf2; Oxidative stress.

MeSH terms

Acute Disease
Amylases
Animals
Ceruletide / pharmacology
Lipase
Macrophages / metabolism
Mice
Molecular Docking Simulation
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
Oxidative Stress
Pancreatitis* / chemically induced
Pancreatitis* / drug therapy
Pancreatitis* / metabolism
Reactive Oxygen Species / metabolism

Substances

NF-E2-Related Factor 2
Reactive Oxygen Species
Ceruletide
Lipase
Amylases