PMID- 37364326 OWN - NLM STAT- MEDLINE DCOM- 20231023 LR - 20231023 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 121 DP - 2023 Aug TI - AKBA alleviates experimental pancreatitis by inhibiting oxidative stress in Macrophages through the Nrf2/HO-1 pathway. PG - 110501 LID - S1567-5769(23)00824-X [pii] LID - 10.1016/j.intimp.2023.110501 [doi] AB - BACKGROUND: Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology. Acetyl-11-keto-beta-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. CI - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Yuan, Chenchen AU - Yuan C AD - 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. FAU - Dong, Xiaowu AU - Dong X AD - 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. FAU - Xu, Songxin AU - Xu S AD - 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. FAU - Zhu, Qingtian AU - Zhu Q AD - 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. FAU - Xu, Xingmeng AU - Xu X AD - 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. FAU - Zhang, Junxian AU - Zhang J AD - 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. FAU - Gong, Weijuan AU - Gong W AD - 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. FAU - Ding, Yanbing AU - Ding Y AD - 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. FAU - Pan, Jiajia AU - Pan J AD - 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. FAU - Lu, Guotao AU - Lu G AD - 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. FAU - Chen, Weiwei AU - Chen W AD - Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, China. FAU - Xie, Ting AU - Xie T AD - Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China. Electronic address: tingxie1981@126.com. FAU - Li, Baiqiang AU - Li B AD - 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. FAU - Xiao, Weiming AU - Xiao W AD - 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. LA - eng PT - Journal Article DEP - 20230624 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (NF-E2-Related Factor 2) RN - 0 (Reactive Oxygen Species) RN - 888Y08971B (Ceruletide) RN - EC 3.1.1.3 (Lipase) RN - EC 3.2.1.- (Amylases) SB - IM MH - Animals MH - Mice MH - *Pancreatitis/chemically induced/drug therapy/metabolism MH - NF-E2-Related Factor 2/genetics/metabolism MH - Reactive Oxygen Species/metabolism MH - Ceruletide/pharmacology MH - Acute Disease MH - Molecular Docking Simulation MH - Oxidative Stress MH - Macrophages/metabolism MH - Lipase MH - Amylases OTO - NOTNLM OT - AKBA OT - Acute pancreatitis OT - Macrophages OT - Nrf2 OT - Oxidative stress COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/06/26 19:07 MHDA- 2023/10/23 00:43 CRDT- 2023/06/26 18:00 PHST- 2023/02/01 00:00 [received] PHST- 2023/06/01 00:00 [revised] PHST- 2023/06/11 00:00 [accepted] PHST- 2023/10/23 00:43 [medline] PHST- 2023/06/26 19:07 [pubmed] PHST- 2023/06/26 18:00 [entrez] AID - S1567-5769(23)00824-X [pii] AID - 10.1016/j.intimp.2023.110501 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Aug;121:110501. doi: 10.1016/j.intimp.2023.110501. Epub 2023 Jun 24.