PMID- 37307937 OWN - NLM STAT- MEDLINE DCOM- 20230630 LR - 20230630 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 953 DP - 2023 Aug 15 TI - Sinomenine alleviates lipopolysaccharide-induced acute lung injury via a PPARbeta/delta-dependent mechanism. PG - 175838 LID - S0014-2999(23)00349-7 [pii] LID - 10.1016/j.ejphar.2023.175838 [doi] AB - Evidence is mounting that sinomenine and peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) are effective against lipopolysaccharide (LPS)-induced acute lung injury (ALI) via anti-inflammatory properties. However, it is unknown whether PPARbeta/delta plays a role in the protective effect of sinomenine on ALI. Here, we initially observed that preemptive administration of sinomenine markedly alleviated lung pathological changes, pulmonary edema and neutrophil infiltration, accompanied by inhibition of the expression of the pro-inflammatory cytokines Tumor necrosis factor-alpha (TNF-alpha) and Interleukin-6 (IL-6), which were largely reversed following the addition of a PPARbeta/delta antagonist. Subsequently, we also noticed that sinomenine upregulated adenosine A(2A) receptor expression in a PPARbeta/delta-dependent manner in LPS-stimulated bone marrow-derived macrophages (BMDMs). Further investigation indicated that PPARbeta/delta directly bound to the functional peroxisome proliferator responsive element (PPRE) in the adenosine A(2A) receptor gene promoter region to enhance the expression of the adenosine A(2A) receptor. Sinomenine was identified as a PPARbeta/delta agonist. It could bind with PPARbeta/delta, and promote the nuclear translocation and transcriptional activity of PPARbeta/delta. In addition, combined treatment with sinomenine and an adenosine A(2A) receptor agonist exhibited synergistic effects and better protective roles than their single use against ALI. Taken together, our results reveal that sinomenine exerts advantageous effects on ALI by activating of PPARbeta/delta, with the subsequent upregulation of adenosine A(2A) receptor expression, and provide a novel and potential therapeutic application for ALI. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Zhao, Li AU - Zhao L AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. FAU - Zhang, Mengjie AU - Zhang M AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. FAU - Liu, Yang-Wuyue AU - Liu YW AD - Department of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Tan, Yan AU - Tan Y AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. FAU - Yin, Jun AU - Yin J AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. FAU - Chen, Yuanyuan AU - Chen Y AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. FAU - Chen, Dewei AU - Chen D AD - Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China; Department of High Altitude Physiology & Pathology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address: cdw528913@163.com. FAU - Ni, Bing AU - Ni B AD - Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing, China. Electronic address: nibingxi@126.com. LA - eng PT - Journal Article DEP - 20230610 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (PPAR-beta) RN - 0 (Lipopolysaccharides) RN - 63LT81K70N (sinomenine) RN - 0 (Receptor, Adenosine A2A) RN - 0 (PPAR delta) SB - IM MH - Humans MH - *PPAR-beta/metabolism MH - Lipopolysaccharides/pharmacology MH - Receptor, Adenosine A2A MH - *PPAR delta/metabolism MH - *Acute Lung Injury/chemically induced/drug therapy/genetics OTO - NOTNLM OT - Acute lung injury OT - Adenosine A(2A) receptor OT - Inflammation OT - PPARbeta/delta OT - Sinomenine COIS- Declaration of competing interest The authors declare that there are no competing financial interests associated with the manuscript. EDAT- 2023/06/13 01:14 MHDA- 2023/06/30 06:42 CRDT- 2023/06/12 19:13 PHST- 2022/11/23 00:00 [received] PHST- 2023/06/02 00:00 [revised] PHST- 2023/06/08 00:00 [accepted] PHST- 2023/06/30 06:42 [medline] PHST- 2023/06/13 01:14 [pubmed] PHST- 2023/06/12 19:13 [entrez] AID - S0014-2999(23)00349-7 [pii] AID - 10.1016/j.ejphar.2023.175838 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Aug 15;953:175838. doi: 10.1016/j.ejphar.2023.175838. Epub 2023 Jun 10.