title: 5-Methoxyl Aesculetin Abrogates Lipopolysaccharide-Induced Inflammation by Suppressing MAPK and AP-1 Pathways in RAW 264.7 Cells.
abstract: For the first time, a pale amorphous coumarin derivative, 5-methoxyl aesculetin (MOA), was isolated from the dried bark of Fraxinus rhynchophylla Hance (Oleaceae). MOA modulates cytokine expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, but the precise mechanisms are still not fully understood. We determined the effects of MOA on the production of inflammatory mediators and pro-inflammatory cytokines in the LPS-induced inflammatory responses of RAW 264.7 macrophages. MOA significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E₂ (PGE₂), tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β. It also effectively attenuated inducible nitric oxide (NO) synthase, cyclooxygenase-2, and TNF-α mRNA expression and significantly decreased the levels of intracellular reactive oxygen species. It inhibited phosphorylation of the extracellular signal-regulated kinase (ERK1/2), thus blocking nuclear translocation of activation protein (AP)-1. In a molecular docking study, MOA was shown to target the binding site of ERK via the formation of three hydrogen bonds with two residues of the kinase, which is sufficient for the inhibition of ERK. These results suggest that the anti-inflammatory effects of MOA in RAW 264.7 macrophages derive from its ability to block both the activation of mitogen-activated protein kinases (MAPKs) and one of their downstream transcription factors, activator protein-1 (AP-1). Our observations support the need for further research into MOA as a promising therapeutic agent in inflammatory diseases.
authors.affiliation: Tianjin Key Laboratory of Pulp &amp; Paper, Tianjin University of Science &amp; Technology, Tianjin 300457, China. wulei858196@163.com.|Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. wulei858196@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Gerontology, Huai'an First People's Hospital, Nanjing Medical University, Huaian 223300, China. wgc1955@sina.com.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. hfwu@implad.ac.cn.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. longway@irm-cams.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Long
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. jiangxj@hytc.edu.cn.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. shenting1019@163.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. qiangqian9197@126.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qiang
authors.affiliation: Tianjin Key Laboratory of Pulp &amp; Paper, Tianjin University of Science &amp; Technology, Tianjin 300457, China. sichli@tust.edu.cn.|State Key Laboratory of Tree Genetics and Breeding, Northeast Forestry University, Harbin 150040, China. sichli@tust.edu.cn.
authors.forename: Chuanling
authors.initials: C
authors.lastname: Si
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. hywdwxf@sohu.com.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea. yunyao@kangwon.ac.kr.
authors.forename: Yunyao
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture &amp; Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China. hu_weicheng@163.com.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D007378:Interleukins; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014468:Umbelliferones; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone; C007628:esculetin
keywords: 5-methoxyl aesculetin; activator protein-1; inflammation; mitogen-activated protein kinases