title: 11-O-acetylcyathatriol inhibits MAPK/p38-mediated inflammation in LPS-activated RAW 264.7 macrophages and has a protective effect on ethanol-induced gastric injury.
abstract: The present study investigated the effects of 11-O-acetylcyathatriol, a natural cyathane diterpene, on the release of inflammatory mediators and on the activation of the nuclear factor (NF)-κB or the mitogen‑activated protein kinase (MAPK) transduction pathways in lipopolysaccharide (LPS)-activated macrophages. MTT was used to evaluate the cytotoxicity. A Griess assay was used to determine the production of nitrous oxide (NO). The levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 were determined using ELISA kits. The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‑2, phosphorylated (p)‑extracellular signal‑regulated kinase (ERK1/2), p‑J‑N‑terminal kinase (JNK), p‑p38 and inhibitor of NFκB (IκB)‑α were detected using western blot analysis. 11‑O‑acetylcyathatriol significantly inhibited the overproduction of NO and the release of IL‑6, but had no inhibitory effect on the release of TNF‑α. It also significantly downregulated the high expression levels of iNOS and COX‑2 induced by LPS. In addition, it markedly inhibited the phosphorylation of the MAPK/p38 protein, but only exhibited weak inhibition on the phosphorylation of the ERK1/2 and JNK proteins, and the degradation of the IκB‑α protein. The possible protective effect of 11‑O‑acetylcyathatriol on ethanol‑induced gastric injury was also examined using an in vivo animal experiment. Following gavage administration, it showed an important protective effect on ethanol‑induced gastric mucosal injury in rats. These results suggested the possibility that the anti‑inflammatory effect of 11‑O‑acetylcyathatriol was predominantly due to the inhibition of iNOS and COX‑2 proteins, and may be associated with the MAPK/p38 transduction pathway, but not the NF‑κB transduction pathway. These findings provide an explanation for the underlying mechanism of anti-inflammatory action of 11-O-acetylcyathatriol, which may assist with its clinical application and future development.
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education of China, School of Pharmacy, Yantai University, Yantai, Shandong 264005, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, P.R. China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Han
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education of China, School of Pharmacy, Yantai University, Yantai, Shandong 264005, P.R. China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education of China, School of Pharmacy, Yantai University, Yantai, Shandong 264005, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, P.R. China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education of China, School of Pharmacy, Yantai University, Yantai, Shandong 264005, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D000431:Ethanol / Q000009:adverse effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004224:Diterpenes; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases