title: Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway.
abstract: The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 μM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 μM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-α were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Zi-Ming
authors.initials: ZM
authors.lastname: Xia
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Shang
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Qiu-Li
authors.initials: QL
authors.lastname: Chao
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Ya-Ru
authors.initials: YR
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Hua-Ying
authors.initials: HY
authors.lastname: Fan
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China.
authors.forename: Da-Quan
authors.initials: DQ
authors.lastname: Chen
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: School of Pharmacy, Yantai University, 30 Qingquan Road of Laishan District, Yantai, 264005, Shandong, People's Republic of China. ytuzhaofeng@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
mesh_terms: D000098:Acetophenones / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D002351:Carrageenan; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016264:Dextran Sulfate; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006614:Hindlimb / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C013638:paeonol; D002351:Carrageenan; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: MAPK; inflammation; metabolite; oxidative stress; paeonol