title: Apigenin-7-O-β-D-glucuronide inhibits LPS-induced inflammation through the inactivation of AP-1 and MAPK signaling pathways in RAW 264.7 macrophages and protects mice against endotoxin shock.
abstract: Apigenin-7-O-β-D-glucuronide (AG), an active flavonoid derivative isolated from the agricultural residue of Juglans sigillata fruit husks, possesses multiple pharmacological activities, including anti-oxidant, anti-complement, and aldose reductase inhibitory activities. To date, no report has identified the anti-inflammatory mechanisms of AG. This study was therefore designed to characterize the molecular mechanisms of AG on lipopolysaccharide (LPS)-induced inflammatory cytokines in RAW 264.7 cells and on endotoxin-induced shock in mice. AG suppressed the release of nitric oxide (NO), prostaglandin E2 (PGE2), and tumour necrosis factor-α (TNF-α) in LPS-stimulated RAW 264.7 macrophages in a dose-dependent manner without affecting cell viability. Additionally, AG suppressed LPS-induced mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α. AG treatment decreased the translocation of c-Jun into the nucleus, and decreased activator protein-1 (AP-1)-mediated luciferase activity through the inhibition of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) phosphorylation. Consistent with the in vitro observations, AG protected mice from LPS-induced endotoxin shock by inhibiting proinflammatory cytokine production. Taken together, these results suggest that AG may be used as a source of anti-inflammatory agents as well as a dietary complement for health promotion.
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Hu
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Pulp & Paper, Tianjin University of Science & Technology, Tianjin 300457, China. sichli@tust.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China.
authors.forename: Lilian
authors.initials: L
authors.lastname: Ji
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, Hubei, China.
authors.forename: Xihong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Tianjin Key Laboratory of Pulp & Paper, Tianjin University of Science & Technology, Tianjin 300457, China. sichli@tust.edu.cn and State Key Laboratory of Tree Genetics and Breeding, Northeast Forestry University, Harbin 150040, China.
authors.forename: Chuan-Ling
authors.initials: CL
authors.lastname: Si
authors.affiliation: Department of Medical Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Yunyao
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Urology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing West Road, Huaian 223300, China. wgc1955@sina.com.
authors.forename: Gongcheng
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D031324:Juglans / Q000737:chemistry; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010936:Plant Extracts; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C456097:apigenin-7-O-glucuronide; D009569:Nitric Oxide; D047310:Apigenin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone