title: Biflorin, Isolated from the Flower Buds of Syzygium aromaticum L., Suppresses LPS-Induced Inflammatory Mediators via STAT1 Inactivation in Macrophages and Protects Mice from Endotoxin Shock.
abstract: Two chromone C-glucosides, biflorin (1) and isobiflorin (2), were isolated from the flower buds of Syzygium aromaticum L. (Myrtaceae). Here, inhibitory effects of 1 and 2 on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages were evaluated, and 1 (IC50 = 51.7 and 37.1 μM, respectively) was more potent than 2 (IC50 > 60 and 46.0 μM). The suppression of NO and PGE2 production by 1 correlated with inhibition of iNOS and COX-2 protein expression. Compound 1 reduced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression via inhibition of their promoter activities. Compound 1 inhibited the LPS-induced production and mRNA expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Furthermore, 1 reduced p-STAT1 and p-p38 expression but did not affect the activity of nuclear factor κ light-chain enhancer of activated B cells (NF-κB) or activator protein 1 (AP-1). In a mouse model of LPS-induced endotoxemia, 1 reduced the mRNA levels of iNOS, COX-2, and TNF-α, and the phosphorylation-mediated activation of the signal transducer and activator of transcription 1 (STAT1), consequently improving the survival rates of mice. Compound 1 showed a significant anti-inflammatory effect on carrageenan-induced paw edema and croton-oil-induced ear edema in rats. The collective data indicate that the suppression of pro-inflammatory gene expression via p38 mitogen-activated protein kinase and STAT1 inactivation may be a mechanism for the anti-inflammatory activity of 1.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Hwi-Ho
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Woo-Seok
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Byeol
authors.initials: B
authors.lastname: Ryu
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Dae Sik
authors.initials: DS
authors.lastname: Jang
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, ‡Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, §Reactive Oxygen Species Medical Research Center College of Pharmacy, and ⊥Department of Physiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced; D019446:Endotoxemia / Q000188:drug therapy; D035264:Flowers / Q000737:chemistry; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009285:Naphthoquinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D050794:STAT1 Transcription Factor / Q000187:drug effects*; D027842:Syzygium / Q000737:chemistry*; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009285:Naphthoquinones; D050794:STAT1 Transcription Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C522781:biflorin; D009569:Nitric Oxide; D002351:Carrageenan; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone