title: Anti-Inflammatory and Antioxidant Mechanism of Tangeretin in Activated Microglia.
abstract: Tangeretin, a flavonoid from citrus fruit peels, has been proven to play an important role in anti-inflammatory responses and neuroprotective effects in several disease models, but further study is necessary for elucidating the detailed mechanisms of these effects. In this study, we examined the anti-inflammatory effect of tangeretin in lipopolysaccharide (LPS)-stimulated microglia. We first observed that tangeretin inhibited LPS-induced production of nitric oxide, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, as well as LPS-induced mRNA expression of inducible nitric oxide synthases and cytokines. Additionally, we found that the activities, mRNA levels, and protein levels of matrix metalloproteinase (MMP)-3 and MMP-8 were inhibited, while the expression of tissue inhibitor of metalloproteinase-2 was enhanced by tangeretin in LPS-stimulated microglia. Further mechanistic study showed that tangeretin suppressed LPS-induced phosphorylation of mitogen-activated protein kinases and Akt. Also, tangeretin inhibited nuclear factor-κB by upregulating sirtuin 1 and 5'-adenosine monophosphate-activated protein kinase. We further demonstrated the antioxidant effect of tangeretin by showing that tangeretin inhibited reactive oxygen species production and p47(phox) phosphorylation, while enhancing the expression of heme oxygenase-1 and the DNA binding activity of nuclear factor-erythroid 2-related factor 2 to the antioxidant response element in LPS-stimulated microglia. Taken together, the results of the present study demonstrate that tangeretin possesses a potent anti-inflammatory and antioxidant effect in microglia.
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea.
authors.forename: Yu Young
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Se-Eun
authors.initials: SE
authors.lastname: Jang
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea. hskimp@ewha.ac.kr.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002957:Citrus; D047309:Flavones / Q000302:isolation & purification / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D047309:Flavones; D018836:Inflammation Mediators; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C059006:tangeretin
keywords: Anti-inflammation; Antioxidant; MMP; Microglia; Molecular mechanism; Tangeretin