title: Novel Danshen methoxybenzo[b]furan derivative antagonizing adipogenic differentiation and production of inflammatory adipokines.
abstract: Many benzo[b]furan lignans are known to be biologically active in nature. 2-(3'-Methoxy-4'-hydroxy-phenyl)-5-(3-hydroxypropyl)-7-methoxy-benzo[b]furan-3-carbaldehyde (XH-14) is found as a bioactive component isolated from the plant Salvia miltiorrhiza, commonly known as Danshen, which is a traditional Chinese medicine that is used as a cardiovascular medication. This study examined whether 3 different XH-14 derivatives can inhibit adipocyte differentiation and induction of the adipokines visfatin and resistin in 3T3-L1 adipocytes. Adipocytes were cultured and differentiated in Dulbecco's modified Eagle medium containing fetal bovine serum, 3-isobytyl-1-methylxanthine, dexamethasone, and insulin for 6-8d in the absence and presence of 1-25μM XH-14-derived benzo[b]furan derivatives. Nontoxic 2-(3'-methoxy-4'-hydroxy-phenyl)-6-(3-hydroxypropyl)-5-methoxy-benzo[b]furan (5-MBF) at ≥5μM attenuated cellular lipid accumulation and down-regulated induction of peroxisome proliferator activated receptors γ (PPARγ) and CCAAT enhancer binding protein α (C/EBPα) in a dose-dependent manner, as evidenced by Oil Red O staining and Western blot analysis. Such inhibition of PPAR( and C/EBP( by 5-MBF was achieved at transcriptional mRNA levels. However, 2-(3'-methoxy-4'-hydroxy-phenyl)-5-(3-hydroxypropyl)-7-methoxy-benzo[b]furan (7-MBF) and 2-(3'-methoxy-4'-hydroxy-phenyl)-5-(3-hydroxypropyl)-7-methoxy-benzo[b]furan (6-MBF) had minimal effects on adipogenic differentiation, suggesting a structure-activity relationship of methoxybenzo[b]furan derivatives as an inhibitor of adipogenic differentiation. Furthermore, ≥5μM 5-MBF retarded protein and mRNA expression of proinflammatory and insulin resistance-enhancing adipokines of visfatin and resistin in differentiated adipocytes. Induction of visfatin and resistin was, at least in part, mediated via adipocyte differentiation-associated activation of PPARγ signal targeting adipocyte protein 2 and stearoyl-CoA desaturase. These results demonstrate that the 2-(3'-methoxy-4'-hydroxy-phenyl)-3-hydroxypropyl benzo[b]furan lignan, with a methoxy group at the 5-position on the benzene ring, may be a promising agent for disturbance of adipogenic differentiation and for blockage of obesity-associated inflammatory and metabolic diseases.
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Sung
authors.forename: Jong-Gab
authors.initials: JG
authors.lastname: Jun
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Daekeun
authors.initials: D
authors.lastname: Shin
authors.forename: Il-Jun
authors.initials: IJ
authors.lastname: Kang
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D054392:Adipokines / Q000096:biosynthesis*; D000818:Animals; D001554:Benzene / Q000737:chemistry; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D054409:Nicotinamide Phosphoribosyltransferase / Q000096:biosynthesis / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D052243:Resistin / Q000235:genetics; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D054392:Adipokines; D001572:Benzofurans; D022763:CCAAT-Enhancer-Binding Protein-alpha; D005663:Furans; D047495:PPAR gamma; D052243:Resistin; C116381:XH-14; D006139:Guaiacol; D054409:Nicotinamide Phosphoribosyltransferase; D001554:Benzene; C039281:furan