title: The anti-inflammatory effect of 3-deoxysappanchalcone is mediated by inducing heme oxygenase-1 via activating the AKT/mTOR pathway in murine macrophages.
abstract: 3-Deoxysappanchalcone (3-DSC), isolated from Caesalpinia sappan (Leguminosae), is a chalcone that exerts a variety of pharmacological activities. In the present study, we demonstrated that 3-DSC exerts anti-inflammatory activity in murine macrophages by inducing heme oxygenase-1 (HO-1) expression at the translational level. Treatment of RAW264.7 cells with 3-DSC induced HO-1 protein expression in a dose- and time-dependent manner without affecting HO-1 mRNA expression. Mitogen-activated protein kinase inhibitors or actinomycin D, a transcriptional inhibitor, did not block 3-DSC-mediated HO-1 induction. However, 3-DSC-mediated HO-1 induction was completely blocked by treatment with cycloheximide, a translational inhibitor, or rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR). Strikingly, 3-DSC increased the phosphorylation level of mTOR downstream target molecules such as eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1), as well as AKT in a dose- and time-dependent manner, suggesting that the 3-DSC induces HO-1 expression by activating the AKT/mTOR pathway. Consistent with the notion that HO-1 has anti-inflammatory properties, 3-DSC inhibited the production of nitric oxide (NO) and interleukin (IL)-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Inhibition of HO-1 activity by treatment with tin protoporphyrin IX, a specific HO-1 inhibitor, abrogated the inhibitory effects of 3-DSC on the production of NO and IL-6 in LPS-stimulated RAW264.7 cells. Taken together, 3-DSC may be an effective HO-1 inducer at the translational level that has anti-inflammatory effects, and a valuable compound for modulating inflammatory conditions.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 200-701, Republic of Korea.
authors.forename: Jun-Hyeong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 200-701, Republic of Korea.
authors.forename: Young-Yeon
authors.initials: YY
authors.lastname: Choo
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 200-701, Republic of Korea.
authors.forename: Nara
authors.initials: N
authors.lastname: Tae
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Gyeongsan 712-702, Republic of Korea.
authors.forename: Byung-Sun
authors.initials: BS
authors.lastname: Min
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 200-701, Republic of Korea. Electronic address: jhlee36@kangwon.ac.kr.
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D029911:Caesalpinia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D047188:Chalcones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C542297:3-deoxysappanchalcone
keywords: 3-Deoxysappanchalcone; Anti-inflammatory effect; Heme oxygenase-1; Translation; mTOR