title: (5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate, a kojic acid derivative, inhibits inflammatory mediator production via the suppression of Syk/Src and NF-κB activation.
abstract: Numerous derivatives of kojic acid have been synthesised to expand its immunopharmacological uses. Kojic acid is known to have anti-cancer, anti-inflammatory, and anti-melanogenesis effects. We found that (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate (MHNC) strongly suppressed the production of nitric oxide (NO) in an initial screening experiment. In this study, we explored the in vitro and in vivo anti-inflammatory activity of MHNC and its inhibitory mechanisms using lipopolysaccharide (LPS)-treated RAW264.7 cells and HCl/EtOH-treated ICR mice. MHNC dose-dependently diminished the secretion of nitric oxide (NO) and prostaglandin (PG)E2 in LPS-treated RAW264.7 cells. This compound also suppressed the upregulation of mRNA levels for the inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 genes. Additionally, the transcriptional activation of these genes was inhibited by MHNC through the suppression of the nuclear translocation of nuclear factor (NF)-κB subunits (p65 and p50), as determined by a luciferase reporter assay. Interestingly, MHNC treatment was found to suppress a series of upstream signalling cascades consisting of IκBα, AKT, PDK1, Src, and Syk for NF-κB activation. Furthermore, a direct enzyme assay with purified Src and Syk and luciferase assays using Src and Syk overexpression indicated that these enzymes were directly inhibited by MHNC. Finally, MHNC (20mg/kg) prevented inflammatory symptoms of the stomach in mice treated with HCl/EtOH by reducing phospho-IκBα levels. Taken together, our data suggest that MHNC may negatively modulate in vitro and in vivo inflammatory responses via the direct suppression of Syk/Src and NF-κB.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: To Thi Mai
authors.initials: TT
authors.lastname: Dung
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mokdong Hospital College of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea.
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.affiliation: Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration, Suwon 441-707, Republic of Korea.
authors.forename: Gi-Ho
authors.initials: GH
authors.lastname: Sung
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Woo Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Han Gyung
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jae Gwang
authors.initials: JG
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Man Hee
authors.initials: MH
authors.lastname: Rhee
authors.affiliation: Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Kye Won
authors.initials: KW
authors.lastname: Park
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Keejung
authors.initials: K
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea.
authors.forename: Yunmi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea. Electronic address: jhkim1@chonbuk.ac.kr.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jaecho@skku.edu.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D000431:Ethanol; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006851:Hydrochloric Acid; D020672:I-kappa B Proteins / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D008813:Mice, Inbred ICR; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D009284:Naphthols / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013270:Stomach / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: C000593974:(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate; D000893:Anti-Inflammatory Agents; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009284:Naphthols; C000606205:Nfkbia protein, mouse; D011753:Pyrones; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D000431:Ethanol; C011890:kojic acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D015232:Dinoprostone; D006851:Hydrochloric Acid
keywords: (5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate; Anti-inflammatory effect; NF-κB; Src; Syk