title: A newly synthesized macakurzin C-derivative attenuates acute and chronic skin inflammation: The Nrf2/heme oxygenase signaling as a potential target.
abstract: Impaired immune responses in skin play a pivotal role in the development and progression of chemical-associated inflammatory skin disorders. In this study, we synthesized new flavonoid derivatives from macakurzin C, and identified in vitro and in vivo efficacy of a potent anti-inflammatory flavonoid, Compound 14 (CPD 14), with its underlying mechanisms. In lipopolysaccharide (LPS)-stimulated murine macrophages and IFN-γ/TNF-α-stimulated human keratinocytes, CPD 14 significantly inhibited the release of inflammatory mediators including nitric oxide (NO), prostaglandins, and cytokines (IC50 for NO inhibition in macrophages: 4.61μM). Attenuated NF-κB signaling and activated Nrf2/HO-1 pathway were responsible for the anti-inflammatory effects of CPD 14. The in vivo relevance was examined in phorbol 12-myristate 13-acetate (TPA)-induced acute skin inflammation and oxazolone-induced atopic dermatitis models. Topically applied CPD 14 significantly protected both irritation- and sensitization-associated skin inflammation by suppressing the expression of inflammatory mediators. In summary, we demonstrated that a newly synthesized flavonoid, CPD 14, has potent inhibitory effects on skin inflammation, suggesting it is a potential therapeutic candidate to treat skin disorders associated with excessive inflammation.
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akram
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Republic of Korea.
authors.forename: Iljin
authors.initials: I
authors.lastname: Shin
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Kyeong-A
authors.initials: KA
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Dabi
authors.initials: D
authors.lastname: Noh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Chang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Republic of Korea. Electronic address: hkimajou@ajou.ac.kr.
authors.forename: Hyoungsu
authors.initials: H
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea. Electronic address: onbae@hanyang.ac.kr.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D002908:Chronic Disease; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010081:Oxazolone; D000067996:RAW 264.7 Cells; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D014409:Tumor Necrosis Factor-alpha; C587525:macakurzi C; D010081:Oxazolone; D009569:Nitric Oxide; D007371:Interferon-gamma; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate
keywords: Anti-inflammatory activity; Oxazolone-induced atopic dermatitis; Synthetic flavonoid; TPA-induced acute inflammation