title: Suppression of melanogenesis by a newly synthesized compound, MHY966 via the nitric oxide/protein kinase G signaling pathway in murine skin.
abstract: BACKGROUND
  Ultraviolet B (UVB) radiation is the main physiological stimulus for skin pigmentation. Nitric oxide (NO) and the NO/PKG signaling pathway play an important role in UVB-induced melanogenesis, which is related to the induction of expression of tyrosinase. In an attempt to find a novel anti-melanogenic agent, we synthesized a new compound, 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY966).
  
  
  OBJECTIVE
  The purpose of this study was to investigate the action of MHY966 on NO and the NO-mediated signaling pathway using in vitro and in vivo models of melanogenesis.
  
  
  METHODS
  NO generation, melanin synthesis, and the expression of tyrosinase and PKG were measured in B16F10 melanoma cells to verify the anti-melanogenic effect of MHY966 in vitro. Next, melanin-possessing hairless mice were pre-treated with MHY966 and then irradiated with UVB repeatedly. Morphological, histological, and biochemical analyses including the expressions of PKG, tryosinase and nuclear MITF, and productions of nitric oxide, peroxynitrite and ROS were conducted.
  
  
  RESULTS
  MHY966 effectively inhibited NO generation and subsequent melanin synthesis induced by sodium nitroprusside, an NO donor, and suppressed the expression of tyrosinase and PKG. Topical application of MHY966 dose-dependently attenuated UVB-induced pigmentation in a mouse model. This hypopigmentation effect induced by MHY966 treatment was mediated by the down-regulation of tyrosinase, PKG, and nuclear MITF, which was accompanied by decreased NO and NO-related oxidative stress.
  
  
  CONCLUSIONS
  The novel compound, MHY966 had an inhibitory effect on NO generation and the NO-mediated signaling pathway leading to the down-regulation of tyrosinase. The significance of the present study is the finding of a promising anti-melanogenic agent targeting the NO/PKG signaling pathway.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Uehara
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Park
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Ha
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Yu Min
authors.initials: YM
authors.lastname: Song
authors.forename: Pusoon
authors.initials: P
authors.lastname: Chun
authors.forename: June Whan
authors.initials: JW
authors.lastname: Park
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism*; D012880:Skin Pigmentation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C580737:MHY966; D008543:Melanins; D010636:Phenols; D009569:Nitric Oxide; D014442:Monophenol Monooxygenase; D017869:Cyclic GMP-Dependent Protein Kinases