ABSTRACT: During our on-going attempts to develop a new skin-whitening agent, we identified a novel candidate compound KHG22394, a 2-imino-1,3-thiazoline derivative. Our data show that KHG22394 significantly inhibits melanin production in a dose-dependent manner, but that it does not directly inhibit tyrosinase, the rate limiting melanogenic enzyme. It has been reported that the activation of extracellular signal-regulated kinase (ERK) reduces melanin synthesis by downregulating microphthalmia-associated transcription factor (Mitf). Thus, we examined the effects of KHG22394 on the ERK pathway and found that it induced ERK and 90 kDa ribosomal S6 kinase (RSK-1) activation. Moreover, alpha-melanocyte-stimulating hormone (alpha-MSH) is known to increase melanin biosynthesis by increasing tyrosinase production, and here, we found that alpha-MSH-induced Mitf and tyrosinase increases were inhibited in B16 melanoma cells treated with KHG22394. These findings suggest that the hypopigmentary effect of KHG22394 results from the downregulation of Mitf and subsequently of tyrosinase, although KHG22394 did not inhibit tyrosinase activity directly. Our findings indicate that 2-imino-1,3-thiazoline derivatives are potential skin whitening agents.
Biological & Pharmaceutical Bulletin 02/2007; 30(1):180-3. · 1.66 Impact Factor
ABSTRACT: We investigated what adenosine receptor type exists and the signaling pathways on the contraction of circular muscle cells isolated by enzymatic digestion from the cat esophagus. Adenosine or the selective A1 receptor agonist R-PIA causes a concentration-dependent contraction. After pretreatment with A1 receptor antagonist, DPCPX, adenosine-mediated contraction was abolished. Adenosine-induced contraction was significantly increased when A1 receptors were preserved by pretreatment with DPCPX followed by inactivation of all unprotected receptors with N-ethylmaleimide. Adenosine- or R-PIA-induced contraction was significantly augmented in the preserved cells and the increase was abolished in the presence of the A1 receptor antagonist DPCPX. PTX abolished contraction induced by adenosine or R-PIA, implying that contraction activated by A1 receptor was coupled to a pertussis toxin (PTX)-sensitive G(i) protein. After permeabilization, contraction was inhibited by G(i2), but not by G(i1) and G(i3), antibodies. These data suggest that adenosine-induced contraction of esophagus depends on PTX-sensitive G(i2.) Adenosine- or R-PIA-induced contraction of esophageal smooth muscle cells was not affected by the phospholipase D (PLD) inhibitor rho-chloromercuribenzoic acid (rhoCMB), phospholipase A(2) (PLA(2)) inhibitor DEDA or PKC antagonist chelerythrine, but was significantly abolished by phospholipase C (PLC) inhibitor, neomycin. PLC-beta3 antibody inhibited R-PIA-induced contraction. R-PIA-induced contraction of esophageal muscle cells was inhibited by IP(3) receptor antagonist heparin, which suggests that the contraction of esophageal smooth muscle cells is dependent on phosphatidylinositol-specific phospholipase (PI-PLC) and IP(3). In conclusion, adenosine- and R-PIA-induced contraction in cat esophageal smooth muscle cell was mediated by A1 receptor. A1 receptor is coupled to PTX-sensitive G protein G(i2), which results in the activation of PI-PLC-beta3. PI hydrolysis by PI-PLC forms IP(3), which binds to IP(3) receptor on endoplasmic reticulum, resulting in the release of intracellular Ca(2+).
Cellular Signalling 05/2002; 14(4):365-72. · 4.06 Impact Factor
ABSTRACT: Endothelin-1 (ET-1), a novel and potent vasoconstrictor in blood vessel, is known to have some functions in the rat central
nervous system (CNS). In order to investigate the central functions of ET-1, ET-1 was administered to the periaqueductal gray
area (PAG) of anesthetized rats to induce barrel rolling and increase the arterial blood pressure (ABP). ET-1 had a modulatory
effect on central cardiovascular and behavioral control. The selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801
(3 μmol/kg, i.p.) blocked the ET-1 induced responses, and both the nitric oxide synthase (NOS) inhibitor L-NAME (N-nitro-L-arginine
methylester 1 mmol/rat) and the nitric oxide (NO) scavenger hemoglobin (15 nmol/rat) had similar effects in reducing the ET-1
(10 pmol/rat)-induced behavioral changes and ABP elevation. However, NO donor sodium nitroprusside (SNP 10 μg, 1 μg/rat) decreased
the ET-1 induced ABP elevation, and recovered the ET-1-induced barrel rolling effect that was reduced by MK-801. These results
suggest that ET-1 might have neuromodulatory functions such as ABP elevation and barrel rolling induction in the PAG of the
rats via the NMDA receptor and NO.
Archives of Pharmacal Research 01/2001; 24(1):64-68. · 1.59 Impact Factor