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A derivative of imidazobenzimidazole, ML106, inhibits melanin synthesis via p38 MAPK activation
Kim, S.Y.,Lee, S.H.,Shin, J.S.,Lee, D.,Lee, T.,Park, K.-C.,Min, K.H.,Kim, D.-S. GOVI VERLAG GMBH 2014 PHARMAZIE Vol.69 No.5
We investigated the effects of ML106 on melanogenesis in B16F10 melanoma cells. Our results showed that ML106 decreased melanin content and tyrosinase activity in a dose-dependent manner. Interestingly, ML106 did not inhibit microphthalmia-associated transcription factor (MITF) expression, but did decrease tyrosinase expression. Thus, we further investigated the expression and degradation of tyrosinase and related signal transduction pathways. Although ML106 increased glycogen synthase kinase 3 beta (GSK3 beta) activation, the level of beta-catenin level was not affected. Thus, we excluded the involvement of GSK3 beta and beta-catenin in ML106-induced hypopigmentation. However, ML106 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), causing down-regulation of tyrosinase. Thus, we next investigated whether tyrosinase down-regulation was due to proteasomal degradation by p38 MAPK activation. We found that ML106-induced tyrosinase down-regulation was restored by MG132, a proteasome inhibitor. Thus, we propose that ML106 has hypopigmentary activity through tyrosinase degradation via p38 MAPK phosphorylation.
Park, Seung Yeon,Shim, Jung-Hyun,Chae, Jung-Il,Cho, Young Sik GOVI VERLAG GMBH 2015 PHARMAZIE Vol.70 No.3
<P>17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) acts as an inhibitor of heat shock protein 90 (HSP 90), which serves as a nodal protein of diverse signaling networks leading to a variety of biological implications. HSP90 plays the role of a chaperone for a variety of client proteins including receptor interacting protein 1 (RIP1). Since RIP1 and RIP3 are, respectively, required for zVAD- and tumor necrosis factor alpha (TNFα)-mediated necrotic cell death, we pursued to address the effects of DMAG on receptor-and nonreceptor-mediated necroptotic cell death. DMAG facilitated the degradation of receptor interacting protein 3 (RIP3) as well as RIP1, a known client protein of HSP90, in L929 cells. Consequently, DMAG rendered cells more sensitive to TNFα stimulation while it rescued cells from necrotic cell death caused by zVAD. From this study, we propose that DMAG-downregulated RIP1 can shift cell death typing from necroptosis to apoptosis. In contrast, the protective effect of DMAG on zVAD-induced cytotoxicity could be partly explained by the fact that zVAD mediates cytotoxicity via a RIP1 -dependent route. In summary, functional disruption of HSP90 by DMAG destabilized necroptosis proteins RIP1 and RIP3, which in turn regulated zVAD- and TNFα-induced necroptosis. Therefore, pharmacological modulation of necroptotic cell death through HSP90 could be a promising strategy for overcoming cancer drug resistance or protecting ischemic cell death.</P>
Yong, C S,Li, D X,Prabagar, B,Park, B C,Yi, S J,Yoo, B K,Lyoo, W S,Woo, J S,Rhee, J D,Kim, J A,Choi, H G GOVI VERLAG GMBH 2007 PHARMAZIE Vol.62 No.10
<P>Clotrimazole, a poorly water-soluble antimycotic agent, is a promising therapeutic agent for various diseases including cancer and sickle cell anemia. The oral bioavailability and hepatic toxicity of clotrimazole were compared with its beta-cyclodextrin inclusion form which was prepared by the spray-drying method. The inclusion complex gave significantly higher initial plasma concentrations, Cmax and AUC than did clotrimazole alone, indicating that the drug from the inclusion compound could be more easily absorbed in rats. Furthermore, mice treated with the inclusion compound showed significantly higher GOT/GPT values compared to clotrimazole alone. The inclusion compound also induced hypertrophy of hepatic cells by fat accumulation and disappearance of hepatic sinusoids, indications of pathological changes of liver, suggesting that the inclusion compound could induce more severe tissue damage in the liver than clotrimazole alone. Thus, hepatotoxicity of clotrimazole seems to be correlated with the enhanced oral bioavailability by inclusion complexation. Our results suggest that, in the development of a novel oral product, appearance or enhancement of hepatic toxicity must be considered along with oral bioavailability.</P>
Neuroprotective effect of curcumin is mainly mediated by blockade of microglial cell activation.
Lee, Hae Sung,Jung, Ki Kyung,Cho, Jae Youl,Rhee, Man Hee,Hong, Sungyoul,Kwon, Moosik,Kim, Seung Hee,Kang, Seog Youn GOVI VERLAG GMBH 2007 PHARMAZIE Vol.62 No.12
<P>Curcumin, the major yellow pigment in turmeric (Curcuma longa), is a well-documented naturally-occurring anti-oxidant with numerous pharmacological activities such as anti-inflammatory, anti-carcinogenic and anti-bacterial effects. In this study, curcumin's neuroprotective effect was carefully examined using a coculture system, based on reports that curcumin-containing plants are neuroprotective. Coculturing neuronal cells and activated microglial cells enhanced dopamine-induced neuronal cell death from 30% up to 50%. However, curcumin did not protect dopamine-directed neuronal cell death and sodium nitroprosside (SNP)-induced NO generation, but only blocked activated microglial cell-mediated neuronal cell damage under inflammatory conditions. Indeed, curcumin blocked the production of pro-inflammatory and cytotoxic mediators such as NO, TNF-alpha, IL-1alpha, and IL-6 produced from Abeta(25-35)/IFN-gamma- and LPS-stimulated microglia, in a dose-dependent manner. Therefore, our results suggest that curcumin-mediated neuroprotective effects may be mostly due to its anti-inflammatory effects.</P>