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June Whan Park, Young Mi Ha,
Kyung-Mi Moon,
So-Ra Kim,
Hyoung Oh Jeong,
Yun Jung Park,
Hye Jin Lee,
Ji Young Park,
Yu Min Song,
Pusoon Chun,
Youngjoo Byun,
Hyung Ryong Moon,
Hae Young Chung
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ABSTRACT: In this study, we have synthesized and studied de novo tyrosinase inhibitor, MHY1556, which showed significantly better efficacy than other pre-existing tyrosinase inhibitors in vitro experiments. The IC50 value of MHY1556 was 0.50μM which was significantly lower than that of kojic acid (IC50=53.95μM), which is a well-known tyrosinase inhibitor and was used as a positive control in this study. We predicted the tertiary structure of tyrosinase, simulated the docking with compound MHY1556 and confirmed that the compound strongly interacts with mushroom tyrosinase residues. Substitutions with a hydroxy group at both R1 and R3 of the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase, especially through the hydrogen bonding interaction of the hydroxyl group at R1 with GLY281. In addition, MHY1556 showed concentration-dependent inhibitory effects in melanin content assay where B16F10 melanoma cells were treated with α-melanocyte stimulating hormone (α-MSH), and also there is no significant cytotoxicity of this compound in cell viability assay conducted in B16F10 melanoma cells. The tyrosinase activity assay results with MHY1556 also support its potent inhibitory effects. Therefore, our data strongly suggest MHY1556 suppresses the melanogenesis via a tyrosinase inhibitory effect.
Bioorganic & medicinal chemistry letters 05/2013; · 2.65 Impact Factor
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Seongjoon Park,
Bokyung Sung,
Eun Ji Jang,
Dae Hyun Kim,
Chan Hum Park,
Yeon Ja Choi, Young Mi Ha,
Mi Kyung Kim,
Nam Deuk Kim,
Byung Pal Yu,
Hae Young Chung
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ABSTRACT: In the present study, the anti-inflammatory effect of salicylideneamino-2-thiophenol (SAL-2), a derivative of salicylate, on a potent oxidant 4-hydroxynonenal (HNE)-induced oxidative stress was investigated using rat prostate endothelial (YPEN-1) cells. We focused on anti-inflammatory activity of SAL-2 which was determined by its ability to suppress COX-2 and iNOS gene expression through suppression of NF-κB and redox regulation. We found that SAL-2 effectively inhibited HNE-induced reactive species generation, while upregulated GSH/GSSG ratio. Prostagrandin (PG) E2 production stimulated by arachidonic acid was suppressed by SAL-2. SAL-2 also downregulated COX-2 and iNOS expression induced by HNE, but salicylate did not. We found that SAL-2 inhibited HNE-mediated IKK phosphorylation, IκBα degradation and nuclear translocation of p65 which are linked to NF-κB activation. Furthermore, SAL-2 inhibited HNE-induced activation of mitogen-activated protein kinases. Collectively, SAL-2 inhibited COX-2 and iNOS gene expression through suppression of NF-κB leading to the inhibition of PGE2 synthesis. Based on these data, we propose that with its combined effect on strong anti-oxidant and anti-inflammatory action, SAL-2 can be a potent anti-inflammatory agent for treatment of inflammatory-related diseases.
Archives of Pharmacal Research 04/2013; · 1.59 Impact Factor
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Dae Hyun Kim,
Jae Heun Chung,
Ji Sung Yoon, Young Mi Ha,
Sungjin Bae,
Eun Kyeong Lee,
Kyung Jin Jung,
Min Sun Kim,
You Jung Kim,
Mi Kyung Kim,
Hae Young Chung
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ABSTRACT: Ginsenoside Rd is a primary constituent of the ginseng rhizome and has been shown to participate in the regulation of diabetes and in tumor formation. Reports also show that ginsenoside Rd exerts anti-oxidative effects by activating anti-oxidant enzymes. Treatment with ginsenoside Rd decreased nitric oxide and prostaglandin E2 (PGE2) in lipopolysaccharides (LPS)-challenged RAW264.7 cells and in ICR mouse livers (5 mg/kg LPS; LPS + ginsenoside Rd [2, 10, and 50 mg/kg]). Furthermore, these decreases were associated with the down-regulations of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and of nuclear factor (NF)-κB activity in vitro and in vivo. Our results indicate that ginsenoside Rd treatment decreases; 1) nitric oxide production (40% inhibition); 2) PGE2 synthesis (69% to 93% inhibition); 3) NF-κB activity; and 4) the NF-κB-regulated expressions of iNOS and COX-2. Taken together, our results suggest that the anti-inflammatory effects of ginsenoside Rd are due to the down-regulation of NF-κB and the consequent expressional suppressions of iNOS and COX-2.
Journal of ginseng research 03/2013; 37(1):54-63.
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ABSTRACT: We synthesized a novel series of (E)-2-((substituted phenyl)diazenyl)phenyl 4-methylbenzenesulfonate derivatives (2 and 3) and (E)-2-((substituted phenyl)diazenyl)phenol derivatives (4 and 5), and conducted an evaluation in order to determine their inhibitory effects on mushroom tyrosinase, with the aim of discovering a tyrosinase inhibitor. Most of the compounds (3-5) exhibited higher inhibitory effects than kojic acid (IC(50) = 49.08 µM), a representative tyrosinase inhibitor. A novel synthesized compound, (E)-2-((2,4-dihydroxyphenyl)diazenyl)phenyl 4-methylbenzenesulfonate (3), showed the best results with an IC(50) of 17.85 µM, and showed competitive inhibition on Lineweaver-Burk plots, as further confirmed by the docking results. In addition, active compounds 3-5 were not cytotoxic to cultured B16F10 cells at the concentrations tested, and inhibited both tyrosinase and melanin synthesis. Therefore the active compounds (3-5) might be considered excellent candidates for use in the development of therapeutic agents for diseases associated with hyperpigmentation.
Bioscience Biotechnology and Biochemistry 01/2013; · 1.28 Impact Factor
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ABSTRACT: We simulated the docking of the tertiary structure of mushroom tyrosinase with our compounds. From the structure-tyrosinase inhibitory activity relationship, it is notable that compounds 4, 8 and 11 showed similar or better activity rates than kojic acid which was used as a positive control. Compounds 17, 21, and 23 among benzene analogs that possess the same substituent showed significantly lower tyrosinase inhibitory effects. Therefore, we have confirmed that among the compounds showing better tyrosinase inhibitory effects than kojic acid, the compounds with triene analogs have better tyrosinase inhibitory effect than the compounds with benzene analogs. Docking simulation suggested the mechanism of compounds by several key residues which had possible hydrogen bonding interactions. The pharmacophore model underlined the features of active compounds, 4,4'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)diphenol, 5,5'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)bis(2-methoxy-phenol), and 5,5'-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)dibenzene-1,3-diol among triene derivatives which had several hydrogen bond groups on both terminal rings. The soundness of the docking results and the agreement with the pharmacophores suggest that it can be conveniently exploited to design inhibitors with an improved affinity for tyrosinase.
Biological & Pharmaceutical Bulletin 01/2013; 36(1):55-65. · 1.66 Impact Factor
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ABSTRACT: Ten azo compounds including azo-resveratrol (5) and azo-oxyresveratrol (9) were synthesized using a modified Curtius rearrangement and diazotization followed by coupling reactions with various phenolic analogs. All synthesized compounds were evaluated for their mushroom tyrosinase inhibitory activity. Compounds 4 and 5 exhibited high tyrosinase inhibitory activity (56.25% and 72.75% at 50μM, respectively). The results of mushroom tyrosinase inhibition assays indicate that the 4-hydroxyphenyl moiety is essential for high inhibition and that 3,5-dihydroxyphenyl and 3,5-dimethoxyphenyl derivatives are better for tyrosinase inhibition than 2,5-dimethoxyphenyl derivatives. Particularly, introduction of hydroxyl or methoxy group into the 4-hydroxyphenyl moiety diminished or significantly reduced mushroom tryosinase inhibition. Among the synthesized azo compounds, azo-resveratrol (5) showed the most potent mushroom tyrosinase inhibition with an IC(50) value of IC(50)=36.28±0.72μM, comparable to that of resveratrol, a well-known tyrosinase inhibitor.
Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
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Yeon Ja Choi,
Yohei Uehara,
Ji Young Park,
Ki Wung Chung, Young Mi Ha,
Ji Min Kim,
Yu Min Song,
Pusoon Chun,
June Whan Park,
Hyung Ryong Moon,
Hae Young Chung
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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. CONCLUSION: 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.
Journal of dermatological science 10/2012; · 3.71 Impact Factor
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ABSTRACT: We attempted to design and synthesize (E)-N-substituted benzylidene-hydroxy or methoxy-aniline derivatives and to evaluate their inhibitory effect on tyrosinase activity and anti-melanogenesis activity in murine B16F10 melanoma cells. Derivatives with a 4-methoxy- or 4-hydroxy-anilino group exerted more potent inhibition against mushroom tyrosinase than those with a 2-hydroxyanilino group. (E)-4-((4-Hydroxyphenylimino)methyl)benzene-1,2-diol exhibited the most potent and non-competitive inhibition on mushroom tyrosinase showing an IC(50) of 17.22 ± 0.38 μM and being more effective than kojic acid (51.11 ± 1.42 μM). This compound decreased melanin production stimulated by the alpha-melanocyte-stimulating hormone and inhibited murine tyrosinase activity in a dose-dependent manner. Therefore, we propose (E)-4-((4-hydroxyphenylimino)methyl)benzene-1,2-diol as a new candidate of potent tyrosinase inhibitors that could be used as therapeutic agent with safe skin-whitening efficiency.
European journal of medicinal chemistry 09/2012; 57C:383-390. · 3.27 Impact Factor
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Young Mi Ha,
Yohei Uehara,
Daeui Park,
Hyoung Oh Jeong,
Ji Young Park,
Yun Jung Park,
Ji Yeon Lee,
Hye Jin Lee,
Yu Min Song,
Hyung Ryong Moon,
Hae Young Chung
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ABSTRACT: We describe the design, synthesis, and biological activities of 5-chloro-2-(substituted phenyl)benzo[d]thiazole derivatives as novel tyrosinase inhibitors. Among them, 4-(5-chloro-2,3-dihydrobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (MHY884) and 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl)phenol (MHY966) showed inhibitory activity higher than or similar to kojic acid, against mushroom tyrosinase. Therefore, we carried out kinetic studies on the two compounds with potent tyrosinase inhibitory effects. Kinetic analysis of tyrosinase inhibition revealed that all of these compounds are competitive inhibitors. MHY884 and MHY966 effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-melanocyte stimulating hormone (α-MSH). These data strongly suggest that the newly synthesized compounds MHY884 and MHY966 could suppress production of melanin via inhibition of tyrosinase activity.
Applied biochemistry and biotechnology 09/2012; · 1.94 Impact Factor
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ABSTRACT: Among the many experimental paradigms used for the investigation of aging, the calorie restriction (CR) model has been proven to be the most useful in gerontological research. Exploration of the mechanisms underlying CR has produced a wealth of data. To identify key molecules controlled by aging and CR, we integrated data from 84 mouse and rat cDNA microarrays with a protein-protein interaction network. On the basis of this integrative analysis, we selected three genes that are upregulated in aging but downregulated by CR and two genes that are downregulated in aging but upregulated by CR. One of these key molecules is lymphocyte-specific protein tyrosine kinase (LCK). To further confirm this result on LCK, we performed a series of experiments in vitro and in vivo using kidneys obtained from aged ad libitum-fed and CR rats. Our major significant findings are as follows: (1) identification of LCK as a key molecule using integrative analysis; (2) confirmation that the age-related increase in LCK was modulated by CR and that protein tyrosine kinase activity was decreased using a LCK-specific inhibitor; and (3) upregulation of LCK leads to NF-κB activation in a ONOO(-) generation-dependent manner, which is modulated by CR. These results indicate that LCK could be considered a target attenuated by the anti-aging effects of CR. Integrative analysis of cDNA microarray and interactome data are powerful tools for identifying target molecules that are involved in the aging process and modulated by CR.
Age 07/2012; · 6.28 Impact Factor
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ABSTRACT: Epithelial barrier function is determined by both transcellular and paracellular permeability, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. We investigated the protective effects of ferulate on epithelial barrier integrity by examining permeability, TJ protein expression, and apoptosis in Caco-2 cells treated with tert-butyl hydroperoxide (t-BHP), a strong reactive species inducer. Caco-2 cells pretreated with ferulate (5 or 15 μM) were exposed to t-BHP (100 μM), and ferulate suppressed the t-BHP-mediated increases in reactive species and epithelial permeability in Caco-2 cells. Moreover, ferulate inhibited epithelial cell leakage induced by t-BHP, which was accompanied by decreased expression of the TJ proteins zonula occludens-1 and occludin. In addition, pretreatment with ferulate markedly protected cells against t-BHP-induced apoptosis, as evidenced by decreased nuclear condensation, cytochrome c release, and caspase-3 cleavage and an increased Bax/Bcl-2 ratio. These results suggest that ferulate protects the epithelial barrier of Caco-2 cells against oxidative stress, which results in increased epithelial permeability, decreased TJ protein expression, and increased apoptosis. The most significant finding of our study is the demonstration of protective, ferulate-mediated antioxidant effects on barrier integrity, with a particular focus on intracellular molecular mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.
Phytotherapy Research 05/2012; · 2.09 Impact Factor
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Young Mi Ha,
Sang Woon Chung,
Ji Min Kim,
Dae Hyun Kim,
Ji Young Kim,
Eun Kyeong Lee,
Jaewon Lee,
Young Jin Kim,
Mi Ae Yoo,
Kyu Shik Jeong,
Hae Young Chung
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ABSTRACT: The effects of γ-irradiation on inflammatory gene expression, including NF-κB activation, in the kidney of C57/BL6 mice exposed
to 1–9Gy doses of 60Co γ-irradiation. Radiation enhanced the NF-κB activation and oxidative stress caused a dose-dependent disruption in the redox
balance. The significance of this study is the new molecular information gained on γ-irradiation effects through the activation
of pro-inflammatory genes by NF-κB via the MAPK signaling pathway. Considering the exquisite sensitivity of NF-κB and other
pro-inflammatory mediators to the redox status, we conclude that the activation of inflammatory processes by irradiation is
likely initiated by increased oxidative stress.
Biotechnology Letters 04/2012; 32(3):373-378. · 1.68 Impact Factor
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ABSTRACT: Tyrosinase inhibitors have become increasingly important because of their ability to inhibit the synthesis of the pigment melanin. A search for new agents with strong tyrosinase activity led to the synthesis of the tyrosinase inhibitor (E)-3-(2,4-dihydroxybenzylidene)pyrrolidine-2,5-dione (3-DBP).
The inhibitory effect of 3-DBP on tyrosinase activity and melanin production was examined in murine melanoma B16F10 cells. Additional experiments were performed using HRM2 hairless mice to demonstrate the effects of 3-DBP in vivo.
The novel compound, 3-DBP, showed an inhibitory effect against mushroom tyrosinase (IC50=0.53 μM), which indicated that it was more potent than the well-known tyrosinase inhibitor kojic acid (IC50=8.2 μM). When tested in B16F10 melanoma cells treated with α-melanocyte stimulating hormone (α-MSH), 3-DBP also inhibited murine tyrosinase activity, which in turn induced a decrease in melanin production in these cells. The anti-melanogenic effect of 3-DBP was further verified in HRM2 hairless mice. The skin-whitening index (L value) of HRM2 hairless mice treated with 3-DBP before irradiation with UVB was greater than that of UVB-irradiated mice that were not treated with 3-DBP.
The newly synthesized 3-DBP has a potent inhibitory effect on tyrosinase. In addition to an in vitro investigation of the effects of 3-DBP on tyrosinase, in vivo studies using an HRM2 hairless mouse model demonstrated the anti-melanogenic potency of 3-DBP. Our newly synthesized 3-DBP showed efficient tyrosinase inhibitory effect in vivo and in vitro. Our finding suggests that 3-DBP can be an effective skin-whitening agent.
Biochimica et Biophysica Acta 04/2012; 1820(7):962-9. · 4.66 Impact Factor
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ABSTRACT: In continuing our search for novel tyrosinase inhibitors, a series of 5-(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a-2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and L-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC(50) values of 13.36 and 9.87 μM, respectively, than kojic acid (IC(50) = 24.72 μM). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-melanocyte-stimulating hormone (α-MSH). These data strongly suggest that compounds 2a and 2f suppress the production of melanin via the inhibition of tyrosinase activity.
European journal of medicinal chemistry 03/2012; 49:245-52. · 3.27 Impact Factor
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ABSTRACT: We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity.
The structure of MHY384 was established using (1)H and (13)C NMR spectroscopy and mass spectral analyses. To investigate dual mechanisms of action of MHY384 for the inhibition of melanin synthesis, we confirmed the inhibitory effect of tyrosinase catalytic activity of MHY384. Then, we confirmed the inhibitory effect of MHY384 on transcription of tyrosinase mRNA through alpha-MSH-induced cAMP-PKA-MITF signaling. In addition, we supported the inhibitory mechanism of MHY384 against tyrosinase using a kinetic study and docking programs.
To determine how MHY384 regulates melanogenesis, we measured melanin levels and expression of the genes for microphthalmia-associated transcription factor (MITF) and tyrosinase in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. MHY384 potently inhibited tyrosinase activity and melanin production in B16F10 melanoma cells. Through docking models, we were able to construct the tertiary structure of mushroom tyrosinase and simulate its docking with MHY384. The result supports that MHY384 strongly interacts with tyrosinase residues in the active site and it can directly inhibit tyrosinase. To investigate additional mechanisms of action of MHY384, we confirmed that the inhibition of tyrosinase activity was found to be due to the modulation of the expression of tyrosinase and its transcription factor, MITF, through cAMP, which regulates protein kinase A.
This study strongly indicates that the depigmenting effect of MHY384 results from the down-regulation of MITF and tyrosinase through direct tyrosinase inhibition.
Our findings suggest that MHY384 can be an effective skin-whitening agent.
Biochimica et Biophysica Acta 01/2012; 1820(4):542-9. · 4.66 Impact Factor
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Yeon Ja Choi,
Yun Jung Park,
Ji Young Park,
Hyoung Oh Jeong,
Dae Hyun Kim, Young Mi Ha,
Ji Min Kim,
Yu Min Song,
Hyoung-Sam Heo,
Byung Pal Yu,
Pusoon Chun,
Hyung Ryong Moon,
Hae Young Chung
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ABSTRACT: Autophagy is a major degradative process responsible for the disposal of cytoplasmic proteins and dysfunctional organelles via the lysosomal pathway. During the autophagic process, cells form double-membraned vesicles called autophagosomes that sequester disposable materials in the cytoplasm and finally fuse with lysosomes. In the present study, we investigated the inhibition of autophagy by a synthesized compound, MHY1485, in a culture system by using Ac2F rat hepatocytes. Autophagic flux was measured to evaluate the autophagic activity. Autophagosomes were visualized in Ac2F cells transfected with AdGFP-LC3 by live-cell confocal microscopy. In addition, activity of mTOR, a major regulatory protein of autophagy, was assessed by western blot and docking simulation using AutoDock 4.2. In the result, treatment with MHY1485 suppressed the basal autophagic flux, and this inhibitory effect was clearly confirmed in cells under starvation, a strong physiological inducer of autophagy. The levels of p62 and beclin-1 did not show significant change after treatment with MHY1485. Decreased co-localization of autophagosomes and lysosomes in confocal microscopic images revealed the inhibitory effect of MHY1485 on lysosomal fusion during starvation-induced autophagy. These effects of MHY1485 led to the accumulation of LC3II and enlargement of the autophagosomes in a dose- and time-dependent manner. Furthermore, MHY1485 induced mTOR activation and correspondingly showed a higher docking score than PP242, a well-known ATP-competitive mTOR inhibitor, in docking simulation. In conclusion, MHY1485 has an inhibitory effect on the autophagic process by inhibition of fusion between autophagosomes and lysosomes leading to the accumulation of LC3II protein and enlarged autophagosomes. MHY1485 also induces mTOR activity, providing a possibility for another regulatory mechanism of autophagy by the MHY compound. The significance of this study is the finding of a novel inhibitor of autophagy with an mTOR activating effect.
PLoS ONE 01/2012; 7(8):e43418. · 4.09 Impact Factor
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Hyun Ae Lim,
Eun Kyeong Lee,
Ji Min Kim,
Min Hi Park,
Dae Hyun Kim,
Yeon Ja Choi, Young Mi Ha,
Jeong-Hyun Yoon,
Jae Sue Choi,
Byung Pal Yu,
Hae Young Chung
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ABSTRACT: Baicalin, a herb-derived flavonoid compound, has beneficial activities, including the modulation of oxidative stress and inflammation. Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor that plays an important role in regulating nuclear factor-κB (NF-κB)-induced age-related inflammation. We investigated the anti-inflammatory action of baicalin, which depends on its ability to activate PPARγ, and subsequently to suppress NF-κB. We examined baicalin-treated kidney tissue from 24-month-old Fischer 344 aged rats (10 or 20 mg/kg/day for 10 days) and baicalin-fed mice (10 mg/kg/day for 3 days) for in vivo investigations, and used endothelial YPEN-1 cells for in vitro studies. In the baicalin-fed aged rats, there was a marked enhancement of both nuclear protein levels and DNA binding activity of PPARγ, and a decreased expression of NF-κB target genes (VCAM-1, IL-1β, and IL-6) compared with non-baicalin-fed aged rats. Furthermore, to confirm the anti-inflammatory action of PPARγ activated by baicalin, we used lipopolysaccharide (LPS)-treated cells and mice. The results showed that baicalin induced PPARγ-selective activation in YPEN-1 cells, and that the effects of baicalin were blocked by the PPARγ receptor antagonist, GW9662. In addition, baicalin treatment prevented RS generation, NF-κB activation and the expression of pro-inflammatory genes, whereas it increased PPARγ expression in LPS-treated cells and mouse kidney. Our data suggest that baicalin-induced PPARγ expression reduced age-related inflammation through blocking pro-inflammatory NF-κB activation. These results indicate that baicalin is a novel PPARγ activator and that this agent may have the potential to minimize inflammation.
Biogerontology 10/2011; 13(2):133-45. · 3.34 Impact Factor
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Young Mi Ha,
Yun Jung Park,
Ji Yeon Lee,
Daeui Park,
Yeon Ja Choi,
Eun Kyeong Lee,
Ji Min Kim,
Jin-Ah Kim,
Ji Young Park,
Hye Jin Lee,
Hyung Ryong Moon,
Hae Young Chung
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ABSTRACT: Herein we describe the design, synthesis and biological activities of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors. The target compounds 2a-2j were designed and synthesized from the structural characteristics of N-phenylthiourea, tyrosinase inhibitor and tyrosine, and l-DOPA, the natural substrates of tyrosinase. Among them, (2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid (2g) caused the greatest inhibition 66.47% at 20 μM of l-DOPA oxidase activity of mushroom tyrosinase. Kinetic analysis of tyrosinase inhibition revealed that 2g is a competitive inhibitor. We predicted the tertiary structure of tyrosinase, and simulated the docking of mushroom tyrosinase with 2g. These results suggest that the binding affinity of 2g with tyrosinase is high. Also, 2g effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-MSH. These data strongly suggest that 2g can suppress the production of melanin via the inhibition of tyrosinase activity.
Biochimie 09/2011; 94(2):533-40. · 3.02 Impact Factor
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ABSTRACT: Angiotensin II (Ang II), a main effector of the renin-angiotensin system, is recognized as a pro-inflammatory mediator on age-related vascular inflammation. Ang II is one of the most important oxidative stress inducer, activates the redox-sensitive transcription factor, nuclear factor-κB (NF-κB) during aging. Genistein, a major component found in isoflavone, has anti-inflammatory activities that are often associated with its anti-oxidative activity. The purpose of this study is to document molecular mechanism of altered Ang II-related NF-κB activation during aging and inhibitory molecular events by genistein regarding to age-related Ang II-induced NF-κB activation. At present, we utilized young (6 months old), old (24 months old), and genistein-treated (2 and 4 mg/kg/day for 10 days) old rats. For our current study, we choose to use the kidney and rat endothelial cell line, YPEN-1 because of its vulnerability to age-related oxidative stress and inflammatory responsiveness. The results of the analysis showed that Ang II and AT1 expression increased during aging and that these increases were blunted by treatment with genistein. Furthermore, we investigated the inhibitory effects of genistein on the Ang II-induced redox imbalance in aged rat kidneys. Genistein reduced age-related increases in NF-κB activity and NF-κB-dependent pro-inflammatory genes expression. We also determined genistein attenuated Ang II-induced NF-κB activation through its anti-oxidant activity in YPEN-1 cells. Taken together, our present results show that genistein has potent anti-inflammatory effect resulting in the attenuation of the Ang II-induced NF-κB activation during aging. The most significant new finding from this study is that genistein exerts its anti-Ang II action during aging by suppressive effect of NF-κB activation. Based on these data, genistein may be an anti-Ang II agent that may be used in anti-inflammatory therapies.
Biogerontology 06/2011; 12(6):537-50. · 3.34 Impact Factor
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ABSTRACT: Ferulate (4-hydroxy-3-methoxycinnamic acid) is a well-known phenolic compound that scavenges free radicals and exerts anti-inflammatory effects. Forkhead box O3a (FOXO3a), a transcription factor that plays important roles in aging processes, decreases with age and is negatively regulated through phosphorylation by phosphatidylinositol 3-kinase (PI3K)/Akt signaling. The present study investigated the efficacy of short-term ferulate feeding on age-related changes in PI3K/Akt/FOXO3a and upstream insulin signaling pathways in aged rats. In addition, changes in manganese superoxide dismutase (MnSOD) and catalase expression were examined because of their dependence on PI3K/Akt/FOXO3a activity. Short-term feeding experiments were done with a diet containing ferulate that was given to aged rats at doses of 3 or 6 mg kg(-1) day(-1) for 10 days. Results showed that FOXO3a activity was increased in the ferulate-fed old group compared with the control old group. Also, ferulate suppressed the PI3K/Akt signaling pathway that is responsible for FOXO3a inhibition in aged rats. Plasma insulin levels and the upstream insulin signaling pathway were also modulated by ferulate correspondingly with PI3K/Akt/FOXO3a activity. The age-related decrease in two major antioxidant enzymes, MnSOD and catalase, was blunted by ferulate, which was accompanied by FOXO3a transcriptional activity. The significance of the present study is the finding that short-term feeding of ferulate effectively modulates age-related renal FOXO3a, PI3K/Akt and insulin signaling pathways, and MnSOD and catalase expression, all of which may be beneficial for attenuating the aging process.
Age 04/2011; 34(2):317-27. · 6.28 Impact Factor
