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Jee Sun Yang,
Doona Song,
Won Jin Ko,
Bunyea Kim,
Bo-Kyung Kim,
Song-Kyu Park,
Misun Won, Kiho Lee,
Kyeong Lee,
Hwan Mook Kim,
Gyoonhee Han
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ABSTRACT: A series of novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated for their anticancer effects involving induction of RhoB. Most of these compounds, featuring open-ring forms of aliphatic amido-quaternary ammonium salts, exhibited potent anti-proliferative activities in human cancer cell lines, including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. In further evaluation, the representative compound N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide (3b) exhibited potent pro-apoptotic activity, through RhoB activation, in HeLa cells.
European journal of medicinal chemistry 03/2013; 63C:621-628. · 3.27 Impact Factor
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Jung Hyu Shin,
Chang Woo Lee,
Soo Jin Oh,
Jieun Yun, Kiho Lee,
Song-Kyu Park,
Hwan Mook Kim,
Sang-Bae Han,
Youngsoo Kim,
Hyung Chin Kim,
Jong Soon Kang
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ABSTRACT: Silymarin has been known to exert antioxidant, anti-carcinogenic and anti-inflammatory effects. In this study, we examined the effect of silymarin on gastritis in rats. Oral administration of silymarin dose-dependently decreased gastric lesions in ethanol-induced gastritis model. Silymarin also significantly suppressed the development of gastric lesions in aspirin- or water immersionrestraint stress-induced gastritis models. Further study demonstrated that the gastroprotective effect of silymarin was blocked by nitric oxide (NO) synthase inhibitor L-NAME, SH blocker Nethylmaleimide or TRPV1 antagonist capsazepine in ethanol-induced gastritis model. In addition, ex vivo analysis revealed that ethanol-induced decrease in gastric mucus and non-protein sulfhydryl (NPSH) groups was significantly reversed by silymarin treatment and lipid peroxidation was also suppressed by silymarin in ethanol-induced gastritis model. Taken together, these results suggest that silymarin exerts gastroprotective effects and the gastroprotective effects of silymarin might be related to the protection of gastric mucosal NO and NP-SH and the modulation of capsaicin-sensitive gastric sensory afferents.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 01/2013; · 2.99 Impact Factor
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Misun Cho,
Eunhyun Choi,
Jee Sun Yang,
Chulho Lee,
Jeong Jea Seo,
Beom Seok Kim,
Soo Jin Oh,
Hwan Mook Kim, Kiho Lee,
Song-Kyu Park,
Ho Jeong Kwon,
Gyoonhee Han
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ABSTRACT: Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc-dependent HDACs induce proliferation, dedifferentiation, and anti-apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone-based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone-based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam-based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine-based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)-N-hydroxy-3-{1-[3-(naphthalen-2-yl)propyl]-2-oxo-1,2-dihydropyridin-3-yl}acrylamide, exhibited the highest level of HDAC inhibition (IC(50) =0.07 μM), highly selective inhibition of class I HDAC1 and class II HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect in vitro activities. Overall, the findings reported herein regarding pyridone-based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.
ChemMedChem 01/2013; · 3.15 Impact Factor
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Doona Song,
Jee Sun Yang,
Seo Joong Kim,
Bo-Kyung Kim,
Song-Kyu Park,
Misun Won, Kiho Lee,
Hwan Mook Kim,
Kang-Yell Choi,
Kyeong Lee,
Gyoonhee Han
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ABSTRACT: RhoB, one of the upstream signaling proteins of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, is frequently mutated in human cancer. Based on a piperazine alkyl derivative that induced apoptosis via up-regulation of RhoB, we synthesized novel aliphatic amido/sulfonamido-quaternary ammonium salts and evaluated their biological activities using an in vitro growth inhibition assay and RhoB promoter assay in human cancer cells. Compound 3a was the most promising anticancer agent in the series, based upon its potent growth inhibition via RhoB-mediated signaling. These novel aliphatic amido/sulfonamido-quaternary ammonium salts may be useful as a platform for development of anticancer chemotherapeutic agents.
Bioorganic & medicinal chemistry 12/2012; · 2.82 Impact Factor
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Eunhyun Choi,
Chulho Lee,
Misun Cho,
Jeong Jea Seo,
Jee Sun Yang,
Soo Jin Oh, Kiho Lee,
Song-Kyu Park,
Hwan Mook Kim,
Ho Jeong Kwon,
Gyoonhee Han
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ABSTRACT: Hydroxamate based HDAC inhibitors have promising anticancer activities but metabolic instability and poor phar-macokinetic profiles cause poor in vivo results. From QSAR and PK studies, gamma-lactam core and diverse substituents on cap group including halo, alkyl, and alkoxy groups with various carbon chain linkers improved HDAC inhibition and metabolic stability. The biological properties of prepared gamma-lactam HDAC inhibitors were evaluated and compound 10f had potent anticancer activity and high oral bioavailability.
Journal of Medicinal Chemistry 11/2012; · 4.80 Impact Factor
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ABSTRACT: Artemisinin is a well-known anti-malarial drug and has been shown to inhibit nitric oxide (NO) production. In this study, we investigated the effect of artemisinin on lipopolysaccharide (LPS)-induced production of IFN-β and characterized the potential relationship between artemisinin-mediated inhibition of IFN-β and NO production. Artemisinin suppressed IFN-β production and mRNA expression in a dose-dependent manner in LPS-stimulated RAW 264.7 cells. LPS-induced phosphorylation of signal transducer and activator of transcription-1 (STAT-1) was also inhibited by artemisinin treatment in RAW 264.7 cells. In addition, artemisinin suppressed LPS-induced production of NO in RAW 264.7 cells. Further study demonstrated that artemisinin-mediated inhibition of NO production and STAT-1 phosphorylation was reversed by addition of exogenous IFN-β. Moreover, artemisinin does not affect IFN-β-induced STAT-1 phosphorylation in RAW 264.7 cells. Collectively, these results suggest that the inhibition of IFN-β production by artemisinin and concomitant attenuation of STAT-1 activation might be involved in artemisinin-mediated inhibition of NO production in macrophages.
International immunopharmacology 10/2012; 14(4):580-584. · 2.21 Impact Factor
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ABSTRACT: Burst firing is a feature of many neuroendocrine cell types including the hypothalamic gonadotropin-releasing hormone (GnRH) neurons that control fertility. The role of intrinsic and extrinsic influences in generating GnRH neuron burst firing is presently unclear. We questioned here the role of fast amino acid transmission in burst firing by examining the effects of receptor antagonists on bursting displayed by green fluorescent protein GnRH neurons in the sagittal brain slice prepared from adult male mice. The blockade of ionotropic 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors with a cocktail of CNQX and AP5 was found to have no effects on burst firing in GnRH neurons. The frequency of bursts, dynamics of individual bursts, or percentage of firing clustered in bursts was not altered. Similarly, GABA(A) receptor antagonists bicuculline and picrotoxin had no effects upon burst firing in GnRH neurons. To examine the importance of both glutamate and GABA ionotropic signaling, a cocktail including picrotoxin, CNQX and AP5 was used but, again, this was found to have no effects on GnRH neuron burst firing. To further question the impact of endogenous amino acid release on burst firing, electrical activation of anteroventral periventricular nuclei GABA/glutamate inputs to GnRH neurons were undertaken and found to have no impact on burst firing. Together, these observations indicate that bursting in GnRH neurons is not dependent upon acute ionotropic GABA and glutamate signaling and suggest that extrinsic inputs to GnRH neurons acting through AMPA, NMDA and GABA(A) receptors are unlikely to be required for burst initiation in these cells. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.
Journal of Neuroendocrinology 07/2012; · 3.14 Impact Factor
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Moo Rim Kang,
Song-Kyu Park,
Chang Woo Lee,
Ig Jun Cho,
Yeong Nang Jo,
Jeong Wook Yang,
Jin-Ah Kim,
Jieun Yun,
Ki Hoon Lee,
Hyun Ju Kwon,
Byung Woo Kim, Kiho Lee,
Jong Soon Kang,
Hwan Mook Kim
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ABSTRACT: Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose- and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase‑3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation.
Oncology Reports 05/2012; 27(5):1407-12. · 1.84 Impact Factor
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ABSTRACT: Histone deacetylases (HDACs) are involved in post-translational modification and epi-genetic expression, and have been the intriguing targets for treatment of cancer. In previous study, we reported synthesis and the biological preliminary results of γ-lactam based HDAC inhibitors. Based on the previous results, smaller γ-lactam core HDAC inhibitors are more active than the corresponding series of larger δ-lactam based analogues and the hydrophobic and bulky cap groups are required for better potency which decreased microsomal stability. Thus, γ-lactam analogues with methoxy, trifluoromethyl groups of ortho-, meta-, para-positions of cap group were prepared and evaluated their biological potency. Among them, trifluoromethyl analogues, which have larger lipophilicity, showed better HDAC inhibitory activity than other analogues. In overall, lipophilicity leads to increase hydrophobic interaction between surface of HDAC active site and HDAC inhibitor, improves HDAC inhibitory activity.
Bioorganic & medicinal chemistry letters 04/2012; 22(12):4189-92. · 2.65 Impact Factor
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Bit Lee,
Jae-Hwan Kwak,
Shin-Won Huang,
Jae-Yong Jang,
Sanglae Lim,
Young-Shin Kwak, Kiho Lee,
Hyung Sook Kim,
Sang-Bae Han,
Jin-Tae Hong,
Heesoon Lee,
Sukgil Song,
Seung-Yong Seo,
Jae-Kyung Jung
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ABSTRACT: A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure-activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was oriented towards modification of the potential metabolic soft spots (e.g., phenol and olefin) or by altering the polar surface area via incorporating heterocycles such as isoxazole and triazole. Most of all exhibited the inhibitory effects on COX-2 and PGF(1) production but not macrophage NO production. Especially, aryl carbamates 10 and 11 exhibited more potent inhibitory activity against COX-2 and PGF(1) production.
Bioorganic & medicinal chemistry 03/2012; 20(9):2860-8. · 2.82 Impact Factor
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Moo Rim Kang,
Jong Soon Kang,
Jeong Wook Yang,
Bo Geun Kim,
Jin-Ah Kim,
Yeong Nang Jo, Kiho Lee,
Chang Woo Lee,
Ki Hoon Lee,
Jieun Yun,
Hwan Mook Kim,
Gyoonhee Han,
Jong Seong Kang,
Song-Kyu Park
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ABSTRACT: The aim of this study was to investigate the anti-tumor activity of KBH-A42, a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 was shown to significantly suppress the proliferation of all 14 human cancer cell lines tested. Among these cell lines, the human leukemia cell line K562 was the most sensitive, whereas the UM-UC-3 bladder cancer cells were the least sensitive. Additionally, in a human tumor xenograft model using Balb/c nude mice, KBH-A42 was shown to significantly inhibit the growth of K562 tumors, although it only slightly inhibited the growth of UM-UC-3 tumors. The results of flow cytometry analysis and caspase 3/7 activation assays showed that the growth inhibition of K562 cells by KBH-A42 was mediated, at least in part, by the induction of apoptosis, but its growth inhibitory effects on UM-UC-3 cells were not mediated by apoptotic induction. In an effort to gain insight into the mechanism by which KBH-A42 inhibits the growth of cancer cells, a microarray analysis was conducted. Four genes were selected from the genes that were down-regulated or up-regulated by KBH-A42 and confirmed via reverse transcription-polymerase chain reaction as follows: Harakiri (HRK), tumor necrosis factor receptor superfamily, member 10b (TNFRSF10B), PYD and CARD domain containing protein gene (PYCARD) and tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Collectively, the in vitro and in vivo results suggested that KBH-A42 exhibits anti-cancer activity, but various types of cells may be regulated differentially by KBH-A42.
Oncology letters 01/2012; 3(1):113-118. · 0.11 Impact Factor
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ABSTRACT: The gonadotropin-releasing hormone (GnRH) neurons are the key output cells of a complex neuronal network controlling fertility in mammals. To examine calcium homeostasis in postnatal GnRH neurons, we generated a transgenic mouse line in which the genetically encodable calcium indicator ratiometric Pericam (rPericam) was targeted to the GnRH neurons. This mouse model enabled real-time imaging of calcium concentrations in GnRH neurons in the acute brain slice preparation. Investigations in GnRH-rPericam mice revealed that GnRH neurons exhibited spontaneous, long-duration (~8s) calcium transients. Dual electrical-calcium recordings revealed that the calcium transients were correlated perfectly with burst firing in GnRH neurons and that calcium transients in GnRH neurons regulated two calcium-activated potassium channels that, in turn, determined burst firing dynamics in these cells. Curiously, the occurrence of calcium transients in GnRH neurons across puberty or through the estrous cycle did not correlate well with the assumption that GnRH neuron burst firing was contributory to changing patterns of pulsatile GnRH release at these times. The GnRH-rPericam mouse was also valuable in determining differential mechanisms of GABA and glutamate control of calcium levels in GnRH neurons as well as effects of G-protein-coupled receptors for GnRH and kisspeptin. The simultaneous measurement of calcium levels in multiple GnRH neurons was hampered by variable rPericam fluorescence in different GnRH neurons. Nevertheless, in the multiple recordings that were achieved no evidence was found for synchronous calcium transients. Together, these observations show the great utility of transgenic targeting strategies for investigating the roles of calcium with specified neuronal cell types.
Cell calcium 12/2011; 51(3-4):267-76. · 4.29 Impact Factor
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Bo-Kyung Kim,
Dong-Myung Kim,
Kyung-Sook Chung,
Song-Kyu Park,
Shin-Jung Choi,
Alexander Song, Kiho Lee,
Chang-Woo Lee,
Kyung-Bin Song,
Gyoonhee Han,
Julian Simon,
Hwan Mook Kim,
Misun Won
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ABSTRACT: We describe here a piperazine alkyl derivative, NSC126188, which induced apoptosis of HeLa cells by upregulating RhoB expression. NSC126188 caused multi-septation of fission yeast and hypersensitized a ∆rho3 mutant, which implicates the involvement of functional human homolog RhoB. The treatment of cells with NSC126188 induced apoptosis and a dramatic increase in RhoB expression. In addition, RhoB knockdown using siRNA rescued cells from apoptosis, indicating a crucial role of RhoB in NSC126188-induced apoptosis. In a reporter assay using luciferase and EGFP under control of the RhoB promoter, NSC126188 increased both luciferase activity and the expression of EGFP, implicating transcriptional activation of RhoB by NSC126188. Furthermore, NSC126188 demonstrated in vivo anti-tumor activity, inhibiting tumor growth by 66.8% in a nude mouse xenograft using PC-3 human prostate cancer cells. These results suggest that NSC126188 is a potential lead compound and that upregulation of RhoB is associated with NSC126188-induced apoptosis.
Investigational New Drugs 10/2011; 29(5):853-60. · 3.36 Impact Factor
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Jong Soon Kang,
Won Kyung Lee,
Chang Woo Lee,
Won Kee Yoon,
Nayang Kim,
Sang-Ki Park,
Heon-Sik Lee,
Hyoung Kook Park,
Sang-Bae Han,
Jieun Yun, Kiho Lee,
Ki Hoon Lee,
Song-Kyu Park,
Hwan Mook Kim
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ABSTRACT: In the present study, we examined the effect of a mixture of dietary components, including red grape extract, soy isoflavone and L-carnitine (RISC), on obesity. RISC substantially inhibited high-fat diet (HFD)-induced increase in body weight in a dose-dependent manner in C57BL/6 mice. The amount of subcutaneous and mesenteric fat was also significantly decreased by RISC treatment in HFD-fed C57BL/6 mice, whereas epididymal fat was not affected. Moreover, HFD-induced plasma leptin levels were down-regulated by RISC treatment. In these mice, RISC treatment significantly increased the plasma level of high density lipoprotein cholesterol without affecting the level of low density lipoprotein cholesterol and triglycerides. In addition, HFD-induced increase in liver weight and lipid accumulation in liver was significantly suppressed by RISC treatment in C57BL/6mice. Plasma level of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase was also inhibited by RISC treatment. These results demonstrate that RISC suppresses HFD-induced obesity and suggest that RISC supplementation might be a promising adjuvant therapy for the treatment of obesity and its complications, such as cardiovascular and non-alcoholic fatty liver diseases.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 09/2011; 49(9):2453-8. · 2.99 Impact Factor
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ABSTRACT: We synthesized novel aliphatic amido-quaternary ammonium salts in an effort to discover anticancer agents that increase Ras homolog gene family, member B, (RhoB) levels. These compounds exert anti-proliferative activities against several human cancer cell types. Seventeen compounds, varying in aliphatic carbon chain length and N-substituents, were synthesized and their biological activities were evaluated. Of these 17 compounds, compound 3i emerged as the most promising anticancer compound by promoting apoptosis through the RhoB mediated pathway. Potent biological activities observed for these novel aliphatic amido-quaternary ammonium salt analogues support their potential as anticancer, chemotherapeutic agents.Graphical abstractA series of aliphatic amido-quaternary ammonium salts were designated, synthesized and evaluated for anticancer chemotherapy. Compound 3i was emerged as the most promising anticancer compound promoting apoptosis through RhoB mediated pathway.Highlights►17 Novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated.►3c, 3f, and 3i showed better in vitro activity than the lead compound.►3i emerged as the most promising agent through RhoB mediated pathway.►Anti-proliferative activity is significantly related to the RhoB activation.►These compounds could be promising anticancer agents for anticancer chemotherapy.
European journal of medicinal chemistry 07/2011; 46(7):2861-2866. · 3.27 Impact Factor
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ABSTRACT: It is known that gender differences in drug metabolism are largely attributed to changes in sex and growth hormones. Serum concentrations of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone change markedly during the human menstrual cycle and the rat estrous cycle. However, little information is available regarding the effects of the human menstrual cycle or the rat estrous cycle on expression and activity of cytochrome P450 (CYP) isoforms. The present study was carried out to determine the expression and activity of CYP-dependent drug-metabolizing enzymes in the liver and ovary during the estrous cycle. The expression and activity of microsomal CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2B1, CYP2C11, CYP2C12, CYP2E1, CYP3A1, CYP3A2, and CYP4A), cytochrome b(5) and NADPH-dependent CYP reductase in the liver and ovary were measured in female rats in diestrus and proestrus. Our results indicated that hepatic and ovarian expression and activity of CYP isoforms, cytochrome b(5), and NADPH-dependent CYP reductase were not different between diestrus and proestrus, although serum estradiol concentration and uterus weight were markedly increased in the proestrus phase. These results suggest that the cytochrome P450-dependent system is not sensitive to changes in the estrous cycle, and further studies are warranted to determine the effects of the estrous cycle on in vivo metabolism of xenobiotics.
Archive für Toxikologie 06/2011; 86(1):75-85. · 4.67 Impact Factor
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ABSTRACT: This study was performed to elucidate the anticancer mechanism of a lipid-soluble ginseng extract (LSGE) by analyzing induction of apoptosis and arrest of cell cycle progression using the NCI-H460 human lung cancer cell line. Proliferation of NCI-H460 cells was potently inhibited by LSGE in a dose-dependent manner. The cell cycle arrest at the G0/G1 phase in NCI-H460 cells was induced by LSGE. The percentage of G0/G1 phase cells significantly increased, while that of S phase cells decreased after treatment with LSGE. The expression levels of cyclin-dependent kinase2 (CDK2), CDK4, CDK6, cyclin D3 and cyclin E related to G0/G1 cells progression were also altered by LSGE. In addition, LSGE-induced cell death occurred through apoptosis, which was accompanied by increasing the activity of caspases including caspase-8, caspase-9 and caspase-3. Consistent with enhancement of caspase activity, LSGE increased protein levels of cleaved caspase-3, caspase-8, caspase-9, and poly-ADP-ribose polymerase (PARP). These apoptotic effects of LSGE were inhibited by the pan-caspase inhibitor Z-VAD-fmk. These findings indicate that LSGE inhibits NCI-H460 human lung cancer cell growth by cell cycle arrest at the G0/G1 phase and induction of caspase-mediated apoptosis.
Materiae Vegetabiles 05/2011; 66(2):101-6. · 2.51 Impact Factor
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Jong Soon Kang,
Won Kyung Lee,
Won Kee Yoon,
Nayang Kim,
Sang-Ki Park,
Hyoung Kook Park,
Sun Yung Ly,
Sang-Bae Han,
Jieun Yun,
Chang Woo Lee, Kiho Lee,
Ki Hoon Lee,
Song-Kyu Park,
Hwan Mook Kim
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ABSTRACT: To develop a therapeutic agent for obesity-related metabolic disorders, a mixture of dietary components was prepared, including grape extract, green tea extract and l-carnitine (RGTC), and its effects on obesity, hyperlipidemia and non-alcoholic fatty liver disease examined. The RGTC dramatically inhibited the high-fat diet (HFD)-induced increase in body weight and fat in C57BL/6 mice, whereas food consumption was not affected by RGTC treatment. The RGTC also concentration-dependently suppressed the HFD-induced increase in plasma lipids, such as low-density lipoprotein cholesterol and triglycerides. In addition, increases in liver weight and liver steatosis were returned to normal by RGTC treatment in HFD-fed C57BL/6 mice. The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were also significantly down-regulated by RGTC treatment. These results suggest that RGTC suppressed HFD-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease, suggesting that RGTC supplementation might be a promising adjuvant therapy for the treatment of these metabolic disorders.
Phytotherapy Research 04/2011; 25(12):1789-95. · 2.09 Impact Factor
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ABSTRACT: Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.
Bioorganic & medicinal chemistry letters 02/2011; 21(4):1218-21. · 2.65 Impact Factor
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ABSTRACT: GnRH neurons are hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH) which stimulates the release of gonadotropins, one of the crucial hormones for sexual development, fertility and maturation. A mathematical model was built to help elucidate the mechanisms underlying electrical bursting and synchronous [Ca²(+)] transients in GnRH neurons (Lee et al., 2010). The model predicted that bursting in GnRH neurons (at least of the short-bursting type) requires the existence of a [Ca²(+)]-dependent slow after-hyperpolarisation current (sI(AHP-UCL)), and this predicted current was found experimentally. GnRH behaviour under a wide range of conditions (inhibition of Na(+) channels, IP₃ receptors, [Ca²(+)]-dependent K(+) channels, or Ca²(+) pumps, or in the presence of zero extracellular [Ca²(+)]) is successfully reproduced by the model. In this paper, a simplified version of the previous model, with the same qualitative behaviour, is constructed and studied using timescale separation techniques and bifurcation analysis.
Journal of Theoretical Biology 02/2011; 276(1):22-34. · 2.21 Impact Factor
