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Suigen, South Korea

Kim Y.-H.,Korea Research Institute of Bioscience and Biotechnology | Hwang J.H.,Korea Research Institute of Bioscience and Biotechnology | Noh J.-R.,Korea Research Institute of Bioscience and Biotechnology | Gang G.-T.,Korea Research Institute of Bioscience and Biotechnology | And 6 more authors.
Cardiovascular Research | Year: 2011

Aims Hypertension is one of the most common human diseases worldwide, and extensive research efforts are focused upon the identification and utilizing of novel therapeutic drug targets. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important regulator of blood pressure (BP). β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase (NQO1), increases the cellular NAD +/NADH ratio via the activation of NQO1. In this study, we evaluated whether βL-induced activation of NQO1 modulates BP in an animal model of hypertension. Methods and results Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of βL and its mode of action. βL treatment stimulated endothelium-dependent vascular relaxation in response to acetylcholine in aorta of SHR and dramatically lowered BP in SHR, but the hypotensive effect was completely blocked by eNOS inhibition withnitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in βL-treated SHR. In vitro studies revealed that βL treatment elevated the intracellular NAD +/NADH ratio and concentration of free Ca 2+ ([Ca 2+]i), and resulted in Akt/AMP-activated protein kinase/eNOS activation. These effects were abolished by NQO1 siRNA and [Ca 2+]i inhibition through a ryanodine receptor blockade. Conclusion This study is the first to demonstrate that NQO1 activation has a hypotensive effect mediated by eNOS activation via cellular NAD +/NADH ratio modulation in an animal model. These results provide strong evidence suggesting NQO1 might be a new therapeutic target for hypertension. © The Author 2011. Source


Shin B.H.,Gwangju Institute of Science and Technology | Lim Y.,Gwangju Institute of Science and Technology | Oh H.J.,Gwangju Institute of Science and Technology | Park S.M.,Gwangju Institute of Science and Technology | And 6 more authors.
PLoS ONE | Year: 2013

Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington's disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). β-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, β-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. β-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by β-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of β-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, β-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that β-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, β-lap provides a novel therapeutic opportunity for the treatment of HD. © 2013 Shin et al. Source


Park I.-J.,Kyung Hee University | Kim M.-J.,Kyung Hee University | Park O.J.,Hannam University | Park M.G.,Mazence Inc | And 4 more authors.
Cancer Letters | Year: 2010

Fas/APO-1/CD95, a member of the tumor necrosis factor (TNF) receptor superfamily, is a potential anti-cancer factor as it can induce apoptosis in tumor cells. However, despite the fact that many cancer cells express Fas on the membrane, some tumors such as prostate cancer display resistance to Fas-induced apoptosis. In these cases, combination therapy using chemotherapeutic agents and Fas may be more suitable than therapy using Fas alone. In the present study, we demonstrate that the apoptosis inhibitory protein, Bcl-2, was highly expressed in response to Fas in DU145 prostate cancer cells, thereby conferring resistance to apoptosis. We have screened a number of naturally occurring products that may overcome this resistance. Here we report that cryptotanshinone, the major tanshinone isolated from Salvia miltiorrhiza Bunge, can suppress Bcl-2 expression and augment Fas sensitivity in DU145 cells. We further show that JNK and p38 MAPK act upstream of Bcl-2 expression in Fas-treated DU145 cells, and that cryptotanshinone significantly blocked activation of these kinases. Moreover, cryptotanshinone sensitized several tumor cells to a broad range of anti-cancer agents. Collectively, our data suggest that cryptotanshinone has therapeutic potential in the treatment of human prostate cancer. © 2010 Elsevier Ireland Ltd. Source


Park M.-G.,Kyonggi University | Park M.-G.,Mazence Inc | Ha T.-Y.,Korea Food Research Institute | Shin K.-S.,Kyonggi University
Journal of the Korean Society of Food Science and Nutrition | Year: 2011

Aspartic acid chelated iron (Asp-Fe) was synthesized by a new method using calcium carbonate, aspartic acid, and ferrous sulfate. This study was carried out to investigate the bioavailability of Asp-Fe in iron-deficient rats. We divided the rats into four experimental groups. The first was the normal diet control group, or NC. The second was the no treated control group of iron-deficient (ID) rats, or ID+C. The third was the heme-iron (heme-Fe) treated group of ID rats, ID+heme-Fe. And the fourth was the Asp-Fe treated group of ID rats, or ID+Asp-Fe. There were no differences among any of the experimental groups in diet consumption, change of body weight, or the weight of the livers, kidneys, or spleens. After 7 days of feeding, the iron content in the sera of the ID+Asp-Fe group (175.2 μg/dL) and the ID+heme-Fe group (140.8 μg/dL) were significantly higher than that of the ID-C group (96.1 μg/dL). The total iron binding capacity (TIBC) of the ID+Asp-Fe group (735.4 μg/dL) was significantly normalized compared to the ID+C group (841.9 μg/dL) or ID+heme-Fe group (824.6 μg/dL). The hematocrit level of the ID+Asp-Fe group was increased to normal levels, but there was no statistical difference among ID groups. The absorption ratio of heme-Fe was 21.3% and that of Asp-Fe was 50.2%, which indicates a 2.3 times higher ratio in comparison with heme iron. With the above results we found that Asp-Fe seems to be an efficient form of iron to supply iron deficient rats in order to cure them of anemia. Thus, these findings suggest that aspartic acid chelated iron has the potential to serve as a functional food related to iron metabolism. Source


Lee J.-W.,Seoul National University | Choe S.S.,Seoul National University | Jang H.,Seoul National University | Kim J.,Ewha Womans University | And 11 more authors.
Journal of Lipid Research | Year: 2012

In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)α in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source

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