Suigen, South Korea
Suigen, South Korea

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Bae J.H.,Korea University | Kim J.W.,Korea University | Kweon G.R.,Chungnam National University | Park M.G.,Mazence Inc. R and nter | And 3 more authors.
Journal of Sexual Medicine | Year: 2011

Introduction. Adenosine monophosphate-activated protein kinase (AMPK) activation is suggested to relax smooth muscle by endothelial nitric oxide synthase (eNOS) phosphorylation. Aim. To assess the mechanism and effect of a novel AMPK activator, beta-lapachone, upon cavernosal smooth muscle relaxation and the therapeutic potential for erectile dysfunction. Methods. Human umbilical vein endothelial cells (HUVECs) were treated with beta-lapachone. The lysates were blotted with specific antibodies for phosphorylated AMPK (p-AMPK) or phosphorylated eNOS (p-eNOS). The membranes were re-blotted for total AMP total eNOS, or beta-actin. The eNOS activity was measured by the conversion of L-14C-arginine to L-14C-citrulline in HUVECs lysates. In a separated experiment, cavernosal strips from New Zealand white rabbits were harvested for organ bath study and the relaxation effect of beta-lapachone on phenylephrine-induced contracted strips was evaluated and compared with sodium nitroprusside, zaprinast, metformin, and aminoimidazole carboxamide ribonucleotide (AICAR). Methylene blue and L-NAME were used to assess the inhibition of cyclic guanosine monophosphate/nitric oxide pathway. Zinc-protoporphyrin-IX (ZnPP) was also used to investigate the contribution of mevalonate pathway. Main Outcome Measures. The expression of p-AMPK, p-eNOS, AMPK and eNOS induced by beta-lapachone in HUVECs study and the percent relaxation of cavernosal tissue in organ bath study. Results. Beta-lapachone clearly induced AMPK phosphorylation and, as a consequence, eNOS phosphorylation in HUVECs. Beta-lapachone-induced upregulation of eNOS activity was also observed in HUVECs and steadily increased up to 1 hour. In organ bath study, beta-lapachone significantly relaxed the phenylephrine pretreated strips in a dose-dependent manner. This relaxation effect was not totally blocked by methylene blue or L-NAME. After removing endothelium, the relaxation was totally blocked by ZnPP. Conclusions. A novel AMPK activator, beta-lapachone has a strong relaxation effect on precontracted cavernosal smooth muscle strips in the rabbit. And phosphorylation of AMPK and eNOS strongly related to the action of beta-lapachone. Mevalonate pathway also might be considered as a suggestive mechanism. © 2010 International Society for Sexual Medicine.

Shin S.,Chungnam National University | Park J.,Chungnam National University | Li Y.,Chungnam National University | Li Y.,PLA Fourth Military Medical University | And 11 more authors.
Cellular Signalling | Year: 2014

Alcohol-induced liver injury is the most common liver disease in which fatty acid metabolism is altered. It is thought that altered NAD+/NADH redox potential by alcohol in the liver causes fatty liver by inhibiting fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. β-Lapachone (βL), a naturally occurring quinone, has been shown to stimulate fatty acid oxidation in an obese mouse model by activating adenosine monophosphate-activated protein kinase (AMPK). In this report, we clearly show that βL reduced alcohol-induced hepatic steatosis and induced fatty acid oxidizing capacity in ethanol-fed rats. βL treatment markedly decreased hepatic lipids while serum levels of lipids and lipoproteins were increased in rats fed ethanol-containing liquid diets with βL administration. Furthermore, inhibition of lipolysis, enhancement of lipid mobilization to mitochondria and upregulation of mitochondrial β-oxidation activity in the soleus muscle were observed in ethanol/βL-treated animals compared to the ethanol-fed rats. In addition, the activity of alcohol dehydrogenase, but not aldehyde dehydrogenase, was significantly increased in rats fed βL diets. βL-mediated modulation of NAD+/NADH ratio led to the activation of AMPK signaling in these animals. Conclusion: Our results suggest that improvement of fatty liver by βL administration is mediated by the upregulation of apoB100 synthesis and lipid mobilization from the liver as well as the direct involvement of βL on NAD+/NADH ratio changes, resulting in the activation of AMPK signaling and PPARα-mediated β-oxidation. Therefore, βL-mediated alteration of NAD+/NADH redox potential may be of potential therapeutic benefit in the clinical setting. © 2013 Elsevier Inc.

Cha H.-N.,Yeungnam University | Kim Y.-W.,Yeungnam University | Kim J.-Y.,Yeungnam University | Kim Y.-D.,Yeungnam University | And 3 more authors.
Experimental Gerontology | Year: 2010

Inducible nitric oxide synthase (iNOS) is involved in obesity-induced insulin resistance. Since aging is accompanied by increased iNOS expression, the effect of iNOS gene deletion on aging-associated insulin resistance was investigated in 7-month-old (adult) and 22-month-old (old) iNOS knockout and wild-type mice using the hyperinsulinemic-euglycemic clamp. While body weight and fat mass were increased, muscle mass was reduced with aging in wild-type mice. However, body composition was not changed with aging in iNOS knockout mice due to increased locomotor activity. NO metabolites in plasma, and protein levels of iNOS and nitrotyrosine in skeletal muscle increased with aging in wild-type mice. Deletion of iNOS gene attenuated NO metabolites and nitrotyrosine with aging in iNOS knockout mice. Glucose uptake in whole body and skeletal muscle was reduced with aging in both wild-type and iNOS knockout mice and there was no difference between two groups. Plasma level of tumor necrosis factor-α and gene expression of proinflammatory cytokines in peripheral tissues were increased with aging in both groups, and that was more heightened in iNOS knockout mice. These results suggest that lack of iNOS does not prevent aging-associated insulin resistance in mice and heightened production of proinflammatory cytokines may be involved. © 2010 Elsevier Inc.

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