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Yang W.S.,University of Ulsan | Chang J.W.,University of Ulsan | Han N.J.,Asan Institute for Life science | Park S.-K.,University of Ulsan
Free Radical Biology and Medicine | Year: 2011

Recombinant human erythropoietin (r-HuEPO) is widely used to correct anemia in end-stage renal disease patients, who commonly suffer from atherosclerosis. Endothelin-1 (ET-1) has been implicated in the pathogenesis of atherosclerosis. Here, we tested whether darbepoetin alfa, a hypersialylated analogue of r-HuEPO, regulates tumor necrosis factor-α (TNF-α)-induced ET-1 production in human aortic endothelial cells, and sought to identify the signal pathways involved. Darbepoetin alfa attenuated TNF-α-induced ET-1 production. It also diminished TNF-α-induced reactive oxygen species (ROS) accumulation and subsequent activation of c-Jun NH2-terminal kinase (JNK), which regulates the DNA-binding activities of both AP-1 and NF-κB required for ET-1 gene transcription. Like a JNK inhibitor, darbepoetin alfa did not affect IκBα degradation or p65 nuclear translocation, but did inhibit mitogen- and stress-activated protein kinase 1 (MSK1) activation and attenuated p65 phosphorylation (serine 276), effects that may account for the reduction in NF-κB DNA-binding activity. Desialylation completely abolished darbepoetin alfa's inhibitory effects on TNF-α-induced ROS accumulation, MSK1 activation, and ET-1 gene expression, without affecting its stimulation of STAT5 activity. These data demonstrate that darbepoetin alfa suppresses TNF-α-induced ET-1 production through its antioxidant action and suggest that the sialic acid residues of darbepoetin alfa are essential for its antioxidant effect, possibly by scavenging ROS. © 2011 Elsevier Inc. All rights reserved.

Lee S.-Y.,Hallym University | Kang M.-J.,Asan Institute for Life science | Kwon J.-W.,Seoul National University | Park K.-S.,Presbyterian Medical Center | Hong S.-J.,University of Ulsan
Allergy, Asthma and Immunology Research | Year: 2013

Breastfeeding is widely recommended to reduce risk of sensitization, eczema and asthma. However, the role of breastfeeding in prevention of allergic diseases is uncertain. We aimed to investigate whether the relationship between breastfeeding and sensitization to aeroallergens is modified by cluster of differentiation 14 (CD14) genotype. This study included 1,828 school children aged 9-12. We administered a detailed questionnaire and genotyped the CD14C-159T polymorphism. Skin prick tests for 12 aeroallergens were performed. School children who had been breastfed were less likely sensitized to aeroallergens (adjusted odds ratio [aOR] 0.712, 95% confidence interval [CI]: 0.555-0.914). There was no significant association between CD14C-159T genotype and atopy. Breastfeeding was associated with a decreased risk of atopic sensitization in children with CT/CC genotype (aOR 0.667, 95% CI: 0.463-0.960). Our data might identify the gene-environment interaction between the CD14C-159T polymorphism and breastfeeding in relation to aeroallergen sensitization. © The Korean Academy of Asthma, Allergy and Clinical Immunology. The Korean Academy of Pediatric Allergy and Respiratory Disease.

Rho J.K.,Asan Institute for Life science | Kim T.W.,University of Ulsan | Choi E.K.,University of Ulsan | Yoon S.-J.,Neopharm | And 5 more authors.
Cancer Research | Year: 2014

In non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets bothMETand AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement. © 2014 American Association for Cancer Research.

Seo H.,University of Ulsan | Lim K.H.,Asan Institute for Life science | Choi J.-H.,University of Ulsan | Jeong S.-M.,University of Ulsan
International Journal of Developmental Neuroscience | Year: 2013

The aim of this study was to evaluate the effect of ischemic and hypoxic preconditioning on hypoxia-ischemia (HI) in the neonatal rat. Seven-day-old Sprague-Dawley rats were divided into four groups: control, sham, ischemic preconditioning, and hypoxic preconditioning. Ischemic preconditioning with a 10-min occlusion of the right carotid artery and hypoxic preconditioning with 4-h of hypoxia (8% oxygen) were performed 24-h before HI. For HI, all rats underwent right carotid artery ligature, followed by 2.5-h of hypoxia. Proton magnetic resonance spectroscopy (1H MRS) and TUNEL staining were evaluated at 1 and 7 days after HI. At 2 weeks after HI, all rats were sacrificed for morphological analysis. The lipid (Lip), N-acetyl aspartate (NAA), creatine (Cr), and choline-ratios were calculated and compared with TUNEL staining and brain morphologies. Both the ischemic and hypoxic preconditioning groups showed lower Lip/NAA and Lip/Cr ratios and morphological scores, and fewer TUNEL-positive cells than the control and sham groups (P<0.05). There were no significant differences between the two preconditioning groups. In addition, the ratios correlated with the TUNEL staining and the degrees of morphological changes in all of the groups (P<0.05). These results suggest that ischemic and hypoxic preconditioning in neonatal rats with HI similarly attenuate brain injury. Moreover, Lip/NAA and Lip/Cr ratios may be used as markers for assessing the extent of brain damage. © 2013 ISDN.

Lee E.-J.,Sookmyung Womens University | Lee E.-J.,Asan Institute for Life science | Oh S.-Y.,Sookmyung Womens University | Sung M.-K.,Sookmyung Womens University
Food and Chemical Toxicology | Year: 2012

This study investigated the inhibitory effect of luteolin on MDA-MB-231 estrogen receptor (ER) negative breast tumor growth both in vitro and in vivo. Study results showed that luteolin suppresses 3H thymidine incorporation indicating cell growth inhibition, and this was accompanied by cell cycle arrest at the G2/M and S stages and apoptotic activity. Further analyses showed that luteolin exhibited cell cycle arrest and apoptotic activity by decreasing AKT, PLK1, cyclin B1, cyclin A, CDC2, CDK2, and Bcl-xL expression and increasing p21 and Bax expression. Underlying mechanisms of action exerted by luteolin included the down-regulation. EGFR mRNA expression followed by the inhibition of EGF-induced MAPK activation, including the phosphorylation of ERK, p38 and AKT. Luteolin-supplementation at 0.01% or 0.05% significantly reduced tumor burden in nude mice inoculated with MDA-MB-231 cells. In conclusion, luteolin effectively suppresses MDA-MB-231 ER-negative breast cancer cell growth, and its anticancer activity may be partly derived from inhibitory effects on EGFR-mediated cell survival. © 2012 Elsevier Ltd.

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