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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.


Park C.S.,Inje University | Bang B.-R.,Asan Institute for Life Science | Kwon H.-S.,University of Ulsan | Moon K.-A.,Asan Institute for Life Science | And 4 more authors.
Biochemical Pharmacology | Year: 2012

Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4- carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma. © 2012 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.


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.


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.


Kim M.,Yeshiva University | Kim M.,University of Ulsan | Kim M.,Asan Institute for Life science | Kim M.,Korea University | And 4 more authors.
Mechanisms of Ageing and Development | Year: 2012

Mesenchymal stem cells (MSC) have attracted considerable attention in the fields of cell and gene therapy due to their intrinsic ability to differentiate into multiple lineages. The various therapeutic applications involving MSC require initial expansion and/or differentiation . in vitro prior to clinical use. However, serial passages of MSC in culture lead to decreased differentiation potential and stem cell characteristics, eventually inducing cellular aging which will limit the success of cell-based therapeutic interventions. Here we review the age-related changes that occur in MSC with a special focus on the shift of differentiation potential from osteogenic to adipogenic lineage during the MSC aging processes and how aging causes this preferential shift by oxidative stress and/or energy metabolism defect. Oxidative stress-related signals and some microRNAs affect the differentiation potential shift of MSC by directly targeting key regulatory factors such as Runx-2 or PPAR-γ, and energy metabolism pathway is involved as well. All information described here including transcription factors, microRNAs and FoxOs could be used towards development of treatment regimens for age-related bone diseases and related defects based on mutually exclusive lineage fate determination of MSC. © 2012 Elsevier Ireland Ltd.


Kim Y.-G.,University of Ulsan | Lee C.-K.,University of Ulsan | Oh J.S.,University of Ulsan | Kim S.-H.,Konkuk University | And 2 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. Interleukin-32 (IL-32) induces various inflammatory molecules in human monocytes and differentiation of monocytes into macrophage-like cells. This study was undertaken to evaluate the effects of IL-32γ, the most biologically active isoform, on the differentiation and activation of osteoclasts. Methods. CD14+ monocytes were obtained from healthy volunteers, and samples of synovial tissue and synovial fluid were obtained from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). The concentration and expression levels of IL-32γ in RA and OA samples were evaluated by enzyme-linked immunosorbent assay and immunoblotting, respectively. To examine the osteoclastogenic effects and functional activities, isolated monocytes were treated with either IL-32γ or IL-17 in the presence or absence of soluble RANKL (sRANKL) on a culture system and on Osteologic disks. The expression of RANKL and osteoprotegerin (OPG) messenger RNA (mRNA) in RA fibroblast-like synoviocytes (FLS) was measured using reverse transcription-polymerase chain reaction (PCR) and real-time PCR. Results. The concentration and expression levels of IL-32γ were higher in the RA samples than in the OA samples. Upon costimulation with sRANKL, the osteoclast count and resorbed area increased more significantly in the IL-32γ- stimulated cultures than in those stimulated with IL-17. In the IL-32γ-treated group without sRANKL stimulation, osteoclasts were differentiated, but the cells displayed low resorption activity. In RA FLS, RANKL mRNA expression increased in the presence of both IL-32γ and IL-17. However, transcription of OPG decreased following IL-32γ stimulation, resulting in a significant increase in the RANKL:OPG ratio. Conclusion. Our results suggest that IL-32γ is a potent mediator of active osteoclast generation in the presence of sRANKL. Moreover, this novel cytokine creates more favorable conditions for osteoclastogenesis in the RA joint by increasing the RANKL:OPG ratio in FLS. © 2010, American College of Rheumatology.


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.


Cheng H.M.,Royal Perth Hospital | Kim S.,Kangwon National University | Park G.-H.,Hallym University | Chang S.E.,University of Ulsan | And 5 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background The effect of vitamin D on allergic conditions is unclear. In particular, large-scale, population-based studies examining this relationship in adult Asian populations are lacking. Objective To evaluate the association between serum vitamin D levels and allergic conditions in the general adult Korean population. Methods A cross-sectional study was performed by using data collected from 15,212 individuals 19 years or older who participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2010. The confounder-adjusted mean serum 25-hydroxyvitamin D (25[OH]D) levels of participants with and without allergic conditions (including atopic dermatitis, asthma, allergic rhinitis, and increased total and allergen-specific serum IgE) were compared by using multiple linear regression analyses. Multiple logistic regression analyses with confounder adjustment estimated the odds ratios (ORs) for developing each condition according to adequate, inadequate, or deficient serum 25(OH)D levels. Results After adjusting for potential confounders, mean serum 25(OH)D levels were significantly lower in participants diagnosed with atopic dermatitis than in those without this diagnosis (mean ± SE, 18.58 ± 0.29 ng/mL vs 19.20 ± 0.15 ng/mL; P =.02). Compared with participants with adequate vitamin D levels (≥20 ng/mL), confounder-adjusted ORs of atopic dermatitis were significantly higher in those with inadequate (12-19.99 ng/mL) or deficient (<12 ng/mL) levels (OR [95% CI], 1.50 [1.10-2.06] and 1.48 [1.04-2.12], respectively; P =.02). This relationship was not observed in participants with the other allergic conditions. Conclusion Vitamin D-insufficient adult individuals within the general Korean population have an increased likelihood of atopic dermatitis, but not asthma, allergic rhinitis, or IgE sensitization. © 2013 American Academy of Allergy, Asthma & Immunology.


Kim S.C.,University of Ulsan | Kim S.C.,Asan Institute for Life Science | Han D.J.,University of Ulsan | Lee J.Y.,Asan Institute for Life Science
Current Stem Cell Research and Therapy | Year: 2010

Stem cells are considered an ideal tool for the supply of insulin-producing cells or repairing damaged pancreatic tissues to treat diabetes mellitus, with the possibility of unlimited sources. This cell population includes embryonic, adult bone marrow, pancreatic stem cells, extra pancreatic (such as hepatic cells) and adipose-derived stem cells. Multipotent adipose tissue-derived stem cells (ADSCs) are abundant in the human body, and thus are an ideal donor source for autologous transplantation to generate insulin-producing cells. Moreover these cells are better sources than bone marrow stem cells (BMSCs) for clinical applications, owing to minimal invasive procedures, high proliferation and multi-differentiation potential. Human adipose tissue-derived stem cells (hADSCs) may thus provide an alternative stem cell source, replacing BM-MSCs or embryonic stem cells (ESCs) for future clinical use in diabetes mellitus treatment. © 2010 Bentham Science Publishers Ltd.

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