Publications (10)35.11 Total impact
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Article: ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells.
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ABSTRACT: Mitochondrial dysfunction induces apoptosis of pancreatic β-cells and leads to type 2 diabetes, but the mechanism involved in this process remains unclear. Chronic endoplasmic reticulum (ER) stress plays a role in the apoptosis of pancreatic β-cells; therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced β-cells apoptosis. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse pancreatic β-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2α, GRP78 and GRP 94, as well as ER stress-associated apoptotic factor, CHOP, and activated JNK. AMP-activated protein kinase (AMPK) was also activated under mitochondria dysfunction by metabolic stress. However, the inhibition of AMPK by treatment with compound C, inhibitor of AMPK, and overexpression of mutant dominant negative AMPK (AMPKK45R) blocked the induction of ER stress, which was consist-ent with the decreased β-cell apoptosis and increase of insulin content. Furthermore, mitochondrial dysfunction increased the expression of the inducible nitric oxide synthase (iNOS) gene and the production of nitric oxide (NO), but NO production was prevented by compound C and mutant dominant negative AMPK (AMPK-K45R). Moreover, treatment with 1400W, which is an inhibitor of iNOS, prevented ER stress and apoptosis induced by mitochondrial dysfunction. Treatment of MIN6N8 cells with lipid mixture, physiological conditions of impaired mitochondria function, activated AMPK, increased NO production and induced ER stress. Collectively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic β-cells apoptosis.Molecules and Cells 12/2010; 30(6):545-9. · 2.18 Impact Factor -
Article: Mitochondrial dysfunction: glucokinase downregulation lowers interaction of glucokinase with mitochondria, resulting in apoptosis of pancreatic beta-cells.
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ABSTRACT: Mitochondrial dysfunction has been considered a critical component in the development of diabetes. In pancreatic beta-cells especially, mitochondrial dysfunction impairs insulin secretion and the eventual apoptosis of beta-cells. The aim of this study was to elucidate the molecular mechanism underlying these events. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, a mouse pancreatic beta-cells, and the effects of glucokinase (GCK) and mitochondria were investigated. Concurrent with reduction in mitochondrial membrane potential (DeltaPsim) and cellular ATP content, impaired mitochondrial function reduced GCK expression and resulted in decreased insulin secretion and beta-cell apoptosis. Specifically, lowered GCK expression led to decreased interactions between GCK and mitochondria, which increased Bax binding to mitochondria and cytochrome C release into cytoplasm. However, these events were blocked by treatment with the antioxidant, N-acetyl-cysteine (NAC), as well as GCK overexpression. Moreover, examination of the GCK promoter in antimycin-treated cells demonstrated that the promoter region within -287 bases from transcription site is involved in the transcriptional repression of GCK by mitochondrial stress, whose region contains a putative binding site for pancreatic duodenal homeobox-1 (PDX-1). Mitochondrial stress reduced PDX-1 expression, and increased ATF3 expression dependent on reactive oxygen species (ROS). Collectively, these data demonstrate that mitochondrial dysfunction by metabolic stress reduces GCK expression through PDX-1 downregulation via production of ROS, which then decreases the association of GCK with mitochondria, resulting in pancreatic beta-cell apoptosis and reduction of insulin secretion.Cellular signalling 11/2008; 21(1):69-78. · 4.09 Impact Factor -
Article: ENHANCEMENT OF 1,25‐DIHYDROXYVITAMIN D3‐ AND ALL‐TRANS RETINOIC ACID‐INDUCED DIFFERENTIATION OF HUMAN LEUKEMIA HL‐60 CELLS BY BLOOD SHELL, SCAPHARCA BROUGHTONII
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ABSTRACT: Human myeloid leukemia HL-60 cells are differentiated into monocytic or granulocytic lineage when treated with 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) or all-trans retinoic acid (RA), respectively. In this study, the effect of ethanol fraction prepared from the blood shell, Scapharca broughtonii, on cell differentiation was investigated in an HL-60 cell culture system. Treatment of HL-60 cells with 2.5- to 20-µg/mL ethanol fraction of the blood shell for 72 h inhibited cell proliferation and induced a 20% increase in cell differentiation, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium and nitroblue tetrazolium reduction assay. Interestingly, synergistic induction of HL-60 cell differentiation was observed when the ethanol fraction of the blood shell was combined with either 5-nM 1,25-(OH)2D3 or 50-nM all-trans RA. Flow cytometric analysis and morphologic studies confirmed that combinations of either 1,25-(OH)2D3 or all-trans RA and the ethanol fraction of the blood ark shell stimulated leukemia cell differentiation. These results suggest a possibility of blood shell in the treatment of human leukemia.PRACTICAL APPLICATIONSThe ethanol fraction (SIII) of blood shell, Scapharca broughtonii, potentiates 1,25-(OH)2D3- and all-trans retinoic acid (RA)-induced differentiation in HL-60 myeloid leukemia cells. HL-60 cells might be synergistically differentiated into monocytes or granulocytes when treated with the ethanol fraction in combination with either 1,25-(OH)2D3 or all-trans RA. These results imply a possible application of blood ark shell in the treatment of leukemia patients with less toxicity.Journal of Food Biochemistry 01/2008; 32(1):96 - 106. · 0.81 Impact Factor -
Article: AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic beta-cell apoptosis.
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ABSTRACT: We previously demonstrated that chronic high glucose (33.3 mM) induced beta-cell dysfunction and apoptosis through glucokinase (GCK) downregulation, but the exact mechanisms involved remain unclear. Here, we show that prolonged exposure of 5-aminoimidazole-4-carboxamide (AICA)-riboside potentiated apoptosis induced by high glucose in MIN6N8 pancreatic beta-cells, correlating with enhanced GCK downregulation and decreased production of ATP and insulin. These events are potentiated in AMPK-overexpressing cells, but are prevented in cells transfected with mutant dominant-negative AMPK (AMPK-K45R). Furthermore, AMPK activation increases production of reactive oxygen species (ROS) and loss of mitochondria membrane potential induced by high glucose, which is significantly inhibited by treatment with compound C or by AMPK-K45R overexpression. Overexpression of GCK prevents apoptosis; decreased cellular ATP and insulin secretion, and ROS production enhanced by AICAR, but does not affect AMPK activation. Similar results are obtained using isolated primary islet cells. Collectively, these data demonstrate that AMPK activation potentiates beta-cell apoptosis induced by chronic high glucose through augmented GCK downregulation mediated by enhanced ROS production.Cellular Signalling 05/2007; 19(4):791-805. · 4.06 Impact Factor -
Article: Production and biological activity of laidlomycin, anti-MRSA/VRE antibiotic from Streptomyces sp. CS684.
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ABSTRACT: Culture broth of a streptomycete isolate, Streptomyces sp. CS684 showed antibacterial activity on methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE). Among purified substances from the organism, CSU-1, which is active against MRSA and VRE, is a C37H62O12Na (M+, 721.3875), and identified as laidlomycin. The anti-MRSA and anti-VRE activity of CSU-1 was stronger than oxacillin and vancomycin. Phylogenetic analysis showed that strain CS684 is very similar to Streptomyces ardus NRRL 2817T, whereas the ability of Streptomyces sp. CS684 to produce laidlomycin was shown to be unique.The Journal of Microbiology 03/2007; 45(1):6-10. · 1.10 Impact Factor -
Article: Inhibition of mouse macrophages interleukin-12 production: suppression of nuclear factor-kappaB binding activity by a specific factor isolated from Scapharca broughtonii.
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ABSTRACT: Pharmacological inhibition of interleukin-12 (IL-12) production may allow a therapeutic strategy for preventing development and progression of disease in experimental models of autoimmunity. In this study we investigated the effects of an ethanol fraction of the Scapharca broughtonii, on the production of IL-12 by mouse macrophages stimulated with lipopolysaccharides (LPS). The ethanol fraction (S3) prepared from Scapharca broughtonii potently inhibited LPS-induced IL-12 production in the RAW264.7 monocyte cell-line in a dose-dependent manner. The activation effect of the ethanol fraction (S3) on the IL-12 gene promoter was analyzed by transfecting RAW264.7 cells with IL-12 gene promoter/luciferase constructs. The repressive effect mapped to a region in the IL-12 gene promoter that contained a binding site for NF-kappaB. Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the NF-kappaB site, which significantly decreased upon addition of the ethanol fraction, indicating that the ethanol fraction of the blood shell inhibited IL-12 production in LPS-activated macrophages via inhibition of NF-kappaB binding activity.Archives of Pharmacal Research 03/2007; 30(3):350-4. · 1.59 Impact Factor -
Article: Expression of a thioredoxin-related protein-1 is induced by prostaglandin E(2).
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ABSTRACT: Prostaglandin E(2) (PGE(2)) plays an important role in protection of the gastric mucosa against various damaging agents and growth-inhibitory activity on tumor cells. However, the precise regulation mechanism of PGE(2) in gastric cancer cells is still unclear. In this study, we isolated a gene, which is regulated by PGE(2) in SNU-1, human gastric adenocarcinoma cells, using differential display RT-PCR (DD RT-PCR) and characterized the function of the gene induced by PGE(2). The full-length cDNA of the gene was cloned by the rapid amplification of cDNA ends method. The 1659 base pair cDNA consists of a 30-nt 5'-noncoding region, an 891-nt open reading frame and a 738-nt 3'noncoding region that includes a poly (A) signal. As a result of protein motif search, we found that it has a conserved thioredoxin-active site, Cys-Gly-Pro-Cys and a Myb-DNA binding domain repeat signature. Thus, we designated this gene product as thioredoxin-related protein-1, TRP-1. TRP-1 was expressed in a lower extent in renal, gastric and colon cancer tissues and is translated into 33 kDa protein in nuclear and cytoplasmic fractions. TRP-1 has a thioredoxin activity, which was detected using the insulin disulfide reduction assay. Another potential role of TRP-1 is repression of B-Myb activity through direct binding to B-Myb, a transcriptional factor induced at G1-S transition. Finally, TRP-1 overexpression inhibits mammalian cell proliferation and specifically predispose to G0/G1 phase arrest. In conclusion, these results imply that TRP-1 is a mammalian thioredoxin and plays as a transcriptional repressor through direct binding to the transcription factor B-Myb.International Journal of Cancer 05/2006; 118(7):1670-9. · 5.44 Impact Factor -
Article: Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway.
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ABSTRACT: IFN-gamma and TNF-alpha are major proinflammatory cytokines implicated in islet beta-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic beta-cell line MIN6N8 cells, co-treatment with TNF-alpha and IFN-gamma, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (delta psi m). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-alpha/IFN-gamma through ROS production and loss of delta psi m, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-alpha/IFN-gamma, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-alpha/IFN-gamma. Furthermore, the synergistic effect of TNF-alpha/IFN-gamma on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-alpha/IFN-gamma was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-alpha/IFN-gamma synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic beta-cell via activation of p53 pathway together with ROS.Cellular Signalling 01/2006; 17(12):1516-32. · 4.06 Impact Factor -
Article: Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells.
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ABSTRACT: Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.Diabetes 10/2005; 54(9):2602-11. · 8.29 Impact Factor -
Article: Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats.
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ABSTRACT: Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.Journal of Molecular Endocrinology 04/2005; 34(2):299-315. · 3.48 Impact Factor
Top co-authors
Top Journals
Institutions
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2010
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Pusan National University
- School of Korean Medicine
Pusan, Busan, South Korea
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2007–2008
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Catholic University of Pusan
Pusan, Busan, South Korea
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2005–2007
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National Institutes of Health
Bethesda, MD, USA
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