Sung-Hee Ihm

Hallym University Medical Center, Sŏul, Seoul, South Korea

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Publications (32)118.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We aimed to elucidate the effect of herbimycin A (HMA), a heat shock protein 90 inhibitor, on cell growth and epithelial–mesenchymal transition (EMT) in anaplastic thyroid carcinoma (ATC) cells. HMA inhibited cell growth and migration concomitantly with increase of E-cadherin as well as decrease of N-cadherin and vimentin. Moreover, HMA upregulated p21 and p27, while it downregulated p53 and Akt. In HMA-treated condition, knockdown of E-cadherin and overexpression of p53 increased N-cadherin and vimentin, and mitigated the inhibitory effects of HMA on cell growth and migration. Furthermore, knockdown of p21 and p27 ameliorated inhibition of cell growth and reversal of EMT. In addition, the activation of Akt attenuated growth inhibition, cell death and EMT reversal. Therefore, we propose that HMA suppresses cell growth, and reverses EMT in conjunction with the activation of E-cadherin, p21 and p27 and the inactivation of p53 and PI3K/Akt signaling in ATC cells.
    Biochemical and Biophysical Research Communications 11/2014; 455(3-4). DOI:10.1016/j.bbrc.2014.11.018 · 2.28 Impact Factor
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    ABSTRACT: Context: The influence of the novel heat shock protein 90 (hsp90) inhibitor NVP-AUY922 (AUY922) on anaplastic thyroid carcinoma (ATC) cells has not been investigated. Objective: The effect of AUY922 alone or in combination with the histone deacetylase inhibitor PXD101 on survival of ATC cells was evaluated. Results: In ATC cells, AUY922, compared with 17-allylamino-17-demethoxygeldanamycin, herbimycin A and radicicol, potently lead to growth inhibition and cell death with cleavage of caspase-3 and PARP and concomitant changes in expression of hsp90 client proteins. After treatment of both AUY922 and PXD101, compared with treatment of AUY922 or PXD101 alone, the percentage of non-viable cells, annexin V-stained cells and cytotoxic activity increased. All of the combination index values were lower than 1.0, suggesting the synergism between AUY922 and PXD101 in induction of cell death. In cells treated with both AUY922 and PXD101, compared with cells treated with AUY922 alone, the protein levels of phospho-Akt, cIAP, xIAP, survivin, ATM, and ATR decreased, while those of acetyl. histone H3, acetyl. histone H4, γH2AX, cleaved DFF45 and cleaved PARP increased. Conclusion: Our results demonstrate that AUY922 potently induces cytotoxicity with concomitant modulation of hsp90 client proteins in ATC cells. Moreover, AUY922 has a synergistic activity with PXD101 in induction of cytotoxicity in conjunction with the inactivation of PI3K/Akt signaling and survivin and the activation of DNA damage response in ATC cells.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; 100(2):jc20143101. DOI:10.1210/jc.2014-3101 · 6.31 Impact Factor
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    ABSTRACT: Silencing target genes such as inducible nitric oxide synthase (iNOS) using small interfering double-stranded RNA (siRNA) in islet cells has been attempted to enhance the survival of transplanted islets. However, the efficient and safe delivery of siRNA into intact islets is challenging. Here, we prepared R3V6 peptides containing a three-arginine stretch and a six-valine stretch, which form micelles with hydrophobic valine cores and cationic arginine surfaces in aqueous solution, to co-deliver siRNA and cytoprotective hydrophobic drugs to islet cells. The cationic surfaces bound to the negatively charged iNOS siRNA, and the hydrophobic core was loaded with 17β-estradiol (E2), which exerts anti-apoptotic effects on the islet cells. The E2-loaded R3V6 peptide micelles delivered siRNA-5′-FITC to mouse islets more efficiently than did Lipofectamine 2000, and without cytotoxicity. The micelle complexes containing siRNA-iNOS knocked down the expression of iNOS mRNA by >60% in islets and reduced cytokine-induced apoptotic cell death in vitro significantly. The delivery of siRNA-iNOS and E2 simultaneously using E2-loaded R3V6 peptide micelles improved the diabetes reversal rate of marginal mass islet transplantation into the renal subcapsular space of diabetic syngeneic mice significantly compared with the siRNA-iNOS and E2 alone treatment control groups. Our results demonstrated that the co-delivery of siRNA and a cytoprotective drug within a single non-toxic carrier, R3V6 peptide micelles, provides a novel rational strategy for combined ex vivo islet therapy to improve the outcome of islet transplantation.
    Biomaterials 11/2014; DOI:10.1016/j.biomaterials.2014.10.060 · 8.31 Impact Factor
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    ABSTRACT: In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD-fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells.
    Biochemical and Biophysical Research Communications 10/2014; 454(1). DOI:10.1016/j.bbrc.2014.10.060 · 2.28 Impact Factor
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    ABSTRACT: The aim of the present study was to elucidate whether tunicamycin (TM) induces paraptosis as a cell death subroutine in anaplastic thyroid carcinoma (ATC) cells.
    Anticancer research 09/2014; 34(9):4857-68. · 1.87 Impact Factor
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    ABSTRACT: The aim of the present study was to evaluate the effect of radicicol, an inhibitor of heat shock protein (hsp) 90, alone or in combination with hsp70 inhibition on survival of anaplastic thyroid carcinoma (ATC) cells.
    Anticancer research 09/2014; 34(9):4829-37. · 1.87 Impact Factor
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    ABSTRACT: The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells.
    Endocrine 08/2014; 48(3). DOI:10.1007/s12020-014-0371-2 · 3.53 Impact Factor
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    ABSTRACT: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health.
    Environmental Research 06/2014; 133C:253-259. DOI:10.1016/j.envres.2014.05.033 · 3.95 Impact Factor
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    ABSTRACT: Background Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure.
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    ABSTRACT: The aim of the present study was to evaluate the effect of apigenin in combination with the BRAFV600E inhibitor PLX4032 on cell survival, and to investigate the influence of Akt inhibition on the combined effect of apigenin and PLX4032 in ATC cells harboring BRAFV600E. In 8505C and FRO cells harboring BRAFV600E, after treatment of apigenin and PLX4032, the cell viability decreased, and the percentage of dead cells increased in a time- and concentration-dependent manner, respectively. In apigenin- and PLX4032- treated cells, compared with apigenin alone-treated cells, the cell viability was lessened, and the percentage of dead cells was multiplied. In the addition of PLX4032 to apigenin, compared with the treatment of apigenin alone, the protein levels of cleaved PARP-1 and cleaved caspase-3 were elevated, and phospho-ERK protein levels were reduced, and the protein levels of total ERK, c-Myc, BRAF, phospho-Akt, phospho-p70S6K and phospho-4EBP1 were not varied. Compared with the treatment of PLX4032 alone, phospho-p70S6K protein levels were reduced, and the other protein levels were not altered. Phospho-ERK protein levels were reduced only in 8505C cells. Under the co-treatment of apigenin and PLX4032, administration of the PI3K inhibitor wortmannin further decreased the cell viability, and increased the percentage of dead cells. In conclusion, our results suggest that PLX4032 augments apigenininduced cytotoxicity in ATC cells harboring BRAFV600E. Moreover, Akt suppression potentiates the combined effect of apigenin and PLX4032 in ATC cells harboring BRAFV600E.
    Journal of endocrinological investigation 09/2013; 36(11). DOI:10.3275/9099 · 1.55 Impact Factor
  • 03/2013; DOI:10.1530/endoabs.32.P742
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    ABSTRACT: Apigenin promotes apoptosis in cancer cells. We studied the effect of apigenin on cell survival and c-Myc expression in FRO anaplastic thyroid carcinoma (ATC) cells. Apigenin caused apoptosis via the elevation of c-Myc levels in conjunction with the phosphorylation of p38 and p53. In the c-myc siRNA-transfected and apigenin-treated cells, compared with the apigenin-treated control cells, apoptosis and phosphorylation of p38 and p53 were ameliorated. In the presence of apigenin, diminution of p38 and p53 did not affect cell survival although apigenin activated the phosphorylation of p38 and p53 via increased c-Myc levels. In conclusion, our results indicate that apigenin induces apoptosis mediated via c-Myc with concomitant phosphorylation of p53 and p38 in FRO ATC cells. These findings suggest that augmented c-Myc acts as a core regulator and is necessary for apigenin-induced apoptosis in FRO ATC cells.
    Molecular and Cellular Endocrinology 01/2013; DOI:10.1016/j.mce.2013.01.012 · 4.24 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) stimulates cell proliferation and has anti-apoptotic effects on pancreatic islet β cells. In our previous study, the transduction of mouse islets with a recombinant adenovirus containing GLP-1 cDNA enhanced islet graft survival. In this study, we sought to deliver the GLP-1 gene using a nonviral vector, which raises fewer safety issues in clinical application. We constructed a plasmid, pβ-SP-GLP-1, in which a secretion signal peptide (SP) was inserted to increase GLP-1 secretion, and transfected mouse islets using the nonviral carrier Effectene. Transfection of pβ-SP-GLP-1 induced a significant increase in bioactive GLP-1 levels in islet cultures. Islets transfected with pβ-SP-GLP-1 were protected from H(2) O(2) -induced cell damage in vitro. In addition, glucose-stimulated insulin secretion was significantly increased in pβ-SP-GLP-1-transfected islets. Diabetic syngeneic mice transplanted under the kidney capsule with a marginal mass of pβ-SP-GLP-1-transfected islets rapidly became normoglycemic, with 88% of recipients being normoglycemic at 30 days post-transplantation compared with 52% of mice that received pβ-transfected islet grafts (P < 0.05). Islet grafts retrieved 7 days after transplantation revealed that the pβ-SP-GLP-1-transfected group had significantly more Ki67-positive cells as compared with the pβ-transfected group. In conclusion, delivery of a plasmid containing a secretion SP and GLP-1 cDNA using a nonviral carrier leads to efficient secretion of GLP-1 in mouse islet cells, enhances islet cell survival during the early post-transplant period, and improves islet transplantation outcome.
    Transplant International 01/2013; DOI:10.1111/tri.12052 · 3.16 Impact Factor
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    ABSTRACT: ACTH-independent Cushing syndrome, which is mainly caused by a unilateral adrenal adenoma or adrenal carcinoma, account for 15~20% of Cushing's syndrome. Cushing's syndrome caused by bilateral adrenal masses is rare, including bilateral adrenal adenomas or carcinomas (AIMAH and PPNAD). Adrenal adenoma is commonly treated by Laparoscopic total adrenalectomy. However, bilateral total adrenalectomy causes acute adrenal insufficiency (Addisonian crisis), requiring lifelong steroid replacement. We present a young female patient with bilateral adrenocortical adenoma causing Cushing's syndrome who was completely cured by successful laparoscopic total & partial adrenalectomy. Primarily we decided to remove the right adrenal gland to preserve the residual function of the left adrenal gland. However, after right total adrenalectomy, the patient manifested symptoms of subclinical Cushing syndrome including hypertension, truncal obesity, diabetes, low HDL cholesterol, and elevated triglycerides. Subsequently the patient underwent partial left adrenal mass excision, preserving the normal portion of the adrenal gland. The patient thereafter achieved biochemical resolution and significant improvement of hypertension, obesity, and diabetes without the need of any medication.
    01/2013; 22(4):254. DOI:10.7570/kjo.2013.22.4.254
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    ABSTRACT: Predictive factors of severe diverticulitis are known to be sex, obesity, immunodeficiency and old age. However, the association between obesity and complicated diverticulitis is yet to be defined. We conducted the present study to clarify the association of central obesity with the risk of complicated diverticulitis.
    01/2012; 21(4):245. DOI:10.7570/kjo.2012.21.4.245
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    ABSTRACT: This study investigated the effect of local glucagon-like peptide-1 (GLP-1) production within mouse islets on cytoprotection in vitro and in vivo by gene transfer of GLP-1. Transduction of recombinant adenovirus vector expressing GLP-1 (rAd-GLP-1) induced a significant increase in bioactive GLP-1 in the mouse islet culture, whereas transduction with adenovirus vector expressing β-galactosidase (rAd-LacZ), as a control, had no effect on GLP-1 secretion. Islets transduced with rAd-GLP-1 were protected from H(2) O(2) -induced cell damage in vitro. In addition, glucose-stimulated insulin secretion was significantly increased in rAd-GLP-1-transduced islets. When transplanted under the kidney capsule of diabetic syngeneic mice, islet grafts retrieved 4 or 7 days after transplantation revealed that the rAd-GLP-1-transduced group had significantly more Ki67-positive cells as compared with the rAd-LacZ-transduced group. Regarding blood glucose control, diabetic mice transplanted with a marginal mass of rAd-GLP-1-transduced islets became normoglycemic more rapidly and 78% of the recipients were normoglycemic at 35 days post-transplant, whereas only 48% of the mice transplanted with rAd-LacZ-transduced islets were normoglycemic (P < 0.05). In conclusion, delivery of the GLP-1 gene to islets enhanced islet cell survival during the early post-transplant period, and preserved islet mass and functions over time in the transplants.
    Transplant International 12/2011; 25(2):242-9. DOI:10.1111/j.1432-2277.2011.01394.x · 3.16 Impact Factor
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    ABSTRACT: For gene transfer strategies to improve islet engraftment, vascular endothelial growth factor (VEGF) expression should be regulated in a way that matches the transient nature of revascularization with simultaneously avoiding undesirable effects of overexpression. The aim of this study was to investigate the effects of hypoxia-inducible VEGF gene transfer using the RTP801 promoter on islet grafts. We implanted pSV-hVEGF transfected, pRTP801-hVEGF transfected or nontransfected mouse islets under the kidney capsule of streptozotocin-induced diabetic syngeneic mice. Human VEGF immunostaining of day 3 grafts revealed that the pRTP801-hVEGF transfected group had higher hVEGF expression compared with the pSV-hVEGF transfected group. BS-1 staining of day 3 grafts from the pRTP801-hVEGF transfected group showed the highest vascular density, which was comparable with day 6 grafts from the nontransfected group. In 360 islet equivalent (IEQ)-transplantation which reverted hyperglycemia in all mice, the area under the curve of glucose levels during intraperitoneal glucose tolerance test 7 weeks post-transplant was lower in mice transplanted with pRTP801-hVEGF transfected grafts compared with mice transplanted with nontransfected grafts. In 220 IEQ-transplantations, diabetic mice transplanted with pRTP801-hVEGF islets became normoglycemic more rapidly compared with mice transplanted with pSV-hVEGF or nontransfected islets, and diabetes reversal rate after 50 days was 90%, 68%, and 50%, respectively. In conclusion, our results indicate that regulated overexpression of hVEGF in a hypoxia-inducible manner enhances islet vascular engraftment and preserves islet function overtime in transplants.
    Transplant International 03/2011; 24(3):307-14. DOI:10.1111/j.1432-2277.2010.01194.x · 3.16 Impact Factor
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    ABSTRACT: Activation of the receptor for advanced glycation endproducts (RAGE) by its ligands leads to cellular damage contributing to diabetic complications. It is not clearly known whether RAGE ligands influence pancreatic β-cells. In this study, we investigated the expression of RAGE in islet cells and the effect of RAGE ligands, S100b and HMG-1, on islet cells. RAGE was expressed in INS-1 cells and isolated rat and human islets at mRNA and protein levels. RAGE and its ligand, S100b, were detected on islet cells in 28-week-old diabetic OLETF rats. Both S100b and HMG-1 induced apoptotic cell death of INS-1 and islet cells. This INS-1 cell apoptosis was accompanied by increased intracellular oxidative stress and inhibited by antioxidants or a NADPH oxidase inhibitor. Our results showing S100b/RAGE expression on islets of diabetic rat model and RAGE ligands-induced islet cell apoptosis via NADPH oxidase-mediated ROS generation suggest that RAGE ligands-RAGE interaction may contribute not only to the development of diabetic complications but also to the progressive β-cell loss in type 2 diabetes by inducing oxidative stress.
    International Journal of Molecular Medicine 12/2010; 26(6):813-8. · 1.88 Impact Factor
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    ABSTRACT: Treatment with thiazolidinediones (TZDs) improves glucose homeostasis by increasing insulin sensitivity, but it also leads to weight gain. Our hypothesis was that, in individual adipose depots, there is depot specificity for lipid storage and energy expenditure genes after TZD treatment. After 5 weeks of rosiglitazone treatment on Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus with obesity, and Long-Evans Tokushima Otsuka rats as controls, we measured changes in lipid storage and energy expenditure gene expression in various adipose depots, such as mesenteric and nonmesenteric adipose tissues (subcutaneous, epididymal, and retroperitoneal). Mesenteric fat masses did not change after TZD treatment in OLETF rats, but nonmesenteric fat masses increased. Messenger RNA expression of lipid storage genes increased in nonmesenteric fat, but energy expenditure gene expression increased in mesenteric fat after rosiglitazone treatment. In conclusion, our findings suggest that TZD treatment may be associated with the depot-specific effects of lipid storage and energy expenditure genes on fat redistribution in individual adipose tissues in OLETF rats.
    Metabolism: clinical and experimental 09/2009; 59(1):46-53. DOI:10.1016/j.metabol.2009.07.004 · 3.61 Impact Factor
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    ABSTRACT: In diabetic nephropathy, transforming growth factor beta1 (TGFbeta1) is related to p38 mitogen-activated protein kinase (MAPK) that induces production of fibronectin in mesangial cells. We investigated the effects of alpha-lipoic acid (ALA), a potent antioxidant, on proteinuria and TGFbeta1-p38 MAPK-fibronectin pathway in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. After ALA treatment for 5 weeks in OLETF rats at 30 weeks of age, plasma malondialdehyde, urinary protein excretion, renal cortical TGFbeta1, and fibronectin protein levels were decreased; and urinary protein excretion was positively correlated with renal cortical TGFbeta1 and fibronectin protein levels. Phospho-form but not total-form levels as well as fold activations of each protein consisting of p38 MAPK pathway were also attenuated. These results suggest that ALA ameliorates proteinuria by attenuating expressions of TGFbeta1 and fibronectin proteins, and these favorable effects are related to inhibition of phosphorylating activation of p38 MAPK pathway in renal cortex of OLETF rats.
    Metabolism: clinical and experimental 06/2009; 58(5):616-23. DOI:10.1016/j.metabol.2008.12.006 · 3.61 Impact Factor