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1.  Gallotannin suppresses calcium oxalate crystal binding and oxalate-induced oxidative stress in renal epithelial cells 
Calcium oxalate monohydrate (COM) crystals bind avidly to the surface of proliferating and migrating renal endothelial cells, perhaps a key event in kidney stone formation. Oxalate-induced pre-oxidative stress can further promote crystal attachment cells. Natural products including gallotannins found in green teas have been studied as potentially novel treatments to prevent crystal retention and kidney stone formation. Gallotannin significantly inhibited COM crystal growth and binding to MDCK I renal epithelial cells at non-toxic concentrations and also delayed renal cell migration in a wound healing assay. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that gallotannin significantly attenuated oxalate-induced mRNA expression of monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22phox and p47phox in human primary renal epithelial cells (HRCs). Gallotannin also reduced HRC production of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as enhanced antioxidant enzyme superoxide dismutase (SOD) activity in response to oxalate. Taken together, our findings suggest that gallotannin can contribute to nephrolithiasis prevention via direct effects on renal epithelial cells including suppression of COM binding and MCP-1 and OPN expression, along with augmenting antioxidant activity.
PMCID: PMC3910304  PMID: 22466558
gallotannin; renal epithelial cells; calcium oxalate monohydrate; MCP-1; osteopontin; ROS; SOD
2.  Suppression of STAT3 and HIF-1 Alpha Mediates Anti-Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells 
PLoS ONE  2011;6(6):e21492.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells.
Methodology/Principal Findings
BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia.
Taken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.
PMCID: PMC3123343  PMID: 21731766
3.  Characterization of the Denitrification-Associated Phosphorus Uptake Properties of “Candidatus Accumulibacter phosphatis” Clades in Sludge Subjected to Enhanced Biological Phosphorus Removal 
To characterize the denitrifying phosphorus (P) uptake properties of “Candidatus Accumulibacter phosphatis,” a sequencing batch reactor (SBR) was operated with acetate. The SBR operation was gradually acclimated from anaerobic-oxic (AO) to anaerobic-anoxic-oxic (A2O) conditions by stepwise increases of nitrate concentration and the anoxic time. The communities of “Ca. Accumulibacter” and associated bacteria at the initial (AO) and final (A2O) stages were compared using 16S rRNA and polyphosphate kinase genes and using fluorescence in situ hybridization (FISH). The acclimation process led to a clear shift in the relative abundances of recognized “Ca. Accumulibacter” subpopulations from clades IIA > IA > IIF to clades IIC > IA > IIF, as well as to increases in the abundance of other associated bacteria (Dechloromonas [from 1.2% to 19.2%] and “Candidatus Competibacter phosphatis” [from 16.4% to 20.0%]), while the overall “Ca. Accumulibacter” abundance decreased (from 55.1% to 29.2%). A series of batch experiments combined with FISH/microautoradiography (MAR) analyses was performed to characterize the denitrifying P uptake properties of the “Ca. Accumulibacter” clades. In FISH/MAR experiments using slightly diluted sludge (∼0.5 g/liter), all “Ca. Accumulibacter” clades successfully took up phosphorus in the presence of nitrate. However, the “Ca. Accumulibacter” clades showed no P uptake in the presence of nitrate when the sludge was highly diluted (∼0.005 g/liter); under these conditions, reduction of nitrate to nitrite did not occur, whereas P uptake by “Ca. Accumulibacter” clades occurred when nitrite was added. These results suggest that the “Ca. Accumulibacter” cells lack nitrate reduction capabilities and that P uptake by “Ca. Accumulibacter” is dependent upon nitrite generated by associated nitrate-reducing bacteria such as Dechloromonas and “Ca. Competibacter.”
PMCID: PMC3592233  PMID: 23335771
4.  Essential Oil of Pinus koraiensis Exerts Antiobesic and Hypolipidemic Activity via Inhibition of Peroxisome Proliferator-Activated Receptors Gamma Signaling 
Our group previously reported that essential oil of Pinus koraiensis (EOPK) exerts antihyperlipidemic effects via upregulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A. In the present study, we investigated the antiobesity and hypolipidemic mechanism of EOPK using in vitro 3T3-L1 cells and in vivo HFD-fed rats. EOPK markedly suppressed fat accumulation and intracellular triglyceride associated with downregulation of adipogenic transcription factor expression, including PPARγ and CEBPα in the differentiated 3T3-L1 adipocytes. Additionally, EOPK attenuated the expression levels of FABP and GPDH as target genes of PPARγ during adipocyte differentiation. Furthermore, PPARγ inhibitor GW9662 enhanced the decreased expression of FABP and PPARγ and fat accumulation induced by EOPK. To confirm the in vitro activity of EOPK, animal study was performed by administering normal diet, HFD, and/or EOPK at the dose of 100 or 200 mg/kg for 6 weeks. Consistently, EOPK significantly suppressed body weight gain, serum triglyceride, total cholesterol, LDL cholesterol, and AI value and increased HDL cholesterol in a dose-dependent manner. Immunohistochemistry revealed that EOPK treatment abrogated the expression of PPARγ in the liver tissue sections of EOPK-treated rats. Taken together, our findings suggest that EOPK has the antiobesic and hypolipidemic potential via inhibition of PPARγ-related signaling.
PMCID: PMC3753736  PMID: 23997801
5.  Inhibition of cyclooxygenase-2-dependent survivin mediates decursin-induced apoptosis in human KBM-5 myeloid leukemia cells 
Cancer letters  2010;298(2):212-221.
We demonstrate that decursin induces apoptosis via regulation of cyclooxygenase-2 (COX-2) and survivin in leukemic KBM-5 cells. By activating an apoptotic machinery, decursin is cytotoxic to KBM-5 cells. In this apoptotic process, decursin can activate caspase family members and triggers PARP cleavage. At the same time, the expression of COX-2 and survivin in the cells is downregulated. Furthermore, decursin is in synergy with COX-2 inhibitor, celecoxib or NS398 for the induction of apoptosis. Overall, these results suggest that decursin, via inhibiting COX-2 and survivin, sensitizes human leukemia cells to apoptosis and is a potential chemotherapeutic agent to treat this disease.
PMCID: PMC3689030  PMID: 20673699
Decursin; Apoptosis; COX-2; Survivin; KBM-5
6.  Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells 
Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells. Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.
PMCID: PMC3684033  PMID: 23818927
7.  Activation of AMP-Activated Protein Kinase α and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells 
Here, antitumor mechanism of cinnamaldehyde derivative CB-PIC was elucidated in human SW620 colon cancer cells. CB-PIC significantly exerted cytotoxicity, increased sub-G1 accumulation, and cleaved PARP with apoptotic features, while it enhanced the phosphorylation of AMPK alpha and ACC as well as activated the ERK in hypoxic SW620 cells. Furthermore, CB-PIC suppressed the expression of HIF1 alpha, Akt, and mTOR and activated the AMPK phosphorylation in hypoxic SW620 cells. Conversely, silencing of AMPKα blocked PARP cleavage and ERK activation induced by CB-PIC, while ERK inhibitor PD 98059 attenuated the phosphorylation of AMPKα in hypoxic SW620 cells, implying cross-talk between ERK and AMPKα. Furthermore, cotreatment of CB-PIC and metformin enhanced the inhibition of HIF1α and Akt/mTOR and the activation of AMPKα and pACC in hypoxic SW620 cells. In addition, CB-PIC suppressed the growth of SW620 cells inoculated in BALB/c athymic nude mice, and immunohistochemistry revealed that CB-PIC treatment attenuated the expression of Ki-67, CD34, and CAIX and increased the expression of pAMPKα in CB-PIC-treated group. Interestingly, CP-PIC showed better antitumor activity in SW620 colon cancer cells under hypoxia than under normoxia, since it may be applied to chemoresistance. Overall, our findings suggest that activation of AMPKα and ERK mediates CB-PIC-induced apoptosis in hypoxic SW620 colon cancer cells.
PMCID: PMC3622407  PMID: 23589723
8.  Comparative Survey of Rumen Microbial Communities and Metabolites across One Caprine and Three Bovine Groups, Using Bar-Coded Pyrosequencing and 1H Nuclear Magnetic Resonance Spectroscopy 
Applied and Environmental Microbiology  2012;78(17):5983-5993.
Pyrosequencing of 16S rRNA genes (targeting Bacteria and Archaea) and 1H nuclear magnetic resonance were applied to investigate the rumen microbiota and metabolites of Hanwoo steers in the growth stage (HGS), Hanwoo steers in the late fattening stage (HFS), Holstein-Friesian dairy cattle (HDC), and Korean native goats (KNG) in the late fattening stage. This was a two-part investigation. We began by comparing metabolites and microbiota of Hanwoo steers at two stages of husbandry. Statistical comparisons of metabolites and microbial communities showed no significant differences between HFS and HGS (differing by a dietary shift at 24 months and age [67 months versus 12 months]). We then augmented the study by extending the investigation to HDC and KNG. Overall, pyrosequencing of 16S rRNA genes showed that the rumens had highly diverse microbial communities containing many previously undescribed microorganisms. Bioinformatic analysis revealed that the bacterial sequences were predominantly affiliated with four phyla—Bacteroidetes, Firmicutes, Fibrobacteres, and Proteobacteria—in all ruminants. However, interestingly, the bacterial reads belonging to Fibrobacteres were present at a very low abundance (<0.1%) in KNG. Archaeal community analysis showed that almost all of these reads fell into a clade related to, but distinct from, known cultivated methanogens. Statistical analyses showed that the microbial communities and metabolites of KNG were clearly distinct from those of other ruminants. In addition, bacterial communities and metabolite profiles of HGS and HDC, fed similar diets, were distinctive. Our data indicate that bovine host breeds override diet as the key factor that determines bacterial community and metabolite profiles in the rumen.
PMCID: PMC3416611  PMID: 22706048
9.  Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells 
Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H2O2-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H2O2) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H2O2-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H2O2-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H2O2-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H2O2-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H2O2-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H2O2-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.
PMCID: PMC3518788  PMID: 23243457
10.  Plant Proteins Differently Affect Body Fat Reduction in High-fat Fed Rats 
This study examined the effects of corn gluten (CG), wheat gluten (WG), and soybean protein isolate (SPI), as well as their hydrolysates, on weight reduction in rats fed a high-fat diet. Eight-month-old male Sprague–Dawley rats (n=70) were fed a high-fat diet (40% of the calories were fat) for 4 weeks. Rats were then randomly divided into seven groups and were fed isocaloric diets with different protein sources for 8 weeks. The protein sources were casein (control group), intact CG (CG group), CG hydrolysate (CGH group), intact WG (WG group), WG hydrolysate (WGH group), intact SPI (SPI group), and SPI hydrolysate (SPIH group). Body weight gain, adipose tissue weights, lipid profiles in plasma and liver; and hepatic activities of carnitine palmitoyl transferase, fatty acid synthase (FAS), malic enzyme, and glucose-6-phosphate dehydrogenase were assessed. The CGH group showed significant weight reduction compared with the other groups. Epididymal fat pad and plasma triglycerides in the CGH group were the lowest and were significantly different than those in the control group. FAS activity in the CGH group was significantly lower than that in the other groups. In conclusion, the CGH diet of these experimental animals demonstrated a weight-reducing effect by lowering the adipose tissue weight and by affecting the activities of hepatic lipogenic enzymes.
PMCID: PMC3866736  PMID: 24471088
corn gluten; hydrolysate; soybean protein isolate; weight reduction; wheat gluten
11.  The Genome-Wide Expression Profile of 1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose-Treated MDA-MB-231 Breast Cancer Cells: Molecular Target on Cancer Metabolism 
Molecules and Cells  2011;32(2):123-132.
1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a polyphenolic compound isolated from Rhus chinensis Mill. PGG has been known to have anti-tumor, anti-angiogenic and anti-diabetic activities. The present study revealed another underlying molecular target of PGG in MDA-MB-231 breast cancer cells by using Illumina Human Ref-8 expression BeadChip assay. Through the Beadstudio v3 micro assay program to compare the identified genes expressed in PGG-treated MDA-MB-231 cells with untreated control, we found several unique genes that are closely associated with pyruvate metabolism, glycolysis/gluconeogenesis and tyrosine metabolism, including PC, ACSS2, ACACA, ACYP2, ALDH3B1, FBP1, PRMT2 and COMT. Consistent with microarray data, real-time RT-PCR confirmed the significant down-regulation of these genes at mRNA level in PGG-treated MDA-MB-231 cells. Our findings suggest the potential of PGG as anticancer agent for breast cancer cells by targeting cancer metabolism genes.
PMCID: PMC3887664  PMID: 21614488
cancer metabolism; MDA-MB-231; microarray; PGG; real-time PCR
12.  Complete Genome Sequence of the BTEX-Degrading Bacterium Pseudoxanthomonas spadix BD-a59 
Journal of Bacteriology  2012;194(2):544.
Pseudoxanthomonas spadix BD-a59, able to metabolize all six BTEX (benzene, toluene, ethylbenzene, and o-, m-, and p-xylene) compounds, was isolated from gasoline-contaminated sediment. Here, we report the complete 3.45-Mb genome sequence and annotation of strain BD-a59. These advance the understanding of strain BD-a59's genomic properties and pollutant metabolic versatility.
PMCID: PMC3256636  PMID: 22207748
13.  Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition 
Carcinogenesis  2011;32(6):804-811.
There is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compound 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) can inhibit the growth and metastasis of TNBCa xenograft and target Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) 3-signaling axis. Daily oral gavage of 10 mg PGG/kg body wt decreased MDA-MB-231 xenograft weight by 49.3% (P < 0.01) at 40 days postinoculation, whereas weekly intraperitoneal injections of Taxol at the same dosage resulted in a 21.4% reduction (P > 0.1). PGG treatment also decreased the incidence of lung metastasis. Immunohistochemical staining detected decreased Ki-67 (proliferation) index and increased terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (apoptosis) index in PGG-treated and Taxol-treated xenografts. However, the CD34 (angiogenesis) index was decreased only in PGG-treated xenografts along with decreased phospho-STAT3. In cell culture of MDA-MB-231 cells, PGG decreased pSTAT3 and its downstream target proteins, decreased its upstream kinase pJAK1 and induced the expression of SHP1, a JAK1 upstream tyrosine phosphatase, within as early as 1 h of exposure. The phosphatase inhibitor pervanadate reversed the PGG-induced downregulation of pSTAT3 and caspase activation. Orally administered PGG can inhibit TNBCa growth and metastasis, probably through anti-angiogenesis, antiproliferation and apoptosis induction. Mechanistically, PGG-induced inhibition of JAK1-STAT3 axis may contribute to the observed in vivo efficacy and the effects on the cellular processes.
PMCID: PMC3106430  PMID: 21289371
14.  Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells 
BMC Cancer  2012;12:28.
Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.
Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.
These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.
PMCID: PMC3292511  PMID: 22260501
ergosterol peroxide; JAK2; STAT3; angiogenesis; multiple myeloma
15.  Salivary chemokine levels in patients with primary Sjögren’s syndrome 
Rheumatology (Oxford, England)  2010;49(9):1747-1752.
Objective. The present study aimed to investigate the salivary chemokine levels in patients with primary SS (pSS) and compare them with those in patients with non-SS sicca symptoms or non-sicca controls.
Methods. Unstimulated and stimulated whole saliva samples were obtained from pSS patients (n = 30) and age- and gender-matched patients with non-SS sicca (n = 30) and non-sicca healthy controls (n = 25). Salivary CCL2, CCL3, CCL4, CXCL8 and CXCL10 levels were measured using a Luminex bead-based multiplex assay.
Results. Patients with pSS had significantly different distributions of salivary CCL3 (P = 0.0001 by the Kruskal–Wallis test), CCL4 (P < 0.00001), CXLC8 (P < 0.0001) and CXCL10 (P < 0.05) levels in unstimulated saliva and all chemokine levels in stimulated saliva when compared with non-SS sicca and non-sicca controls. In comparison with chemokine production rate, the CXCL8 and CXCL10 production rates were significantly higher in pSS than in non-SS sicca controls (P < 0.01 by the Mann–Whitney test). Logistic regression analyses revealed that salivary CXCL8 (P < 0.05) and CXCL10 (P < 0.05) were the significant discriminating chemokines between the pSS and non-SS sicca groups. Although CXCL8 and CXCL10 levels were not correlated with the focus scores, CXCL8 and CXCL10 levels were significantly associated with salivary gland dysfunction.
Conclusion. These results support the notion that CXCL8 or CXCL10 chemokine plays a role in the pathogenesis of pSS.
PMCID: PMC2919196  PMID: 20525739
Sjögren’s syndrome; Sicca; Saliva; Chemokine
16.  Randomized clinical trial on the efficacy of Escherichia coli-derived rhBMP-2 with β-TCP/HA in extraction socket 
This randomized clinical trial was conducted to assess the safety and effectiveness of the ErhBMP-2 in alveolar bone regeneration as well as preservation of the β-TCP bone graft material that contains ErhBMP-2.
This study involved 72 patients at the 3 study centers. The patients, who were divided into 2 groups: the experiment group who had ErhBMP-2 coated TCP/HA and the control group who had TCP/HA graft material alone transplanted immediately after tooth extraction. CT was taken before and 3 months after the transplantation and healing status was compared between the two groups. The efficacy endpoints that were used to measure the degree of bone induction included alveolar bone height and 3 measurements of bone width. The paired t test was used to determine the significance of the changes (P<.05).
Changes in alveolar bone height were -1.087 ± 1.413 mm in the control group and -.059 ± 0.960 mm in the experimental group (P<.01). At 25% extraction socket length [ESL], the changes were 0.006 ± 1.149 mm in the control group and 1.279 ± 1.387 mm in the experimental group. At 50% ESL, the changes were 0.542 ± 1.157 mm and 1.239 ± 1.249 mm, respectively (P<.01 for 25% ESL, and P<.05 for 50% ESL). During the experiment, no adverse reactions to the graft material were observed.
ErhBMP-2 coated β-TCP/HA were found to be more effective in preserving alveolar bone than conventional β-TCP/HA alloplastic bone graft materials.
PMCID: PMC3204453  PMID: 22053248
ErhBMP-2; β-TCP/HA; Tooth extraction; Alveolar bone regeneration; Randomized clinical trial
17.  Down-regulation of phosphoglucomutase 3 mediates sulforaphane-induced cell death in LNCaP prostate cancer cells 
Proteome Science  2010;8:67.
Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables that exerts anti-oxidant, anti-inflammatory, anti-cancer and radio-sensitizing activities. Nonetheless, the mechanism responsible for SFN-induced cell death is not fully understood. In the present study, anti-cancer mechanism of SFN was elucidated in LNCaP prostate cancer cells.
SFN exerted cytotoxicity and increased TUNEL positive cells in a concentration-dependent manner in LNCaP cells. Proteomics study revealed that levels of nine proteins including tubulin β-2, phosphoglucomutase-3 (PGM3), melanoma-derived leucine zipper containing extra-nuclear factor, activin A type I receptor precursor, smoothelin-A, KIA0073, hypothetical protein LOC57691 and two unnamed proteins were changed over 8 folds in SFN treated LNCaP cells compared to untreated control. We have further confirmed that SFN reduced PGM3 expression with western blotting and showed that PGM3 siRNA enhanced cytotoxicity demonstrated by cell morphology and TUNEL assays in LNCaP cells.
Taken together, these findings suggest that PGM3 plays a role in mediating SFN-induced cell death in LNCaP cells, and is a potential molecular therapeutic target for prostate cancer.
PMCID: PMC3024296  PMID: 21159204
18.  Analysis of the Fine-Scale Population Structure of “Candidatus Accumulibacter phosphatis” in Enhanced Biological Phosphorus Removal Sludge, Using Fluorescence In Situ Hybridization and Flow Cytometric Sorting▿  
Applied and Environmental Microbiology  2010;76(12):3825-3835.
To investigate the fine-scale diversity of the polyphosphate-accumulating organisms (PAO) “Candidatus Accumulibacter phosphatis” (henceforth referred to as “Ca. Accumulibacter”), two laboratory-scale sequencing batch reactors (SBRs) for enhanced biological phosphorus removal (EBPR) were operated with sodium acetate as the sole carbon source. During SBR operations, activated sludge always contained morphologically different “Ca. Accumulibacter” strains showing typical EBPR performances, as confirmed by the combined technique of fluorescence in situ hybridization (FISH) and microautoradiography (MAR). Fragments of “Ca. Accumulibacter” 16S rRNA genes were retrieved from the sludge. Phylogenetic analyses together with sequences from the GenBank database showed that “Ca. Accumulibacter” 16S rRNA genes of the EBPR sludge were clearly differentiated into four “Ca. Accumulibacter” clades, Acc-SG1, Acc-SG2, Acc-SG3, and Acc-SG4. The specific FISH probes Acc444, Acc184, Acc72, and Acc119 targeting these clades and some helpers and competitors were designed by using the ARB program. Microbial characterization by FISH analysis using specific FISH probes also clearly indicated the presence of different “Ca. Accumulibacter” cell morphotypes. Especially, members of Acc-SG3, targeted by probe Acc72, were coccobacillus-shaped cells with a size of approximately 2 to 3 μm, while members of Acc-SG1, Acc-SG2, and Acc-SG4, targeted by Acc444, Acc184, and Acc119, respectively, were coccus-shaped cells approximately 1 μm in size. Subsequently, cells targeted by each FISH probe were sorted by use of a flow cytometer, and their polyphosphate kinase 1 (ppk1) gene homologs were amplified by using a ppk1-specific PCR primer set for “Ca. Accumulibacter.” The phylogenetic tree based on sequences of the ppk1 gene homologs was basically congruent with that of the 16S rRNA genes, but members of Acc-SG3 with a distinct morphology comprised two different ppk1 genes. These results suggest that “Ca. Accumulibacter” strains may be diverse physiologically and ecologically and represent distinct populations with genetically determined adaptations in EBPR systems.
PMCID: PMC2893498  PMID: 20418432
19.  Paeonol Oxime Inhibits bFGF-Induced Angiogenesis and Reduces VEGF Levels in Fibrosarcoma Cells 
PLoS ONE  2010;5(8):e12358.
We previously reported the anti-angiogenic activity of paeonol isolated from Moutan Cortex. In the present study, we investigated the negative effect of paeonol oxime (PO, a paeonol derivative) on basic fibroblast growth factor (bFGF)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs) (including tumor angiogenesis) and pro-survival activity in HT-1080 fibrosarcoma cell line.
Methodology/Principal Findings
We showed that PO (IC50  = 17.3 µg/ml) significantly inhibited bFGF-induced cell proliferation, which was achieved with higher concentrations of paeonol (IC50 over 200 µg). The treatment with PO blocked bFGF-stimulated migration and in vitro capillary differentiation (tube formation) in a dose-dependent manner. Furthermore, PO was able to disrupt neovascularization in vivo. Interestingly, PO (25 µg/ml) decreased the cell viability of HT-1080 fibrosarcoma cells but not that of HUVECs. The treatment with PO at 12.5 µg/ml reduced the levels of phosphorylated AKT and VEGF expression (intracellular and extracelluar) in HT-1080 cells. Consistently, immunefluorescence imaging analysis revealed that PO treatment attenuated AKT phosphorylation in HT-1080 cells.
Taken together, these results suggest that PO inhibits bFGF-induced angiogenesis in HUVECs and decreased the levels of PI3K, phospho-AKT and VEGF in HT-1080 cells.
PMCID: PMC2925949  PMID: 20808805
20.  Transcriptional activation by TLX1/HOX11 involves Gro/TLE corepressors 
The role of Groucho/transducin-like Enhancer of split (Gro/TLE) family members as corepressors of transcription is well documented. TLX1 is a homeodomain transcription factor involved in splenogenesis and neuron formation, and its aberrant expression gives rise to T-cell acute lymphoblastic leukemia. We demonstrate by glutathione-S-transferase pull-down assays, in vivo biotinylation tagging and confocal laser microscopy that TLX1 interacts with TLE1 via an Eh1-like motif. Paradoxically, we found that this motif is essential for optimal transcriptional activation of two TLX1 target genes, Aldh1a1 and Fhl1. Using a well characterized target of the Hairy/Enhancer of split 1 (HES1)·TLE1 repressor complex, the ASCL1 gene, we show that TLX1 counteraction of ASCL1 repression by HES1 in SK-N-BE(2) neuroblastoma cells is associated with dismissal of TLE1 from the ASCL1 promoter and requires the Eh1-like motif for maximal effect. Collectively, these results indicate that TLX1-mediated target gene activation can occur in part via derepression strategies involving Gro/TLE corepressors.
PMCID: PMC2654413  PMID: 19250647
TLX1 homeodomain transcription factor; Gro/TLE corepressors; Eh1-like motif; Derepression strategies
21.  Results of immediate loading for implant restoration in partially edentulous patients: a 6-month preliminary prospective study using SinusQuick™ EB implant system 
Many dental clinicians are concerned about immediate loading of inserted implants. However, there have been few clinical studies surveying the success rates of immediate loading, based on Korean implant systems.
The aim of this study was to evaluate the outcome of immediate functional loading of the implant (SinusQuick™ EB, Neobiotech Co., Seoul, Korea) in partially edentulous maxilla or mandible.
Total 15 implants were placed. Within 2 weeks after implant insertion, provisional implant-supported fixed partial dentures were delivered to the patients. Quantitatively, marginal bone loss was measured at the time of immediate loading, after 3-months of continued loading and at the last follow-up. The mean follow-up period was 4.8 months.
Mean marginal bone loss from implant surgery to early loading, 3-months follow-up and last follow-up was 0.03 ± 0.07 mm, 0.16 ± 0.17 mm and 0.29 ± 0.19 mm. No implant failed up to 6 months after insertion, resulting in a 100% survival rate.
Immediate loading exhibited high success rate in partial edentulism for up to 6 months. Well-controlled long term clinical studies with large sample size are necessary to confirm this finding.
PMCID: PMC2994691  PMID: 21165269
Immediate loading; Partially edentulous; Dental implant; Prospective clinical study; Marginal bone loss
23.  Substance P and beta-endorphin mediate electro-acupuncture induced analgesia in mouse cancer pain model 
Opioid analgesics are generally used to combat the pain associated with cancerous conditions. These agents not only inhibit respiratory function and cause constipation, but also induce other significant side effects such as addiction and tolerance, all of which further contribute to a reduced quality of life for cancer patients. Thus, in the present study, the effects of electro-acupuncture treatment (EA) on mechanical allodynia were examined in a cancer pain mouse model.
In order to produce a neuropathic cancer pain model, S-180 sarcoma cells were inoculated around the sciatic nerve of left legs of Balb/c mice. Magnetic Resonance Imaging (MRI) scanning confirmed the mass of S-180 cancer cells embedded around the sciatic nerve. Mechanical allodynia was most consistently induced in the mouse sarcoma cell line S-180 (2 × 106sarcoma cells)-treated group compared to all the other groups studied. EA stimulation (2 Hz) was administered daily to ST36 (Zusanli) of S-180 bearing mice for 30 min for 9 days after S-180 inoculation.
EA treatment significantly prolonged paw withdrawal latency from 5 days after inoculation. It also shortened the cumulative lifting duration from 7 days after inoculation, compared to the tumor control. Also, the overexpression of pain peptide substance P in the dorsal horn of the spinal cord was significantly decreased in the EA-treated group compared to the tumor control on Day 9 post inoculation. Furthermore, EA treatment effectively increased the concentration of β-endorphin in blood and brain samples of the mice to a greater extent than that of the tumor control as well as the normal group. The concentration of β-endorphin for EA treatment group increased by 51.457% in the blood and 12.6% in the brain respectively, compared to the tumor control group.
The findings of this study suggest that a S-180 cancer pain model is useful as a consistent and short time animal model. It also indicated that EA treatment could be used as an alternative therapeutic method for cancer pain due to a consequent decrease in substance P and increase in β-endorphin levels.
PMCID: PMC2724388  PMID: 19607689
24.  The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population 
BMC Cancer  2008;8:359.
Human Epidermal Growth Factor Receptor 2 (HER-2; also known as erbB-2 or neu), a proto-oncogene of the receptor tyrosine kinase superfamily, has been associated with carcinogenesis and prognosis of human cancers, acting as a binding partner of other epidermal growth factor receptor (EGFR) family in the activation of EGFR signaling. Amplification of the HER-2 gene has been reported in lung cancer, where it has been associated with poor prognosis. In this study, we investigated whether the four polymorphisms (-3444C>T, -1985 G>T, I655A A>G and P1170A C>G) of the HER-2 gene are associated with the risk of lung cancer in Korean populations.
The frequencies of 4 polymorphisms of the HER-2 gene were examined by the polymerase chain reaction-restriction fragment length polymorphism or the single-nucleotide polymorphism-identification technology assay in the 407 lung cancer patients and 407 healthy controls.
The frequencies of the 4 polymorphisms were not significantly different between patient and control groups in overall subjects. However, in the subgroup analysis, the 3 single nucleotide polymorphisms (-3444C>T, -1985G>T and P1170A C>G) showed statistically significant differences in the subgroups of females, non-smokers, and non-drinkers (p < 0.05). Additionally, we found the association between the risk of lung cancer and the polymorphisms of HER-2 gene in non-smoker subgroups with adenocarcinoma (p < 0.05).
Our results suggest that the polymorphisms of the HER-2 gene are associated with an increased susceptibility to lung cancer in females, non-smokers and non-drinkers subgroups in the Korean population.
PMCID: PMC2661000  PMID: 19055823
25.  Economic Burden of Schizophrenia in South Korea 
Journal of Korean Medical Science  2008;23(2):167-175.
This study estimates the treated prevalence of schizophrenia and the annual costs associated with the illness in Korea in 2005, from a societal perspective. Annual direct healthcare costs associated with schizophrenia were estimated from National Health Insurance and Medical Aid records. Annual direct non-healthcare costs were estimated for incarceration, transport, community mental health centers, and institutions related to schizophrenia. Annual indirect costs were estimated for the following components of productivity loss due to illness: unemployment, reduced productivity, premature mortality, and caregivers' productivity loss using a human capital approach based on market wages. All costs were adjusted to 2005 levels using the healthcare component of the Consumer Price Index. The treated prevalence of schizophrenia in 2005 was 0.4% of the Korean population. The overall cost of schizophrenia was estimated to be $ 3,174.8 million (3,251.0 billion Won), which included a direct healthcare cost of $ 418.7 million (428.6 billion Won). Total direct non-healthcare costs were estimated to be $ 121 million (123.9 billion Won), and total indirect costs were estimated at $ 2,635.1 million (2,698.3 billion Won). Unemployment was identified as the largest component of overall cost. These findings demonstrate that schizophrenia is not rare, and that represents a substantial economic burden.
PMCID: PMC2526443  PMID: 18436996
Schizophrenia; Cost of Illness; Prevalence; Direct Cost; Indirect Cost

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