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1.  Relationship between Metabolic Syndrome and Lower Urinary Tract Symptoms: Hallym Aging Study 
BioMed Research International  2015;2015:130917.
The aim of the study was to test the hypothesis that the metabolic syndrome (MS) is linked to lower urinary tract symptoms (LUTS) in Korean men. This was a longitudinal study that used data collected from 328 men aged 50–89 years who were randomly selected among 1,520 participants in 2004. We collected information from 224 (68.3%) men among the original responders on the biological, medical, psychological, social, lifestyle, and economic factors in 2007. The prevalence of the MS was 187/328 (57.0%) in 2004 and 125/224 (55.8%) in 2007 among men, respectively. There was no significantly greater increase in the IPSS in men with the MS than in men without the MS over a 3-year period of time (2.0 ± 9.37 versus 3.0 ± 8.44, p = 0.402, resp.). In the multivariate logistic regression analysis with control for age and life style factors, the risk factors for moderate/severe LUTS were age and erectile dysfunction (p < 0.05). However, the presence of the MS did not increase the risk of moderate/severe LUTS (OR = 1.09, 95% CI 0.63–1.89, p = 0.748). Our cross-sectional and longitudinal risk factor analyses do not support the hypothesis that the MS is linked to LUTS in Korean men.
doi:10.1155/2015/130917
PMCID: PMC4493267  PMID: 26199934
2.  Association between Lower Urinary Tract Symptoms and Vascular Risk Factors in Aging Men: The Hallym Aging Study 
Korean Journal of Urology  2010;51(7):477-482.
Purpose
The aim of this study was to investigate the relationship between lower urinary tract symptoms (LUTS) and risk factors for vascular diseases in a population-based cohort study, the Hallym Aging Study (HAS).
Materials and Methods
Among the 1,520 participants in HAS, 280 men aged more than 50 years, who underwent detailed health evaluations, including health-related questionnaires, evaluations of their medical history, and various life style factors, as well as clinical measurements, were included in the study. Vascular risk factors used in the present study including hypertension, diabetes mellitus, hyperlipidemia, and smoking and were assessed by medical history and clinical measurements. LUTS were assessed by validated questionnaires, the International Prostate Symptom Score (IPSS), and the relationship between LUTS and vascular risk factors was investigated.
Results
Of the 280 men, 175 (62.5%) had moderate/severe LUTS (IPSS>7) and 260 (93%) had one or more vascular risk factors. The IPSS was similar in those with no (11.6±9.7) and one or two (11.5±8.5) vascular risk factors, but increased to 15.1±9.3 in those with 3 or more vascular risk factors (p<0.05). The multiple logistic regression analysis, controlling for age and body mass index (BMI) showed that men with 3 or more vascular risk factors were 3 times more likely to have moderate/severe LUTS than men without vascular risk factors (p<0.05).
Conclusions
Men with risk factors for vascular diseases are more likely to have LUTS and these findings suggest that vascular risk factors play a role in the development of LUTS.
doi:10.4111/kju.2010.51.7.477
PMCID: PMC2907497  PMID: 20664781
Diagnosis; Risk factors; Urinary tract; Vascular diseases
3.  NAG-1/GDF15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism 
Summary
Objective
Obesity is a major health problem associated with high morbidity and mortality. NSAID activated gene, (NAG-1) is a TGF-β superfamily member reported to alter adipose tissue levels in mice. We investigated whether hNAG-1 acts as a regulator of adiposity and energy metabolism.
Design/Subjects
hNAG-1 mice, ubiquitously expressing hNAG-1, were placed on a control or high fat diet (HFD) for 12 weeks. hNAG-1 expressing B16/F10 melanoma cells were used in a xenograft model to deliver hNAG-1 to obese C57BL/6 mice.
Results
As compared to wild-type littermates, transgenic hNAG-1 mice have less white fat and brown fat despite equivalent food intake, improved glucose tolerance, lower insulin levels and are resistant to dietary- and genetic-induced obesity. hNAG-1 mice are more metabolically active with higher energy expenditure. Obese C57BL/6 mice treated with hNAG-1 expressing xenografts show decreases in adipose tissue and serum insulin levels. hNAG-1 mice and obese mice treated with hNAG-1 expressing xenografts show increased thermogenic gene expression (UCP1, PGC1α, ECH1, Cox8b, Dio2, Cyc1, PGC1β, PPARα, Elvol3) in brown adipose tissue (BAT) and increased expression of lipolytic genes (Adrb3, ATGL, HSL) in both white adipose tissue (WAT) and BAT, consistent with higher energy metabolism
Conclusion
hNAG-1 modulates metabolic activity by increasing the expression of key thermogenic and lipolytic genes in BAT and WAT. hNAG-1 appears to be a novel therapeutic target in preventing and treating obesity and insulin resistance.
doi:10.1038/ijo.2014.27
PMCID: PMC4135041  PMID: 24531647
NAG-1/GDF-15; insulin resistance; BAT; thermogenesis; lipolysis
4.  TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer 
The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice.
doi:10.3390/ijms160510411
PMCID: PMC4463653  PMID: 25961950
resveratrol; phytochemicals; TCF4; colon cancer
5.  ATF3 Mediates Anti-Cancer Activity of Trans-10, cis-12-Conjugated Linoleic Acid in Human Colon Cancer Cells 
Biomolecules & Therapeutics  2015;23(2):134-140.
Conjugated linoleic acids (CLA) are a family of isomers of linoleic acid. CLA increases growth arrest and apoptosis of human colorectal cancer cells through an isomer-specific manner. ATF3 belongs to the ATF/CREB family of transcription factors and is associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which t10, c12-CLA stimulates ATF3 expression and apoptosis in human colorectal cancer cells. t10, c12-CLA increased an apoptosis in human colorectal cancer cells in dose dependent manner. t10, c12-CLA induced ATF3 mRNA and luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by t10, c12-CLA is located between −147 and −1850 of ATF3 promoter. mRNA stability of ATF3 was not affected by t10, c12-CLA treatment. t10, c12-CLA increases GSK3β expression and suppresses IGF-1-stimulated phosphorylation of Akt. The knockdown of ATF3 suppressed expression of GSK3β and NAG-1 and PARP cleavage. The results suggest that t10, c12-CLA induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells.
doi:10.4062/biomolther.2014.107
PMCID: PMC4354314  PMID: 25767681
Conjugated linoleic acid; Activating transcription factor 3; Colon cancer
6.  Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of NF-κB Signaling 
Biomolecules & Therapeutics  2015;23(1):39-44.
Tolfenamic acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-κB) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-κB pathway in TNF-α stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-α and LPS. Transcriptional activity of NF-κB, IκB-α-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-α- or LPS-stimulated NF-κB transactivation in a dose-dependent manner. TA treatment reduced degradation of IκB-α and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-κB signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-κB pathway in different types of cells.
doi:10.4062/biomolther.2014.088
PMCID: PMC4286748  PMID: 25593642
Tolfenamic acid; NF-kappa B; Inflammation
7.  The Involvement of Endoplasmic Reticulum Stress in the Suppression of Colorectal Tumorigenesis by Tolfenamic Acid 
Cancer prevention research (Philadelphia, Pa.)  2013;6(12):10.1158/1940-6207.CAPR-13-0220.
The nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic effect remains unclear. Previous data from our group and others indicate that TA alters expression of apoptosis- and cell cycle arrest-related genes in colorectal cancer cells. Here, we show that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with cyclin D1 down-regulation in vitro and in vivo. Mechanistically, TA promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2α-ATF4 branch of the UPR pathway plays a role in TA-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates TA-induced apoptosis. Taken together, these results suggest ER stress is involved in TA-induced inhibition of colorectal cancer cell growth, which could contribute to anti-tumorigenesis in a mouse model.
doi:10.1158/1940-6207.CAPR-13-0220
PMCID: PMC3855893  PMID: 24104354
Tolfenamic acid; ER stress; cyclin D1; apoptosis; colorectal cancer
8.  3,3′-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells 
A 3,3′-diindolylmethane (DIM) is a major in vivo condensation product of indole-3-carbinol (I3C), which are present in cruciferous vegetables. Although these compounds have been widely implicated in anti-tumorigenic and pro-apoptotic properties in animal as well as in vitro models of cancer, the underlying cellular mechanisms regulated by DIM are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic-region leucine zipper (bZIP) family and has been known to induce apoptosis in human colorectal cancer cells. The present study was performed to elucidate the molecular mechanism of ATF3 induction by DIM in human CRC cells. The DIM treatment induced apoptosis and induced ATF3 gene expression at protein and mRNA levels. DIM increased ATF3 promoter activity and the region of −84 to +34 within ATF3 promoter was responsible for promoter activation by DIM. This region contained an ATF binding site. Deletion and point mutation of the ATF binding site (−23 to −16) abolished ATF3 promoter activation by DIM and overexpression of ATF4 enhanced ATF3 transactivation. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of ATF4 in the ATF3 promoter. Inhibition of ATF4 expression by siRNA results in repression of DIM-induced ATF3 expression. The current study demonstrates that DIM stimulates ATF3 expression through ATF4-mediated pathway and subsequently induces apoptosis in human colorectal cancer cells.
doi:10.1016/j.jnutbio.2012.03.016
PMCID: PMC3481000  PMID: 22819556
DIM; ATF3; ATF4; colon cancer
9.  trans-10,cis-12 conjugated linoleic acid promotes bone formation by inhibiting adipogenesis by peroxisome proliferator activated receptor-γ dependent mechanisms and by directly enhancing osteoblastogenesis from bone marrow mesenchymal stem cells 
Bone undergoes continuous remodeling of osteoblastic bone formation and osteoclastic bone resorption to maintain proper bone mass. It is also reported that bone marrow adiposity has a reciprocal role in osteoblasts due to their same origin from mesenchymal stem cells. In addition, one of the key mediators of adipogenesis, peroxisome-proliferator activated receptor-γ (PPARγ), plays a significant role in osteoblastogenesis in bone marrow mesenchymal stem cells. One dietary component that is known to have significant impact on adiposity and bone mass is conjugated linoleic acid (CLA). However, the link between controlling adiposity to improving bone mass by CLA has not been studied intensively. Thus the purpose of this study is to determine the role of CLA on bone marrow adiposity and bone formation using murine mesenchymal stem cells. The results confirmed that the trans-10,cis-12 CLA, but not the cis-9,trans-11 CLA isomer, significantly inhibited adipogenesis and promoted osteoblastogenesis from mesenchymal stem cells. The inhibition of adipogenesis by the trans-10,cis-12 CLA was mediated by PPARγ, however, the trans-10,cis-12 CLA had direct effect on osteoblastogenesis which was independent to PPARγ in this model. The trans-10,cis-12 CLA also had significant effects on osteoclastogenesis inhibitory factor (OCIF), which suggests potential influence of CLA on osteoclastogenesis. Overall the results suggest that the trans-10,cis-12, but not the cis-9,trans-11 CLA isomer, has positive impact on bone health by both PPARγ mediated and independent mechanisms in mesenchymal stem cells.
doi:10.1016/j.jnutbio.2012.03.017
PMCID: PMC3482420  PMID: 22832076
CLA; trans-10; cis-12 CLA; cis-9; trans-11 CLA; adipogenesis; osteoblastogenesis
10.  Damnacanthal, a Noni component, exhibits anti-tumorigenic activity in human colorectal cancer cells 
Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases including cancer. Although noni has been consumed for a long time in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In this report, we examined systematic approaches on the cancer suppressing capability of damnacanthal in colorectal tumorigenesis. Damnacanthal exhibits cell growth arrest as well as caspase activity induction in colorectal cancer cells. We also examined several potential target proteins and found that the pro-apoptotic protein Nonsteroidal anti-inflammatory activated gene-1 (NAG-1) is highly induced. Subsequently, we have found that damnacanthal also enhances transcription factor C/EBPβ, which controls NAG-1 transcriptional activity. Blocking of C/EBPβ by shRNA results in the reduction of NAG-1 expression as well as caspase activity in the presence of damnacanthal. Taken together, these results indicate that damnacanthal increases anti-tumorigenic activity in human colorectal cancer cells, and C/EBPβ plays a role in damnacanthal-induced NAG-1 expression.
doi:10.1016/j.jnutbio.2011.04.017
PMCID: PMC3222750  PMID: 21852088
Damnacanthal; Noni; NAG-1; GDF15; C/EBPβ; Colorectal cancer
11.  Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells 
Capsaicin is a pungent ingredient in chili red peppers and has been linked to suppression of growth in various cancer cells. However, the underlying mechanism(s) by which capsaicin induces growth arrest and apoptosis of cancer cells is not completely understood. In the present study, we investigated whether capsaicin alters β-catenin-dependent signaling in human colorectal cancer cells in vitro. Exposure of SW480, LoVo, and HCT-116 cells to capsaicin suppressed cell proliferation. Transient transfection with a β-catenin/T-cell factor (TCF)-responsive reporter indicated that capsaicin suppressed the transcriptional activity of β-catenin/TCF. Capsaicin treatment resulted in a decrease of intracellular β-catenin levels and a reduction of transcripts from the β-catenin gene (CTNNB1). These results were confirmed by a reduced luciferase reporter activity driven by promoter-reporter construct containing the promoter region of the Catnb gene. In addition, capsaicin destabilized β-catenin through enhancement of proteosomal-dependent degradation. Western blot and immunoprecipitation studies indicated that capsaicin treatment suppressed TCF-4 expression and disrupted the interaction of TCF-4 and β-catenin. This study identifies a role for the β-catenin/TCF-dependent pathway that potentially contributes to the anti-cancer activity of capsaicin in human colorectal cancer cells.
doi:10.1016/j.jnutbio.2011.03.009
PMCID: PMC3197951  PMID: 21764279
Capsaicin; β-catenin; TCF-4; Colorectal cancer
12.  Detection of Ocular Toxoplasma gondii Infection in Chronic Irregular Recurrent Uveitis by PCR 
Toxoplasma gondii is a zoonotic parasite resulting in human infections and one of the infectious pathogens leading to uveitis and retinochoroiditis. The present study was performed to assess T. gondii infection in 20 ocular patients with chronic irregular recurrent uveitis (20 aqueous humor and 20 peripheral blood samples) using PCR. All samples were analyzed by nested PCR targeting a specific B1 gene of T. gondii. The PCR-positive rate was 25% (5/20), including 5% (1) in blood samples, 25% (5) in aqueous humor samples, and 5% (1) in both sample types. A molecular screening test for T. gondii infection in ocular patients with common clinical findings of an unclear retinal margin and an inflammatory membrane over the retina, as seen by fundus examination, may be helpful for early diagnosis and treatment.
doi:10.3347/kjp.2012.50.3.229
PMCID: PMC3428569  PMID: 22949751
Toxoplasma gondii; toxoplasmosis; uveitis; nested PCR; B1 gene
13.  Is High-Sensitivity C-Reactive Protein Associated with Lower Urinary Tract Symptoms in Aging Men? Results from the Hallym Aging Study 
Korean Journal of Urology  2012;53(5):335-341.
Purpose
The pathogenesis of lower urinary tract symptoms (LUTS) is uncertain. We investigated the potential role of inflammation in the development of LUTS, with the use of high-sensitivity C-reactive protein (hsCRP) as an inflammatory marker, in a population-based study of aging men in Korea.
Materials and Methods
Our study used a multistage stratified design to recruit a random sample of 1,510 men aged 45 years or older in Chuncheon, Korea, in 2003. Men with urologic or neurologic diseases that could cause voiding dysfunction were excluded. Also, men with medical conditions that could affect inflammation, such as infection or the use of nonsteroidal anti-inflammatory drugs, were excluded. LUTS were defined according to the International Prostate Symptom Score (IPSS). Various potential confounding factors were included in the analyses.
Results
A total of 330 subjects were included in the final analyses. There were 155 (47.0%) with an IPSS<8 and 175 (53%) with an IPSS≥8. The mean age of all subjects was 69.2±8.4 years. The mean hsCRP level of all subjects was 2.30±3.27 (median, 1.19) mg/l. The hsCRP levels in subjects with an IPSS≥8 differed significantly from those in subjects with an IPSS<8. Also, IPSS, storage symptom, voiding symptom, and quality of life (QoL) scores increased as hsCRP levels increased, respectively. The hsCRP level remained an independent risk factor of LUTS (IPSS≥8, storage symptom score≥4, incomplete voiding, intermittency, and QoL) after adjustment for variable possible confounding factors.
Conclusions
Our results suggest that inflammatory processes may play an important role in the pathogenesis of LUTS and that hsCRP levels may indicate the severity of LUTS in aging men.
doi:10.4111/kju.2012.53.5.335
PMCID: PMC3364473  PMID: 22670193
C-reactive protein; Inflammation; Lower urinary tract symptoms
14.  Tolfenamic Acid Induces Apoptosis and Growth Inhibition in Head and Neck Cancer: Involvement of NAG-1 Expression 
PLoS ONE  2012;7(4):e34988.
Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is induced by nonsteroidal anti-inflammatory drugs and possesses proapoptotic and antitumorigenic activities. Although tolfenamic acid (TA) induces apoptosis in head and neck cancer cells, the relationship between NAG-1 and TA has not been determined. This study investigated the induction of apoptosis in head and neck cancer cells treated by TA and the role of NAG-1 expression in this induction. TA reduced head and neck cancer cell viability in a dose-dependent manner and induced apoptosis. The induced apoptosis was coincident with the expression of NAG-1. Overexpression of NAG-1 enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering RNA attenuated TA-induced apoptosis. TA significantly inhibited tumor formation as assessed by xenograft models, and this result accompanied the induction of apoptotic cells and NAG-1 expression in tumor tissue samples. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression in head and neck squamous cell carcinoma, providing an additional mechanistic explanation for the apoptotic activity of TA.
doi:10.1371/journal.pone.0034988
PMCID: PMC3334943  PMID: 22536345
15.  Influence of Donor's Renal Function on the Outcome of Living Kidney Transplantation: 10-Year Follow-up 
Korean Journal of Urology  2012;53(2):126-130.
Purpose
With the improved surgical techniques and immunosuppression available today, conventional prognostic factors have taken on less significance. Accordingly, the native renal function of the donor is thought to be more important. Thus, we analyzed the prognostic significance of the donor's renal function as assessed by 24-hour urine creatinine clearance on kidney graft survival for 10 years after living kidney transplantation.
Materials and Methods
From January 1998 to July 2000, 71 living kidney transplantations were performed at a single institution. From among these, 68 recipients were followed for more than 6 months and were included in the present analysis. We analyzed kidney graft survival according to clinical parameters of the donor and the recipient.
Results
Mean follow-up duration of recipients after living kidney transplantation was 115.0±39.4 months (range, 10 to 157 months), and 31 recipients (45.6%) experienced kidney graft loss during this time period. Estimated mean kidney graft survival time was 131.8±6.2 months, and 5-year and 10-year kidney graft survival rates were estimated as 88.2% and 61.0%, respectively. Donor's mean 24-hour urine creatinine clearance (Ccr) before kidney transplantation was 122.8±21.2 ml/min/1.73 m2 (range, 70.1 to 186.6 ml/min/1.73 m2). The 10-year kidney graft survival rates for cases stratified by a donor's Ccr lower and higher than 120 ml/min/1.73 m2 were 39.0% and 67.2%, respectively (p=0.005). In univariate and multivariate analysis, donor's Ccr was retained as an independent prognostic factor of kidney graft survival (p=0.001 and 0.005, respectively).
Conclusions
Donor's 24-hour urine Ccr before living kidney transplantation was an independent prognostic factor of kidney graft survival. Therefore, it should be considered before living kidney transplantation.
doi:10.4111/kju.2012.53.2.126
PMCID: PMC3285708  PMID: 22379593
Creatinine; Kidney transplantation; Survival
16.  Resveratrol-induced Apoptosis is mediated by Early Growth Response-1, Krüppel-like Factor 4, and Activating Transcription Factor 3 
Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess anti-tumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol up-regulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located at −245 to −236) and Krüppel-like factor 4 (KLF4; located at −178 to −174) putative binding sites in resveratrol-mediated ATF3 transactivation. Specificity of these sites to the Egr-1 and KLF4 protein was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Resveratrol increased Egr-1 and KLF4 expression, which preceded ATF3 expression, and further suggests Egr-1 and KLF4 involvement in resveratrol-mediated activity. We provide evidence for Egr-1 and KLF4 interaction in the presence of resveratrol, which may facilitate ATF3 transcriptional regulation by this compound. Furthermore, we demonstrate induction of apoptosis by resveratrol is mediated, in part, by increased ATF3 expression. Taken together, these results provide a novel mechanism by which resveratrol induces ATF3 expression and represent an additional explanation of how resveratrol exerts its anti-tumorigenic effects in human colorectal cancer cells.
doi:10.1158/1940-6207.CAPR-10-0218
PMCID: PMC3064282  PMID: 21205742
resveratrol; apoptosis; ATF3; Egr-1; and KLF4
17.  Molecular targets of apigenin in colorectal cancer cells: Involvement of p21, NAG-1 and p53 
Persuasive epidemiological and experimental evidence suggests that dietary flavonoids have anti-cancer activity. Since conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of most cancer types, including colorectal neoplasia, there is an urgent need to develop alternative approaches for the management of cancer. We sought to develop the best flavonoids for the inhibition of cell growth, and apigenin (flavone) proved the most promising compound in colorectal cancer cell growth arrest. Subsequently, we found that pro-apoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21) were induced in the presence of apigenin, and kinase pathways, including PKCδ and ataxia telangiectasia mutated (ATM), play an important role in activating these proteins. The data generated by in vitro experiments were confirmed in an animal study using APCMIN+ mice. Apigenin is able to reduce polyp numbers, accompanied by increasing p53 activation through phosphorylation in animal models. Our data suggest apparent beneficial effects of apigenin on colon cancer.
doi:10.1016/j.ejca.2010.07.007
PMCID: PMC2988105  PMID: 20709524
Apigenin; p53; p21; NAG-1; PKCδ; colorectal cancer
18.  Spontaneous Recovery of Cavernous Nerve Crush Injury 
Korean Journal of Urology  2011;52(8):560-565.
Purpose
To investigate pathophysiological consequences and spontaneous recovery after cavernous nerve crush injury (CNCI) in a rat model.
Materials and Methods
Twenty 4-week-old male Sprague-Dawley rats were divided into the following groups: sham-operated group (n=10) and bilateral CNCI groups (n=10) for two different durations (12 and 24 weeks). At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expression of hypoxia inducible factor (HIF)-1α and sonic hedgehog (SHH) was examined in penile tissue. Immunohistochemical staining was performed for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and smooth muscle α-actin.
Results
CNCI significantly decreased erectile function at 12 weeks (51.7% vs. 71.9%, mean ICP/BP ratio, p<0.05) and increased the expression of HIF-1α and decreased the expression of eNOS, nNOS, and SHH. At 24 weeks, erectile function in the CNCI group was improved with no significant difference versus the sham group (70.5% vs. 63.3%, mean ICP/BP ratio, p<0.05) or the CN group at 12 weeks (51.7% vs. 63.3%, mean ICP/BP ratio, p<0.05). By RT-PCR, the increase in HIF-1α and decrease in SHH mRNA was restored at 24 weeks. By immunohistochemistry, the expression of eNOS and nNOS was increased at 24 weeks.
Conclusions
CN injury induces significantly impaired erectile function and altered gene and protein expression, which suggests that local hypoxic and inflammatory processes may contribute to this change. Significant spontaneous recovery of erectile function was observed at 6 months after CN crush injury.
doi:10.4111/kju.2011.52.8.560
PMCID: PMC3162223  PMID: 21927704
Erectile dysfunction; Hedgehog proteins; Nerve injury
19.  MCC-555-induced NAG-1 expression is mediated in part by KLF4 
European journal of pharmacology  2010;637(1-3):30-37.
Peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in cell differentiation, metabolism and tumorigenesis. We have investigated the therapeutic properties of 5-[[6-[(2-fluorophenyl)-methoxy]-2-napthalenyl]-methyl]-2,4-thiazolidinedione (MCC-555) a PPARγ agonist in human colorectal cancer cells. To elucidate the molecular mechanism(s), by which MCC-555 exerts its effects on the human colorectal cancer cells, we have analyzed the expression of two proapoptotic proteins, Krüppel-like factor 4 (KLF4) and nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1). MCC-555-induced expression of the transcription factor, KLF-4 was blocked by a PPARγ specific antagonist GW9662 in PPARγ-dependent manner in HCT-116 cells. We further identified a new KLF4 target gene NAG-1, which shows a pro-apoptotic activity. We confirmed that PPARγ agonists-induced NAG-1 expression was abolished using KLF4 siRNA in HCT-116 cells. Subsequently, KLF4 expression enhances the NAG-1 promoter activity in HCT-116 cells, and functional KLF4 binding sites in the NAG-1 promoter were also identified. MCC-555, a PPARγ agonist induced the expression of Klf4 mRNA and protein in murine intestinal tumors from MCC-555-treated mice, as assessed by RT-PCR and immunohistochemistry. This study shows that PPARγ agonists up-regulate KLF4 expression in receptor-dependent manner, and KLF4 was identified as a novel transcription factor that controls NAG-1 promoter activity in human and mouse colorectal cancers.
doi:10.1016/j.ejphar.2010.03.055
PMCID: PMC2878920  PMID: 20385121
MCC-555; KLF4; NAG-1; thiazolidinediones
20.  Effect of Desmopressin with Anticholinergics in Female Patients with Overactive Bladder 
Korean Journal of Urology  2011;52(6):396-400.
Purpose
The aim of this study was to evaluate the effect of desmopressin combined with anticholinergics on daytime frequency and urgency in female patients with overactive bladder (OAB).
Materials and Methods
We included 68 female patients with OAB. Patients were randomly assigned to receive 5 mg of solifenacin (group I) or 5 mg of solifenacin and 0.2 mg of desmopressin (group II) for 2 weeks. A pre/post-treatment 3-day voiding diary and the Urinary Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) were used to assess changes in voiding symptoms and quality of life (QoL); results were compared between the two groups.
Results
Groups I and II included 31 and 37 patients, respectively. Time to first void was 12 min later in group II (105 min vs. 117 min), but this difference was not statistically significant. However, time to the second and third voids (203 min vs. 255 min, 312 min vs. 368 min) and the first urgency episode (212 min vs. 255 min) were significantly longer in group II. Compared with group I, patients in group II showed significant improvement in QoL scores. When improvement after treatment was defined as increase in time to first void of greater than 10% after 2 weeks of treatment, desmopressin with anticholinergics was more effective in patients over the age of 65 years and with more than 150 ml of voided volume.
Conclusions
Desmopressin combined with anticholinergics was more effective than anticholinergics only in the treatment of female patients with OAB.
doi:10.4111/kju.2011.52.6.396
PMCID: PMC3123815  PMID: 21750750
Anticholinergics; Desmopressin; Overactive bladder
21.  NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3β, C/EBPβ and ATF3 
Carcinogenesis  2010;31(4):719-728.
Capsaicin, a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress growth. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and antitumorigenic property in colorectal and lung cancer. Our data demonstrate that capsaicin leads to induction of apoptosis and up-regulates NAG-1 gene expression at the transcriptional level. Overexpression of CCAAT/enhancer binding protein β (C/EBPβ) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBPβ binding sites in the NAG-1 promoter responsible for capsaicin-induced NAG-1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of C/EBPβ to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBPβ, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBPβ with glycogen synthase kinase 3β (GSK3β) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBPβ with GSK3β and ATF3 are decreased by the inhibition of the GSK3β and Protein Kinase C pathways. Knockdown of C/EBPβ, GSK3β or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBPβ phosphorylation through GSK3β may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.
doi:10.1093/carcin/bgq016
PMCID: PMC2847092  PMID: 20110283
22.  Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways 
Oncogene  2010;29(37):5182-5192.
Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug associated with anti-tumorigenic and pro-apoptotic properties in animal and in vitro models of cancer. However, the underlying cellular mechanisms by which TA exerts its effects are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region-leucine zipper family and has been known as a tumor suppressor in human colorectal cancer cells. The present study was performed to observe whether ATF3 mediates TA-induced apoptosis and to elucidate the molecular mechanism of ATF3 transcription induced by TA. TA treatment and ectopic expression of ATF3 increased apoptosis whereas knockdown of ATF3 resulted in significant repression of TA-activated apoptosis. The TA treatment also induced ATF3 promoter activity. Internal deletion and point mutation of the predicted ATF/C/EBP binding site in ATF3 promoter abolished luciferase activation by TA. Overexpression of ATF2 resulted in significant increase of ATF3 promoter activity, and electrophoretic mobility shift assay identified this region as a core sequence to which ATF2 binds. TA treatment resulted in an increase of ATF2 phosphorylation, which was followed by a subsequent increase of ATF3 transcription. Knockdown of ATF2 abolished TA-induced ATF3 expression. We further provide evidence that TA leads to increases of phospho-p38 MAPK, JNK, and ERK levels. Inhibition of these pathways using selective inhibitors and dominant negative constructs ameliorated TA-induced ATF3 expression and promoter activities. The current study demonstrates that TA stimulates ATF3 expression and subsequently induces apoptosis. These pathways are mediated through phosphorylation of ATF2, which is mediated by p38 MAPK, JNK, and ERK-dependent pathways.
doi:10.1038/onc.2010.251
PMCID: PMC2940954  PMID: 20581861
Tolfenamic acid; ATF2; ATF3; apoptosis; colorectal cancer
23.  Antidiabetic Activities of Abutilon indicum (L.) Sweet Are Mediated by Enhancement of Adipocyte Differentiation and Activation of the GLUT1 Promoter 
Abutilon indicum (L.) Sweet is an Asian phytomedicine traditionally used to treat several disorders, including diabetes mellitus. However, molecular mechanisms supporting the antidiabetic effect of A. indicum L. remain unknown. The aim of this study was to evaluate whether extract of A. indicum L. improves insulin sensitivity. First, we observed the antidiabetic activity of aqueous extract of the entire plant (leaves, twigs and roots) of A. indicum L. on postprandial plasma glucose in diabetic rats. The subsequent experiments revealed that butanol fractions of the extract bind to PPARγ and activate 3T3-L1 differentiation. To measure glucose uptake enhanced by insulin-like activity, we used rat diaphragm incubated with various concentrations of the crude extract and found that the extract enhances glucose consumption in the incubated solution. Our data also indicate that the crude extract and the fractions (water and butanol) did not affect the activity of kinases involved in Akt and GSK-3β pathways; however, the reporter assay showed that the crude extract could activate glucose transporter 1 (GLUT1) promoter activity. These results suggest that the extract from A. indicum L. may be beneficial for reducing insulin resistance through its potency in regulating adipocyte differentiation through PPARγ agonist activity, and increasing glucose utilization via GLUT1.
doi:10.1093/ecam/neq004
PMCID: PMC3094712  PMID: 21603234
24.  Cell adhesion property affected by cyclooxygenase and lipoxygenase: Opto-electric approach 
Expression of cyclooxygenases (COX) and lipoxygenases (LOX) has been linked to many pathophysiological phenotypes, including cell adhesion. However, many current approaches to measure cellular changes are performed only in a fixed time point. Since cells dynamically move in conjunction with the cell matrix, there is a pressing need for dynamic or time-dependent methods for the investigation of cell properties. In the presented study, we used stable human colorectal cancer cell lines ectopically expressing COX-1, COX-2, and 15LOX-1, to investigate whether expression of COX-1, COX-2, or 15LOX-1 would affect cell adhesion using our opto-electric methodology. In a fixed time point experiment, only COX-1- and COX-2-expressing cells enhanced phosphorylation of focal adhesion kinase, but all the transfected cells showed invasion activity. However, in a real-time experiment using opto-electric approaches, transmitted cellular morphology was much different with tight adhesion being shown in COX-2 expressing cells, as imaged by differential interference contrast microscopy (DICM) and interference reflection contrast microscopy (IRCM). Furthermore, micro-impedance measurements showed a continued increase in both resistance and reactance of COX- and LOX-transfected cells, consistent with the imaging data. Our data indicate that both COX- and LOX-expressing cells have strong cell-to-cell and cell-to-substrate adhesions, and that cell imaging analysis with cell impedance data generates fully reliable results on cell adhesion measurement.
doi:10.1016/j.bbrc.2009.12.069
PMCID: PMC2814420  PMID: 20026301
Cyclooxygenase; DICM; IRCM; Lipoxygenase; Impedance
25.  Stent Position Is More Important than α-Blockers or Anticholinergics for Stent-Related Lower Urinary Tract Symptoms after Ureteroscopic Ureterolithotomy: A Prospective Randomized Study 
Korean Journal of Urology  2010;51(9):636-641.
Purpose
To evaluate the clinical factors that impact ureteral stent-related lower urinary tract symptoms (LUTS) after ureteroscopic ureterolithotomy, including the stent position and medication.
Materials and Methods
Fifty-three patients who underwent ureteroscopic ureterolithotomy with indwelling a stent were distributed into three groups. On demand analgesics were given to the group 1 (n=18). Daily tamsulosin 0.2 mg was added for group 2 (n=15) and daily tamsulosin 0.2 mg and tolterodine 4 mg was added for group 3 (n=20). The patients were also subclassified into appropriate or inappropriate group according to stent position. All the patients completed a visual analogue scale (VAS) and International Prostate Symptom Score (IPSS) on the 1st and 7th postoperative days. The VAS and IPSS were analyzed according to the medication groups and the stent position.
Results
In the appropriate stent potion group, only the storage symptom scores of groups 2 and 3 on the 1st postoperative day were significantly lower than those of the group 1 (p=0.001). This medication effect on LUTS was not observed in the inappropriate stent position group. In this group, total IPSS (p=0.015) and storage symptom scores (p=0.002) were higher than in the appropriate stent position group on the 7th postoperative day.
Conclusions
Correct placement of the stent was more important than medication for lessening stent-related storage symptoms.
doi:10.4111/kju.2010.51.9.636
PMCID: PMC2941813  PMID: 20856649
Adrenergic alpha-antagonists; Cholinergic antagonists; Ureteroscopy; Urinary catheterization; Urological manifestations

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