Publications by authors named "Sung-Kwon Moon"

193 Publications

Urinary microRNA-1913 to microRNA-3659 expression ratio as a non-invasive diagnostic biomarker for prostate cancer.

Investig Clin Urol 2021 Mar 16. Epub 2021 Mar 16.

Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.

Purpose: MicroRNAs (miRNAs) are small non-coding RNAs and are involved in the development, proliferation, and pathogenesis of prostate cancer (PCa). Urinary miRNAs are promising non-invasive biomarkers for PCa diagnosis because of their stability in urine. Here, we evaluated the diagnostic value of urinary miR-1913 to miR-3659 ratio in PCa patients and benign prostate hyperplasia (BPH) controls.

Materials And Methods: Candidate miRNAs were identified from urinary microarray data and tested by real-time PCR. The urinary miR-1913 to miR-3659 expression ratio was selected and tested in 83 urine samples (44 PCa and 39 BPH) to confirm its validity as a non-invasive diagnostic biomarker for PCa.

Results: The expression ratio of urinary miR-1913 to miR-3659 was significantly higher in PCa than in BPH (p=0.002) and showed a higher area under the receiver operating characteristic curve than prostate-specific antigen (PSA; 0.821 vs. 0.518) in patients within the PSA gray zone (tPSA: 3-10 ng/mL), with sensitivity of 75.0% and specificity of 78.6% (p=0.003).

Conclusions: The urinary miR-1913 to miR-3659 expression ratio was increased in PCa and may serve as a useful supplemental biomarker to PSA for the diagnosis of PCa, particularly in patients within the PSA gray zone.
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http://dx.doi.org/10.4111/icu.20200488DOI Listing
March 2021

Betulinic Acid Restricts Human Bladder Cancer Cell Proliferation In Vitro by Inducing Caspase-Dependent Cell Death and Cell Cycle Arrest, and Decreasing Metastatic Potential.

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

Anti-Aging Research Center, Dong-eui University, Busan 47340, Korea.

Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid and generally found in the bark of birch trees ( sp.). Although several studies have been reported that BA has diverse biological activities, including anti-tumor effects, the underlying anti-cancer mechanism in bladder cancer cells is still lacking. Therefore, this study aims to investigate the anti-proliferative effect of BA in human bladder cancer cell lines T-24, UMUC-3, and 5637, and identify the underlying mechanism. Our results showed that BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest. Furthermore, BA decreased the expression of cell cycle regulators, such as cyclin B1, cyclin A, cyclin-dependent kinase (Cdk) 2, cell division cycle (Cdc) 2, and Cdc25c. In addition, BA-induced apoptosis was associated with mitochondrial dysfunction that is caused by loss of mitochondrial membrane potential, which led to the activation of mitochondrial-mediated intrinsic pathway. BA up-regulated the expression of Bcl-2-accociated X protein (Bax) and cleaved poly-ADP ribose polymerase (PARP), and subsequently activated caspase-3, -8, and -9. However, pre-treatment of pan-caspase inhibitor markedly suppressed BA-induced apoptosis. Meanwhile, BA did not affect the levels of intracellular reactive oxygen species (ROS), indicating BA-mediated apoptosis was ROS-independent. Furthermore, we found that BA suppressed the wound healing and invasion ability, and decreased the expression of Snail and Slug in T24 and 5637 cells, and matrix metalloproteinase (MMP)-9 in UMUC-3 cells. Taken together, this is the first study showing that BA suppresses the proliferation of human bladder cancer cells, which is due to induction of apoptosis, necrosis, and cell cycle arrest, and decrease of migration and invasion. Furthermore, BA-induced apoptosis is regulated by caspase-dependent and ROS-independent pathways, and these results provide the underlying anti-proliferative molecular mechanism of BA in human bladder cancer cells.
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http://dx.doi.org/10.3390/molecules26051381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961550PMC
March 2021

Optimization of resuscitation-promoting broths for the revival of from a viable but nonculturable state.

Food Sci Biotechnol 2021 Jan 18;30(1):159-169. Epub 2020 Nov 18.

Department of Food and Nutrition, Chung-Ang University, 4726, Seodong-daero, Anseong-si, Gyeonggi-do Republic of Korea.

This study was conducted to examine the effect of formulated resuscitation-promoting broths on the revival of viable but nonculturable induced by cold and starvation stresses. was incubated in artificial sea water at 4 °C for more than 8 months until this bacterium became undetectable, while retaining its intact cell count of more than 10 CFU/field over time. On day 250, . was collected and enriched in tryptic soy broth supplemented with 3% NaCl, 10,000 U/mg catalase, 2% sodium pyruvate, 20 mM MgSO, 5 mM EDTA, and a cell-free supernatant taken from ATCC 17802 in the stationary phase (pH 8). returned partially to a culturable state with a maximal cell density of 7.91 log CFU/mL in this formulated medium following 7 days of enrichment at 25 °C. In contrast, no . was resuscitated when enriched in alkaline peptone water and tryptic soy broth.
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http://dx.doi.org/10.1007/s10068-020-00843-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847471PMC
January 2021

A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Urology, Chungbuk National University College of Medicine, Cheongju 28644, Korea.

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools.
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http://dx.doi.org/10.3390/ijms22031450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867154PMC
February 2021

A Novel Cyclic Pentadepsipeptide, -Methylsansalvamide, Suppresses Angiogenic Responses and Exhibits Antitumor Efficacy against Bladder Cancer.

Cancers (Basel) 2021 Jan 7;13(2). Epub 2021 Jan 7.

College of Biotechnology and Natural Resources, Chung-Ang University, Anseong 17546, Korea.

Here, we explored the anti-tumor efficacy of a cyclic pentadepsipeptide, -methylsansalvamide (MSSV), in bladder cancer. MSSV inhibited the proliferation of both bladder cancer 5637 and T24 cells, which was attributed to the G1-phase cell cycle arrest, apoptosis induction, and alteration of mitogen-activated protein kinases (MAPKs) and protein kinase b (AKT) signaling pathways. Additionally, the treatment of bladder cancer cells with MSSV suppressed migratory and invasive potential via the transcription factor-mediated expression of matrix metalloproteinase 9 (MMP-9). MSSV abrogated vascular endothelial growth factor (VEGF)-induced angiogenic responses in vitro and in vivo. Furthermore, our result showed the potent anti-tumor efficacy of MSSV in a xenograft mouse model implanted with bladder cancer 5637 cells. Finally, acute toxicity test data obtained from blood biochemical test and liver staining indicated that the oral administration of MSSV at 2000 mg/kg caused no adverse cytotoxic effects. Our preclinical data described the potent anti-angiogenic and anti-tumor efficacy of MSSV and showed no signs of acute toxicity, thereby suggesting the putative potential of oral MSSV as a novel anti-tumor agent in bladder cancer treatment.
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http://dx.doi.org/10.3390/cancers13020191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827157PMC
January 2021

A prognostic immune predictor, HLA-DRA, plays diverse roles in non-muscle invasive and muscle invasive bladder cancer.

Urol Oncol 2021 Apr 15;39(4):237.e21-237.e29. Epub 2020 Dec 15.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea; Institute of Urotech, Cheongju, South Korea. Electronic address:

Background: There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).

Materials And Methods: Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.

Results: Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.

Conclusions: High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.017DOI Listing
April 2021

Sphingomonas horti sp. nov., a novel bacterial species isolated from soil of a tomato garden.

Arch Microbiol 2021 Mar 24;203(2):543-548. Epub 2020 Sep 24.

Department of Food and Nutrition, Chung-Ang University, Anseong, Gyeonggi-do, 17546, Republic of Korea.

A novel bacterial strain, designated MAH-20, was isolated from a soil sample of a tomato garden. Cells of strain MAH-20 were Gram-stain negative, aerobic, motile, and rod-shaped. The colonies were light brown colored, smooth, spherical, and 0.2-0.7 mm in diameter when grown on Luria-Bertani agar for 2 days. Strain MAH-20 grows at 15-40 °C (optimum growth temperature 30-32 °C), at pH 5.0-10.0 (optimum growth pH 7.0) and at 0-2.0% NaCl. The strain showed positive activity for both oxidase and catalase tests. Cells were able to hydrolyze starch, DNA, urea, gelatin, L-arginine, and Tween 20. According to the 16S rRNA gene sequence similarity, the strain MAH-20 was identified as a new member of the genus Sphingomonas and had the close sequence similarity with Sphingomonas changbaiensis V2M44 (98.9%) and Sphingomonas tabacisoli X1-8 (98.1%). The genomic ANI value between strain MAH-20 and S. changbaiensis NBRC 104936 was 84.4%. The novel strain MAH-20 has a draft genome size of 3,350,026 bp (25 contigs), annotated with 3210 protein-coding genes, 46 tRNA, and 3 rRNA genes. The genomic DNA G + C content of isolate was 67.3 mol%, the predominant quinone was ubiquinone 10 and the major fatty acids were C, C ω6c and summed feature 8 (comprising C ω7c and/or C ω6c). On the basis of DNA-DNA hybridization results, phenotypic, genotypic, and chemotaxonomic data, the isolated strain MAH-20 represents a novel species, for which the name Sphingomonas horti sp. nov. is proposed, with MAH-20 as the type strain (= KACC 19746 = CGMCC1.13658).
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http://dx.doi.org/10.1007/s00203-020-02056-xDOI Listing
March 2021

sp. nov., a novel bacterial species isolated from pine garden soil.

Int J Syst Evol Microbiol 2020 Nov 23;70(11):5841-5847. Epub 2020 Sep 23.

Department of Food and Nutrition, Chung-Ang University, Anseong-si, Gyeonggi-do, 17546, Republic of Korea.

A Gram-stain-negative, aerobic, non-motile and rod- or coccoid-shaped novel bacterial strain, designated MAH-25, was isolated from soil sampled in a pine garden. The colonies were observed to be light pink-coloured, smooth, spherical and 1-2 mm in diameter when grown on nutrient agar for 2 days. Strain MAH-25 was found to be able to grow at 15-35 °C, at pH 5.0-8.0 and at 0-2.0 % NaCl. Cell growth occurred on Reasoner's 2A agar and nutrient agar. The strain was found to be positive in both oxidase and catalase tests. According to 16S rRNA gene sequence comparisons, the isolate was identified as a member of the genus and closely related to 5-10 (98.0 % similarity), TMB834 (97.7 %), TTB310 (97.6 %) and YS3.2.7 (97.3 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain MAH-25 and the four closely related type strains were in the range of 78.8-81.3 % and 22.3-24.1 %, respectively. The novel strain MAH-25 has a draft genome size of 5 505 957 bp (11 contigs), annotated with 5210 protein-coding genes, 46 tRNA and three rRNA genes. The genomic DNA G+C content was determined to be 70.3 mol%. The predominant isoprenoid quinone was ubiquinone 8 (Q-8). The major fatty acids were identified as C, summed feature 3 (C7 and/or C6) and summed feature 8 (C7 and/or C6). The main polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. On the basis of DNA-DNA hybridization, genotypic analysis, chemotaxonomic and physiological data, strain MAH-25 represents a novel species within the genus , for which the name sp. nov. is proposed, with MAH-25 (=KACC 19839=CGMCC1.13660) as the type strain.
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http://dx.doi.org/10.1099/ijsem.0.004486DOI Listing
November 2020

Carnosine Impedes PDGF-Stimulated Proliferation and Migration of Vascular Smooth Muscle Cells In Vitro and Sprout Outgrowth Ex Vivo.

Nutrients 2020 Sep 3;12(9). Epub 2020 Sep 3.

Department of Food and Nutrition, Chung-Ang University, 4726 Seodong-Daero, Daedeok-Myeon, Anseong 17546, Korea.

Carnosine, a naturally producing dipeptide, exhibits various beneficial effects. However, the possible role of carnosine in vascular disorders associated with pathological conditions, including proliferation and migration of vascular smooth muscle cells (VSMCs), largely remains unrevealed. Here, we investigated the regulatory role and mechanism of carnosine in platelet-derived growth factor (PDGF)-induced VSMCs. Carnosine inhibited the proliferation of PDGF-induced VSMCs without any cytotoxic effects. Carnosine treatment also induced G1-phase cell cycle arrest by causing a p21WAF1-mediated reduction in the expression of both cyclin-dependent kinases (CDKs) and cyclins in PDGF-treated VSMCs. Carnosine treatment suppressed c-Jun N-terminal kinase (JNK) phosphorylation in PDGF-stimulated signaling. Additionally, carnosine significantly prevented the migration of VSMCs exposed to PDGF. Carnosine abolished matrix metalloproteinase (MMP)-9 activity via reduced transcriptional binding activity of NF-κB, Sp-1, and AP-1 motifs in PDGF-treated VSMCs. Moreover, using aortic assay ex vivo, it was observed that carnosine addition attenuated PDGF-stimulated sprout outgrowth of VSMCs. Taken together, these results demonstrated that carnosine impeded the proliferation and migration of PDGF-stimulated VSMCs by regulating cell cycle machinery, JNK signaling, and transcription factor-mediated MMP-9 activity as well as prevented ex vivo sprout outgrowth of blood vessels. Thus, carnosine may be a potential candidate for preventing vascular proliferative disease.
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http://dx.doi.org/10.3390/nu12092697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551855PMC
September 2020

Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Anti-Aging Research Center, Dong-Eui University, Busan 47340, Korea.

Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and treatment is very limited due to its high recurrence and low diagnosis rate, and therefore there is an increasing need to develop more effective drugs to treat HCC. Coptisine is one of the isoquinoline alkaloids, and it has various pharmacological effects. However, the evidence for the molecular mechanism of the anticancer efficacy is still insufficient. Therefore, this study investigated the antiproliferative effect of coptisine on human HCC Hep3B cells and identified the action mechanism. Our results showed that coptisine markedly increased DNA damage and apoptotic cell death, which was associated with induction of death receptor proteins. Coptisine also significantly upregulated expression of proapoptotic Bax protein, downregulated expression of anti-apoptotic Bcl-2 protein, and activated caspase-3, -8, and -9. In addition, coptisine remarkably increased the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and release of cytochrome into the cytoplasm. However, -acetylcysteine (NAC), a ROS scavenger, significantly attenuated the apoptosis-inducing effect of coptisine. It is worth noting that coptisine significantly upregulated phosphorylation of ROS-dependent c-Jun N-terminal kinase (JNK), whereas treatment with JNK inhibitor could suppress an apoptosis-related series event. Taken together, our results suggest that coptisine has an anticancer effect in Hep3B cells through ROS-mediated activation of the JNK signaling pathway.
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http://dx.doi.org/10.3390/ijms21155502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432186PMC
July 2020

In Vitro and In Vivo Antitumor Efficacy of Celluclast Extract against Bladder Cancer.

Nutrients 2020 Jul 21;12(7). Epub 2020 Jul 21.

Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea.

Various physiological benefits have been linked to (HF), an edible brown seaweed. Here, fucose-containing sulfated polysaccharides were extracted from celluclast-processed HF (SPHF) and their antitumor efficacy against bladder cancer was evaluated in vitro and in vivo. SPHF possesses high sulfated polysaccharide and fucose contents and free radical scavenging activities compared to those of celluclast-processed HF extracts (CHF). SPHF inhibited bladder cancer EJ cell proliferation via G1-phase cell cycle arrest. This was due to the induction of p21WAF1 expression associated with the downregulation of CDKs and cyclins. Moreover, JNK phosphorylation was identified as an SPHF-mediated signaling molecule. SPHF treatment also hindered the migration and invasion of EJ cells by inhibiting MMP-9 expression, which was attributed to the repression of transcriptional binding to NF-κB, AP-1, and Sp-1 in the MMP-9 promoter region. In an animal study, SPHF treatment suppressed EJ tumor growth in xenograft mice similarly to cisplatin. Furthermore, no toxicity signs were found after weight loss assessment, biochemical tests, and organ tissue immunostaining during oral administration of 20-200 mg/kg SPHF for 20 days. Therefore, our study demonstrates the antitumor efficacy of SPHF in vitro and in vivo, thus highlighting its potential for bladder cancer treatment development.
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http://dx.doi.org/10.3390/nu12072159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401265PMC
July 2020

Peanut Sprout Extracts Cultivated with Fermented Sawdust Medium Inhibits Benign Prostatic Hyperplasia and .

World J Mens Health 2020 Jul 19;38(3):385-396. Epub 2020 Mar 19.

Department of Food and Nutrition, College of Biotechnology and Natural Resources, Chung-Ang University, Anseong, Korea.

Purpose: In this study, we tested whether the resveratrol-enriched peanut sprout extracts cultivated with fermented sawdust medium (PSEFS) could suppress benign prostatic hyperplasia (BPH) and .

Materials And Methods: The mode of action of PSEFS was estimated by employing high-performance liquid chromatography analysis, MTT assay, cell counting, cell cycle analysis, immunoblots, and immunoprecipitation and electrophoretic mobility shift assay. efficacy of PSEFS was analyzed in BPH animal model immunostaining and enzyme-linked immunosorbent assay.

Results: We selected the peanut sprout variety, which contains the highest level of resveratrol. The resveratrol levels in PSEFS were higher than those obtained with hydroponic technology. PSEFS treatment induced cell cycle arrest at the G1-phase by downregulating CDK4 and cyclin D1 p21WAF1 induction in the RWPE-1 and WPMY prostate cells, thereby decreasing their proliferation. Treatment with PSEFS decreased ERK1/2 phosphorylation and increased JNK phosphorylation. The levels of DNA-bound transcription factors associated with proliferation (nuclear factor-κB, Sp-1, and AP-1) decreased upon PSEFS treatment in both prostate cells. Additionally, the levels of the molecular markers of BPH development (5α-reductase, androgen receptor, fibroblast growth factor, Bcl-2, and Bax) also changed by the addition of PSEFS. Finally, in a testosterone propionate-induced BPH model in rats, PSEFS administration attenuated the size, weight, and thickness of prostate tissues with no signs of death.

Conclusions: These results showed that PSEFS inhibited BPH both and and might be useful in the development of a potential BPH therapy.
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http://dx.doi.org/10.5534/wjmh.190173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308230PMC
July 2020

Honokiol ameliorates oxidative stress-induced DNA damage and apoptosis of c2c12 myoblasts by ROS generation and mitochondrial pathway.

Anim Cells Syst (Seoul) 2020 28;24(1):60-68. Epub 2019 Dec 28.

Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan, Republic of Korea.

Honokiol is one of the main active components of , and has been demonstrated to have multiple pharmacological activities against a variety of diseases. Recently, this phenolic compound is known to have antioxidant activity, but its mechanism of action remains unclear. The purpose of the current study was to evaluate the preventive effects of honokiol against oxidative stress-induced DNA damage and apoptosis in C2C12 myoblasts. The present study found that honokiol inhibited hydrogen peroxide (HO)-induced DNA damage and mitochondrial dysfunction, while reducing reactive oxygen species (ROS) formation. The inhibitory effect of honokiol on HO-induced apoptosis was associated with the up-regulation of Bcl-2 and down-regulation of Bax, thus reducing the Bax/Bcl-2 ratio that in turn protected the activation of caspase-9 and -3, and inhibition of poly (ADP-ribose) polymerase cleavage, which was associated with the blocking of cytochrome release to the cytoplasm. Collectively, these results demonstrate that honokiol defends C2C12 myoblasts against HO-induced DNA damage and apoptosis, at least in part, by preventing mitochondrial-dependent pathway through scavenging excessive ROS.
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http://dx.doi.org/10.1080/19768354.2019.1706634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048179PMC
December 2019

Trans-resveratrol extraction from peanut sprouts cultivated using fermented sawdust medium and its antioxidant activity.

J Food Sci 2020 Mar 20;85(3):639-646. Epub 2020 Feb 20.

Dept. of Food and Nutrition, Chung-Ang Univ., Anseoung-si, Gyeonggi-do, 456-756, Korea.

Peanut sprouts are a functional food material rich in phytochemicals, including trans-resveratrol. This study aimed to optimize the recovery of trans-resveratrol from peanut sprouts using a combination of peanut varieties and sawdust medium through accelerated solvent extraction (ASE) and the response surface method (RSM). We also aimed to determine the antioxidant activity of this trans-resveratrol extract. Optimal fermentation periods of sawdust and peanut variety for cultivating peanut sprouts were determined on the basis of trans-resveratrol content via high-performance liquid chromatography. The extraction variables temperature, static time, and ethanol concentration were used to create a 20-sample set fit to a second-order polynomial equation through multiple regression analysis (R = 0.8787, P < 0.01). Trans-resveratrol content (19.62 ± 2.33 µg/g) peaked in the Palgwang variety cultured in sawdust medium fermented for 45 days. Optimal conditions for ASE were determined regarding the extraction temperature (90.29 °C), static time (3.95 min), and solvent (81.54% EtOH/water), and the predicted trans-resveratrol content under optimal conditions was 30.23 µg/g. Sawdust medium was more effective in increasing the trans-resveratrol content than conventional hydroponics, and the optimized process of combining fermented sawdust cultivation for harvesting peanut sprouts with ASE has potential as an efficient method of obtaining mass quantities of trans-resveratrol from peanut sprouts with improved nutritional and functional properties. PRACTICAL APPLICATION: This study showed that sawdust medium is more effective than hydroponics in increasing the trans-resveratrol content in peanut sprouts. The recovery of trans-resveratrol from peanut sprouts and its antioxidant activity were optimized via accelerated solvent extraction (ASE) and the response surface methodology (RSM). The optimized process of combining fermented sawdust cultivation for harvesting peanut sprouts with ASE potentially provides an efficient method to obtain mass quantities of trans-resveratrol from peanut sprouts with improved nutritional and functional properties.
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http://dx.doi.org/10.1111/1750-3841.14981DOI Listing
March 2020

A facile and efficient method for the synthesis of crystalline tetrahydro-β-carbolines via the Pictet-Spengler reaction in water.

Sci Rep 2020 01 23;10(1):1057. Epub 2020 Jan 23.

Department of Biotechnology, Korea National University of Transportation, 61 Daehak-ro, Jeungpyeong-gun, Chungbuk, 27909, Republic of Korea.

A facile and efficient synthesis of tetrahydro-β-carbolines (tryptolines) in one step from tryptamine and aldehydes, in an environmentally friendly water solvent, has been investigated. This convenient and clean synthesis of various tryptolines was facilitated by L-tartaric acid, a natural compound, to obtain the desired products as clear crystals. Among the four crystalline products, the most substituted tryptoline 2 showed the best inhibitory activity against EJ cells and the least cytotoxicity, with an LC value of 1.49 mg/mL, against brine shrimp larvae.
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http://dx.doi.org/10.1038/s41598-020-57911-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978303PMC
January 2020

A novel tumor suppressing gene, , is an independent prognostic biomarker for bladder cancer.

Oncol Lett 2020 Jan 19;19(1):476-486. Epub 2019 Nov 19.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungcheongbuk-do 28644, Republic of Korea.

Screening for genes or markers relevant to bladder cancer (BC) tumorigenesis and progression is of vital clinical significance. The present study used reverse-transcription quantitative PCR reaction assays to examine the expression of mRNA encoding Rho GTPase-activating protein 9 (ARHGAP9) in BC tissue samples and to determine whether is an independent prognostic biomarker for non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). The results revealed that the downregulation of expression in the tissue of patients with NMIBC or MIBC was significantly associated with a poor prognosis. In patients with NMIBC, a high expression of was significantly associated with prolonged recurrence-free survival, whereas in MIBC patients, it was significantly associated with an increased progression-free and cancer-specific survival. The risk of cancer-specific death was 2.923 times higher (95% confidence interval, 1.192-7.163) when levels were decreased. In conclusion, lower expressions of correlated with BC prognosis, indicating that it may be a useful marker for guiding treatment application.
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http://dx.doi.org/10.3892/ol.2019.11123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924059PMC
January 2020

Carnosine exerts antitumor activity against bladder cancers in vitro and in vivo via suppression of angiogenesis.

J Nutr Biochem 2019 12 1;74:108230. Epub 2019 Sep 1.

Department of Food and Nutrition, Chung-Ang University, Anseong 17546, South Korea. Electronic address:

Carnosine, a naturally occurring dipeptide, was recently reported to exhibit anticancer activity; however, the molecular mechanisms and regulators underlying its activity against tumor-associated angiogenesis remain unidentified. In this study, we evaluated the in vitro and in vivo antitumor effects of carnosine in EJ bladder cancer cells and EJ-xenografted BALB/c nude mice, respectively. In addition, in vitro capillary tube formation of HUVECs, ex vivo aortic ring and in vivo Matrigel plug assays were employed to examine the antiangiogenic potential of carnosine. Carnosine significantly inhibited EJ cell proliferation. Flow cytometric and immunoblot analyses indicated that carnosine modulated regulators of the G1 cell cycle phase, including cyclin D1, CDK4 and p21WAF1. The mitogen-activated protein kinases, ERK and p38, but not JNK or AKT, responded to carnosine. Carnosine inhibited the migratory and invasive potential of EJ cells by inhibiting MMP-9 activity, which was associated with suppression of binding activity of NF-κB, SP-1 and AP-1. In xenograft tumors, carnosine exhibited antitumor activity equivalent to cisplatin, but no weight loss occurred in carnosine-treated mice. In HUVECs, carnosine inhibited VEGF-mediated proliferation, colony tube formation, migration and invasion. The antiangiogenic activity of carnosine was partially due to the suppression of VEGFR-2-mediated ERK/AKT/eNOS signaling and MMP-2. Furthermore, using aortic ring and Matrigel plug assays, we confirmed the antiangiogenic activity of carnosine. Given that targeting tumor-associated angiogenesis is a proven effective therapeutic strategy, our results may provide valuable information for the development of preventive or therapeutic agents for bladder cancer patients.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108230DOI Listing
December 2019

Citrus unshiu peel suppress the metastatic potential of murine melanoma B16F10 cells in vitro and in vivo.

Phytother Res 2019 Dec 4;33(12):3228-3241. Epub 2019 Sep 4.

Anti-Aging Research Center, Dong-eui University, Busan, Republic of Korea.

The peel of Citrus unshiu Marcow. fruits (CU) has long been used as a traditional medicine that has therapeutic effects against pathogenic diseases, including asthma, vomiting, dyspepsia, blood circulation disorders, and various types of cancer. In this study, we investigated the effect of CU peel on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells, and in B16F10 cells inoculated-C57BL/6 mice. Our results show that ethanol extracts of CU (EECU) inhibited cell growth and increased the apoptotic cells in B16F10 cells. EECU also stimulated the induction of mitochondria-mediated intrinsic pathway, with reduced mitochondrial membrane potential and increased generation of intracellular reactive oxygen species. Furthermore, EECU suppressed the migration, invasion, and colony formation of B16F10 cells. In addition, the oral administration of EECU reduced serum lactate dehydrogenase activity without weight loss, hepatotoxicity, nor nephrotoxicity in B16F10 cell-inoculated mice. Moreover, EECU markedly suppressed lung hypertrophy, the number and expression of metastatic tumor nodules, and the expression of inflammatory tumor necrosis factor-alpha in lung tissue. In conclusion, our findings suggest that the inhibitory effect of EECU on the metastasis of melanoma indicates that it may be regarded as a potential therapeutic herbal drug for melanoma.
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http://dx.doi.org/10.1002/ptr.6497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916627PMC
December 2019

Triacanthine exerts antitumor effects on bladder cancer in vitro and in vivo.

Phytomedicine 2019 Nov 9;64:153069. Epub 2019 Aug 9.

Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Republic of Korea. Electronic address:

Background: Numerous studies have focused on solvent extracts from locust trees (Gleditsia spp.), which contain diverse bioactive components including saponins, flavonoids, and alkaloids. However, because of the undefined nature of such phytochemicals, their clinical application as chemotherapeutic agents has often been limited.

Purpose: This study aimed to evaluate the anti-oncogenic activity of triacanthine, an alkaloid obtained from Gleditsia triacanthos L.

Study Design: The anti-oncogenicity of triacanthine in vitro was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell-counting kit-8 assay (CCK-8 assay), flow cytometry, imunoblot, migration and invasion assays, zymography, and electrophoretic mobility shift assay in the human bladder carcinoma cell line EJ. The in vivo efficacy of triacanthine was evaluated via oral administration to EJ-xenografted BALB/c nude mice. To identify the side effects of triacanthine, cisplatin was also administered and an acute toxicity test was performed.

Results: Triacanthine significantly inhibited EJ cell proliferation (IC 600 µM). Flow cytometry analysis revealed that cells were arrested in the G1 phase, and apoptotic cells accumulated in sub-G1 phase in a dose-dependent manner. Triacanthine inhibited the G1-S transition by deterring complex formation between cyclin-dependent kinases and cyclins, thereby up-regulating cell cycle inhibitors p21WAF1 and p27KIP1. In addition, triacanthine induced a caspase-dependent extrinsic pathway of apoptosis and autophagy. Early responsive kinases, extracellular signal-regulated kinase (ERK) and Janus kinase (JNK) were up-regulated by triacanthine. Triacanthine-mediated inhibition of the migratory and invasive potential of EJ cells was attributed to reduction of matrix metalloproteinase (MMP)-9 due to suppression of binding activities of the transcription factors activator protein (AP)-1, specificity protein (Sp)-1, and nuclear factor (NF)-κB. In an in vivo study, triacanthine significantly limited growth of xenografted tumors. Interestingly, while cisplatin resulted in significant weight loss after a 5-mg/kg dose, triacanthine did not cause weight loss, behavioral abnormalities, altered biochemical parameters, or tissue staining. A single oral dose acute-toxicity test (triacanthine 2,000 mg/kg) produced no adverse cytotoxic effects via blood biochemical tests and tissue-organ staining.

Conclusion: To our knowledge, this is the first systematic evaluation of the anti-oncogenic activity of triacanthine. Therefore, we believe that our findings may guide the development of novel chemotherapeutic agents for bladder cancers.
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http://dx.doi.org/10.1016/j.phymed.2019.153069DOI Listing
November 2019

Nimbolide Represses the Proliferation, Migration, and Invasion of Bladder Carcinoma Cells via Chk2-Mediated G2/M Phase Cell Cycle Arrest, Altered Signaling Pathways, and Reduced Transcription Factors-Associated MMP-9 Expression.

Evid Based Complement Alternat Med 2019 14;2019:3753587. Epub 2019 Jul 14.

Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Republic of Korea.

Nimbolide, an active chemical constituent of , reportedly has several physiological effects. Here, we assessed novel anticancer effects of nimbolide against bladder cancer EJ and 5637 cells. Nimbolide treatment inhibited the proliferation of both bladder cancer cell lines with an IC value of 3 M. Treatment of cells with nimbolide induced G2/M phase cell cycle arrest via both Chk2-Cdc25C-Cdc2/cyclin B1-Wee1 pathway and Chk2-p21WAF1-Cdc2/cyclin B1-Wee1 pathway. Nimbolide increased JNK phosphorylation and decreased p38MAPK and AKT phosphorylation. Additionally, nimbolide impeded both wound healing migration and invasion abilities by suppressing matrix metalloproteinase-9 (MMP-9) activity. Finally, nimbolide repressed the binding activity of NF-B, Sp-1, and AP-1 motifs, which are key transcription factors for MMP-9 activity regulation. Overall, our study indicates that nimbolide is a potential chemotherapeutic agent for bladder cancer.
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http://dx.doi.org/10.1155/2019/3753587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662486PMC
July 2019

Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells.

Int J Mol Sci 2019 Aug 5;20(15). Epub 2019 Aug 5.

Anti-Aging Research Center, Dong-eui University, Busan 47227, Korea.

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.
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http://dx.doi.org/10.3390/ijms20153820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696302PMC
August 2019

Urinary Cell-Free DNA IQGAP3/BMP4 Ratio as a Prognostic Marker for Non-Muscle-Invasive Bladder Cancer.

Clin Genitourin Cancer 2019 06 9;17(3):e704-e711. Epub 2019 Apr 9.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea. Electronic address:

Background: Disease monitoring in non-muscle-invasive bladder cancer (NMIBC) patients is crucial for early identification of disease recurrence and progression. High IQGAP3/BMP4 and IQGAP3/FAM107A ratios in urinary cell-free DNA (ucfDNA) are a diagnostic biomarker for bladder cancer. We aimed to investigate whether the levels of these biomarkers in ucfDNA can be used to monitor disease recurrence or progression in patients with NMIBC.

Patients And Methods: A total of 103 patients with NMIBC (pTa-pT1) were enrolled. The IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were measured by real-time PCR, and the results were compared with clinical outcome by Kaplan-Meier curves and Cox regression analyses.

Results: Overall, 55 patients (53.4%) experienced recurrence and 29 (28.2%) experienced disease progression during a median follow-up of 42.7 months (range, 6.1-172.2 months). Kaplan-Meier analysis revealed that NMIBC patients with a high IQGAP3/BMP4 ratio had worse recurrence-free survival and progression-free survival (PFS) (P = .001 and < .001, respectively), and those with a high IQGAP3/FAM107A ratio had worse PFS (P = .006). Multivariate Cox regression analysis revealed that the IQGAP3/BMP4 ratio was independently associated with recurrence-free survival (hazard ratio, 2.462; P = .003) and PFS (hazard ratio = 3.871; P = .004), whereas the IQGAP3/FAM107A ratio was not an independent factor for PFS (P = .079).

Conclusion: The IQGAP3/BMP4 ratio in ucfDNA might be a valuable novel biomarker for predicting disease recurrence and progression in patients with NMIBC.
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http://dx.doi.org/10.1016/j.clgc.2019.04.001DOI Listing
June 2019

Hydrangenol suppresses VEGF-stimulated angiogenesis by targeting p27KIP1-dependent G1-cell cycle arrest, VEGFR-2-mediated signaling, and MMP-2 expression.

Anim Cells Syst (Seoul) 2019 Apr 14;23(2):72-81. Epub 2019 Feb 14.

Department of Food and Nutrition, Chung-Ang University, Anseong, Republic of Korea.

We previously reported that hydrangenol has potent antitumor activity against human bladder cancer EJ cells. Here, we investigated the antiangiogenic activity of hydrangenol using and models. Treatment with hydrangenol significantly inhibited the proliferation of vascular endothelial growth factor (VEGF)-induced HUVECs in a concentration-dependent manner (EC= 10 μM). Flow cytometry analysis revealed that hydrangenol suppressed the VEGF-induced inhibition of G1-cell cycle phase and also decreased cyclin D1, cyclin E, CDK2, and CDK4 levels. Hydrangenol-mediated arrest in the G1-cell cycle phase was associated with p27KIP1 level, but not p21WAF1 or p53 level. Hydrangenol also significantly inhibited VEGFR-2-mediated signaling pathways including ERK1/2, AKT, and endothelial nitric oxide synthase. Interestingly, immunoprecipitation assay demonstrated that the inhibition of VEGFR-2 activation was independent of VEGF binding, thereby suggesting an allosteric regulation of hydrangenol against VEGFR-2. Additionally, hydrangenol inhibited migration, invasion, and capillary-like tubular formation in VEGF-stimulated HUVECs. Zymography and immunoblot analyses revealed that these inhibitory activities were partially owing to the VEGF-induced inhibition of matrix metalloproteinase-2 activity. Finally, VEGF-mediated microvessel sprouting was inhibited in the presence of hydrangenol in aortic ring assay. Taken together, hydrangenol possesses a potent antiangiogenesis potential; thus we believe that hydrangenol may be developed as a therapeutic reagent to treat angiogenesis-mediated diseases.
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http://dx.doi.org/10.1080/19768354.2019.1578262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440517PMC
April 2019

Morin inhibits PDGF-induced proliferation, migration, and invasion of vascular smooth muscle cells via modulating p27KIP1, AKT, and MMP-9 activities.

Gen Physiol Biophys 2018 Sep;37(6):633-645

Department of Food Science and Nutrition, Jeju National University, Jeju 63243, South Korea.

Hyper-proliferation and migration of vascular smooth muscle cells (VSMCs) are closely associated with atherosclerosis. Recently, the flavonol morin has been reported to exhibit potent anti-oxidant and anti-inflammatory activities. Therefore, we investigated molecular mechanisms of morin in VSMCs stimulated by PDGF. Morin effectively inhibited PDGF-stimulated proliferation of VSMCs through a G1 cell-cycle arrest, leading to down-regulation of CDK2, CDK4, cyclin D1, and cyclin E proteins. Interestingly, PDGF markedly down-regulated p27KIP1 protein expression; however, morin treatment restored the p27KIP1expression to the basal level. Morin did not affect phosphorylation of MAPKs (ERK, p38, and JNK); however, phosphorylation of AKT was dramatically suppressed by morin in PDGF-stimulated VSMCs. Using the PI3K inhibitor, LY294002, we revealed that AKT is a key regulator in the inhibitory mechanism of morin against PDGF-induced proliferation of VSMCs. Morin disturbed migratory and invasive potential of VSMCs via suppression of matrix metalloproteinase-9 (MMP-9) activity. Using electrophoretic mobility shift assays, we verified that NF-κB, AP-1, and Sp-1 transcription factors are implicated in the mode of action of morin, which suppresses the MMP-9 activity in PDGF-induced VSMCs. Based on the results, we believe that morin may be a potential therapeutic agent for atherosclerosis without negative side effect.
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http://dx.doi.org/10.4149/gpb_2018028DOI Listing
September 2018

mRNA Expression Is Associated with the Aggressiveness of Prostate Cancer.

J Korean Med Sci 2018 Nov 2;33(47):e303. Epub 2018 Nov 2.

Department of Urology, Chungbuk National University, College of Medicine, Cheongju, Korea.

Background: Cell division cycle 6 (CDC6) is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle. CDC6 has been associated with oncogenic activities in human cancers; however, the clinical significance of CDC6 in prostate cancer (PCa) remains unclear. Therefore, we investigated whether the mRNA expression level is a diagnostic and prognostic marker in PCa.

Methods: The study subjects included 121 PCa patients and 66 age-matched benign prostatic hyperplasia (BPH) patients. expression was evaluated using real-time polymerase chain reaction and immunohistochemical (IH) staining, and then compared according to the clinicopathological characteristics of PCa.

Results: mRNA expression was significantly higher in PCa tissues than in BPH control tissues ( = 0.005). In addition, expression was significantly higher in patients with elevated prostate-specific antigen (PSA) levels (> 20 ng/mL), a high Gleason score, and advanced stage than in those with low PSA levels, a low Gleason score, and earlier stage, respectively. Multivariate logistic regression analysis showed that high expression of was significantly associated with advanced stage (≥ T3b) (odds ratio [OR], 3.005; confidence interval [CI], 1.212-7.450; = 0.018) and metastasis (OR, 4.192; CI, 1.079-16.286; = 0.038). Intense IH staining for CDC6 was significantly associated with a high Gleason score and advanced tumor stage including lymph node metastasis stage (linear-by-linear association, = 0.044 and = 0.003, respectively).

Conclusion: expression is associated with aggressive clinicopathological characteristics in PCa. CDC6 may be a potential diagnostic and prognostic marker in PCa patients.
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http://dx.doi.org/10.3346/jkms.2018.33.e303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236078PMC
November 2018

Diagnostic value of combined IQGAP3/BMP4 and IQGAP3/FAM107A expression ratios in urinary cell-free DNA for discriminating bladder cancer from hematuria.

Urol Oncol 2019 01 13;37(1):86-96. Epub 2018 Nov 13.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea. Electronic address:

Background: Urinary cell-free DNA (ucfDNA) has great potential as a "liquid biopsy" for use in diagnosis of urological cancers. In this study, we compared ucfDNA gene expression levels between patients with bladder cancer (BC) and those with hematuria, and determined whether they could be used as a noninvasive urine-based marker.

Methods: The study cohort of 355 patients included a screening group (40 BC and 41 hematuria controls) and a validation cohort (149 BC and 125 hematuria controls). Expression levels ratios of 1 up-regulated gene (IQGAP3) to those of 7 down-regulated genes were examined in ucfDNA in the screening group to identify ratios that differed significantly between BC and hematuria patients. IQGAP3/BMP4 and IQGAP3/FAM107A ratios were selected and combined to develop a discriminant score (DS) index, which was tested in the validation cohort. Receiver operating characteristic curves and areas under the curve were calculated to evaluate the performance of the DS index.

Results: IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were both significantly higher in BC patients than in hematuria patients (both P < 0.001). The DS index had an area under the curve of 0.862, a sensitivity of 71.0%, a specificity of 88.6%, a positive predictive value of 90.3%, and a negative predictive value of 67.2%.

Conclusions: Both IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were significantly higher in patients with BC than in those with hematuria. The DS index exhibits good diagnostic performance as a noninvasive biomarker.
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http://dx.doi.org/10.1016/j.urolonc.2018.10.023DOI Listing
January 2019

Urinary cell-free microRNA biomarker could discriminate bladder cancer from benign hematuria.

Int J Cancer 2019 01 13;144(2):380-388. Epub 2018 Nov 13.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea.

The most common symptom of bladder cancer (BC) is hematuria. However, not all patients with hematuria are diagnosed with BC. Here, we explored a novel method to discriminate BC from hematuria under nonmalignant conditions by measuring differences in urinary cell-free microRNA (miRNA) expression between patients with BC and those with hematuria. A multicenter study was performed using 543 urine samples obtained from the National Biobank of Korea, including 326 BC, 174 hematuria and 43 pyuria without cancer. The urinary miR-6124 to miR-4511 ratio was considerably higher in BC than in hematuria or pyuria, and enabled the discrimination of BC from patients with hematuria at a sensitivity of >90% (p < 0.001). Conclusively, the proposed noninvasive diagnostic tool based on the expression ratio of urinary cell-free miR-6124 to miR-4511 can reduce unnecessary cystoscopies in patients with hematuria undergoing evaluation for BC, with a minimal loss in sensitivity for detecting cancer.
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http://dx.doi.org/10.1002/ijc.31849DOI Listing
January 2019

Hydrangenol inhibits the proliferation, migration, and invasion of EJ bladder cancer cells via p21-mediated G1-phase cell cycle arrest, p38 MAPK activation, and reduction in Sp-1-induced MMP-9 expression.

EXCLI J 2018 6;17:531-543. Epub 2018 Jun 6.

Department of Food and Nutrition, Chung-Ang University, Anseong, Kyung-gi 17546, South Korea.

Hydrangenol is a dihydroisocoumarin that is mainly obtained from . Recently, hydrangenol has garnered attention since several studies have reported that it has anti-inflammatory, anti-allergic, anti-diabetic, and anti-malarial activities. However, there have been few studies on the effect of hydrangenol on oncogenesis. In this study, we evaluated the anti-cancer activity of hydrangenol against the EJ bladder cancer cell line. Hydrangenol significantly inhibited the proliferation of EJ cells in a dose-dependent manner with an IC of 100 µM. Flow cytometry and immunoblotting experiments indicated that EJ cells were arrested in the G1-phase of the cell cycle and showed reduced expression of CDK2, CDK4, cyclin D1, and cyclin E mediated via the upregulation of p21. Hydrangenol increased the phosphorylation of p38 MAPK without affecting the phosphorylation of ERK and JNK. In addition, hydrangenol significantly inhibited the migratory and invasive activities of EJ cells by suppressing the enzymatic activity of MMP-9. Electrophoretic mobility shift assays suggested that the inhibition of MMP-9 activity by hydrangenol was attributable to its suppression of the Sp-1 transcription factor binding activity. This study is the first report on the mode of action of hydrangenol as an inhibitor of bladder cancer. We believe that these results provide novel insights that could aid the development of hydrangenol-based chemotherapeutic agents.
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http://dx.doi.org/10.17179/excli2018-1361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046626PMC
June 2018

Identification of differentially expressed miRNAs and miRNA-targeted genes in bladder cancer.

Oncotarget 2018 Jun 7;9(45):27656-27666. Epub 2018 Feb 7.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.

Background: Differentially expressed genes and their post-transcriptional regulator-microRNAs (miRNAs), are potential keys to pioneering cancer diagnosis and treatment. The aim of this study was to investigate how the miRNA-mRNA interactions might affect the tumorigenesis of bladder cancer (BC) and to identify specific miRNA and mRNA genetic markers in the two BC types: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).

Results: We identified 227 genes that interacted with 54 miRNAs in NMIBC, and 14 genes that interacted with 10 miRNAs in MIBC. Based on this data, we found extracellular matrix-related genes are highly enriched in NMIBC while genes related to core nuclear division are highly enriched in MIBC. Furthermore, using a transcriptional regulatory element database, we found indirect regulatory transcription factors (TFs) for enriched genes could regulate tumorigenesis with or without miRNAs.

Materials And Methods: Tissue samples from 234 patients histologically diagnosed with BC and 83 individuals without BC were analyzed using microarray and next-generation sequencing technology, and we used different cut-offs to identify differentially expressed mRNAs and miRNAs in NMIBC and MIBC. The selected mRNAs and miRNAs were paired using validated target datasets and according to inverse expression relationships. MiRNA interacted genes were compared with the TF-regulating genes in BC. Meanwhile, pathway enrichment analysis was performed to identify the functions of selected miRNAs and genes.

Conclusions: Identification of differential gene expression in specific tumor types could facilitate development of cancer diagnosis and aid in the early detection of BC.
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http://dx.doi.org/10.18632/oncotarget.24441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021253PMC
June 2018

Inhibitory effect of Au@Pt-NSs on proliferation, migration, and invasion of EJ bladder carcinoma cells: involvement of cell cycle regulators, signaling pathways, and transcription factor-mediated MMP-9 expression.

Int J Nanomedicine 2018 1;13:3295-3310. Epub 2018 Jun 1.

Department of Food and Nutrition, Chung-Ang University, Anseong, South Korea.

Background: Although the diverse biological properties of nanoparticles have been studied intensively, research into their mechanism of action is relatively rare. In this study, we investigated the molecular mechanisms of the anticancer activity of heterometallic Au@Pt-nanoseeds (NSs) against bladder cancers.

Materials And Methods: Mode of action of Au@Pt-NSs was investigated through MTT assay, flow cytometry analysis, Western immunoblots, real-time qPCR, wound-healing migration and invasion assays, zymography, and electrophoretic mobility shift assay (EMSA).

Results: Treatment with Au@Pt-NSs significantly inhibited the proliferation of EJ cells in a dose-dependent manner by inducing G1 phase cell cycle arrest. Among the regulators associated with the G1 cell cycle phase, CDK2, CDK4, cyclin D1, cyclin E, and p21WAF1 were shown to participate in the inhibitory pathways of Au@Pt-NSs. In addition, treatment with Au@Pt-NSs led to upregulation of phospho-p38 MAPK and downregulation of phospho-AKT in EJ cells. Interestingly, Au@Pt-NSs inhibited the migratory and invasive potential of the cells, which was attributed to the suppression of the enzymatic activity of matrix metalloproteinase-9 (MMP-9). Using MMP-9-specific oligonucleotides, we showed that transcription factors such as NF-κB and Sp-1 were responsible for the MMP-9-mediated metastatic potential of EJ cells.

Conclusion: Au@Pt-NSs significantly limited the progression, migration, and invasion of bladder cancer EJ cells. Our data represent a novel insight into developing cisplatin-like chemotherapeutic reagents with fewer side effects and provide useful information on molecular markers to monitor patients under Au@Pt-NSs-based chemotherapy.
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http://dx.doi.org/10.2147/IJN.S158463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987858PMC
July 2018