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1.  Icariside II Induces Apoptosis in U937 Acute Myeloid Leukemia Cells: Role of Inactivation of STAT3-Related Signaling 
PLoS ONE  2012;7(4):e28706.
The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937.
Methodology/Principal Findings
Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-xL and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells.
Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML.
PMCID: PMC3320887  PMID: 22493659
2.  Upregulation of miRNA3195 and miRNA374b Mediates the Anti-Angiogenic Properties of Melatonin in Hypoxic PC-3 Prostate Cancer Cells 
Journal of Cancer  2015;6(1):19-28.
Recently microRNAs (miRNAs) have been attractive targets with their key roles in biological regulation through post-transcription to control mRNA stability and protein translation. Though melatonin was known as an anti-angiogenic agent, the underlying mechanism of melatonin in PC-3 prostate cancer cells under hypoxia still remains unclear. Thus, in the current study, we elucidated the important roles of miRNAs in melatonin-induced anti-angiogenic activity in hypoxic PC-3 cells. miRNA array revealed that 33 miRNAs (>2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control. Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells. Consistently, melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells by qRT-PCR analysis. Of note, overexpression of miRNA3195 and miRNA374b mimics attenuated the mRNA levels of angiogenesis related genes such as HIF-1alpha, HIF-2 alpha and VEGF in PC-3 cells under hypoxia. Furthermore, overexpression of miRNA3195 and miRNA374b suppressed typical angiogenic protein VEGF at the protein level and VEGF production induced by melatonin, while antisense oligonucleotides against miRNA 3195 or miRNA 374b did not affect VEGF production induced by melatonin. Also, overexpression of miR3195 or miR374b reduced HIF-1 alpha immunofluorescent expression in hypoxic PC-3 compared to untreated control. Overall, our findings suggest that upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property induced by melatonin in hypoxic PC-3 cells.
PMCID: PMC4278911  PMID: 25553085
melatonin; miRNA3195; miRNA374b; VEGF; HIF-1 alpha; PC-3 cells.
3.  Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis 
Oncotarget  2014;5(14):5624-5636.
Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.
PMCID: PMC4170628  PMID: 25015549
TRAIL sensitizer; tanshinone I; apoptosis; DR5; miR135a; prostate cancer
4.  1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) reduces renal crystallization and oxidative stress in a hyperoxaluric rat model 
Kidney international  2010;79(5):538-545.
Adhesion of calcium oxalate (CaOx) crystals to kidney cells may be a key event in the pathogenesis of kidney stones associated with marked hyperoxaluria. Previously, we found that 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), isolated from a traditional medicinal herb, reduced CaOx crystal adhesion to renal epithelial cells by acting on the cells as well as the crystal surface. Here we used the ethylene glycol (EG) - mediated hyperoxaluric rat model and found evidence of oxidant stress as indicated by decreases in the activities of the renal antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, with increased kidney cell apoptosis and serum malondialdehyde levels, all evident by 21 days of EG treatment. These effects of hyperoxaluria were reversed by concurrent PGG treatment along with decreased urinary oxalate levels and CaOx supersaturation. Renal epithelial cell expression of the crystal binding molecule hyaluronan increased diffusely within 7 days of EG initiation, suggesting it is not a result of but precedes crystal deposition. Renal cell osteopontin (OPN) was also up regulated in EG-treated animals, and PGG significantly attenuated over expression of both OPN and hyaluronan. Thus, our findings demonstrate that PGG reduces renal crystallization and oxidative renal cell injury, and may be a candidate chemo preventative agent for nephrolithiasis.
PMCID: PMC4019041  PMID: 21085110
6.  Point-of-care monitoring of perioperative intraocular pressure using portable tonometry in a patient with Posner-Schlossman syndrome: a case report 
Korean Journal of Anesthesiology  2014;66(3):248-251.
A 56-year-old man with a rotator cuff injury, scheduled for arthroscopic reconstruction surgery, had a history of recurrent symptoms of eyeball pain and blurred vision for several years. After close examination, he was diagnosed with Posner-Schlossman syndrome. Three weeks before the scheduled surgery, his intraocular pressure (IOP) increased (> 30 mmHg) and he became extremely anxious about the surgery. We monitored his IOP intraoperatively and successfully completed general anesthesia without any sequelae. As Posner-Schlossman syndrome can present with severe complications that may lead to postoperative visual loss, intraoperative monitoring of intraocular monitoring and careful anesthetic management are crucial to protect vision.
PMCID: PMC3983424  PMID: 24729850
Anesthesia; Intraocular pressure; Monitoring; Posner-Schlossman syndrome; Tonometry
7.  Gallotannin suppresses calcium oxalate crystal binding and oxalate-induced oxidative stress in renal epithelial cells 
Calcium oxalate monohydrate (COM) crystals bind avidly to the surface of proliferating and migrating renal endothelial cells, perhaps a key event in kidney stone formation. Oxalate-induced pre-oxidative stress can further promote crystal attachment cells. Natural products including gallotannins found in green teas have been studied as potentially novel treatments to prevent crystal retention and kidney stone formation. Gallotannin significantly inhibited COM crystal growth and binding to MDCK I renal epithelial cells at non-toxic concentrations and also delayed renal cell migration in a wound healing assay. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that gallotannin significantly attenuated oxalate-induced mRNA expression of monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22phox and p47phox in human primary renal epithelial cells (HRCs). Gallotannin also reduced HRC production of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as enhanced antioxidant enzyme superoxide dismutase (SOD) activity in response to oxalate. Taken together, our findings suggest that gallotannin can contribute to nephrolithiasis prevention via direct effects on renal epithelial cells including suppression of COM binding and MCP-1 and OPN expression, along with augmenting antioxidant activity.
PMCID: PMC3910304  PMID: 22466558
gallotannin; renal epithelial cells; calcium oxalate monohydrate; MCP-1; osteopontin; ROS; SOD
8.  Serum Magnesium Level Is Associated with Type 2 Diabetes in Women with a History of Gestational Diabetes Mellitus: The Korea National Diabetes Program Study 
Gestational diabetes mellitus (GDM) is a strong predictor of postpartum prediabetes and transition to overt type 2 diabetes (T2DM). Although many reports indicate that low magnesium is correlated with deteriorated glucose tolerance, the association between postpartum serum magnesium level and the risk for T2DM in women with a history of GDM has not been evaluated. We analyzed postpartum serum magnesium levels and development of prediabetes and T2DM in women with prior GDM according to American Diabetes Association (ADA) criteria using the Korean National Diabetes Program (KNDP) GDM cohort. During a mean follow-up of 15.6±2.0 months after screening, 116 women were divided into three groups according to glucose tolerance status. Ultimately, eight patients (6.9%) were diagnosed with T2DM, 59 patients (50.9%) with prediabetes, and 49 patients (42.2%) with normal glucose tolerance (NGT) after follow-up. The T2DM group had the lowest serum magnesium level (0.65 [0.63-0.68] mM/L) in the postpartum period, but there was no significant difference between the prediabetes group (0.70 [0.65-0.70] mM/L) and the NGT group (0.70 [0.65-0.70] mM/L) (P=0.073) Multiple logistic regression analysis showed that postpartum HOMA-IR was a significant predictor of both prediabetes and T2DM. Moreover, we found that postpartum serum magnesium level was also a possible predictor for T2DM development. Serum magnesium level in the postpartum period may be a possible predictor for T2DM development in women with a history of GDM.
PMCID: PMC3890481  PMID: 24431910
Diabetes, Gestational; Serum Magnesium; Hypomagnesaemia; Prediabetes; Diabetes Mellitus; Type 2
9.  Suppression of E-cadherin Mediates Gallotannin Induced Apoptosis in Hep G2 Hepatocelluar Carcinoma Cells 
Though gallotannin was known to have anti-oxidant and antitumor activity, the underlying antitumor mechanism of gallotannin still remains unclear. Thus, in the present study, antitumor mechanism of gallotannin was elucidated in hepatocellular carcinoma cells. Gallotannin significantly exerted cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells with the accumulation of the sub-G1 population and increase of terminal deoxynucleotidyltransferasedUTP nick end labeling (TUNEL) positive cells as an apoptotic feature. Also, gallotannin attenuated the expression of pro-caspase9, pro-caspase3, Bcl2 and integrin β1 and cleaved poly(ADP)-ribose polymerase (PARP) in Hep G2 and Chang cancer cells. Furthermore, gallotannin suppressed cell repair motility by wound healing assay and also inhibited cell adhesion in Hep G2 cells. Of note, gallotannin attenuated the expression of epithelial cadherin (E-cadherin) to form cell-cell adhesion from the early stage, and also beta-catenin at late phase in Hep G2 cells. Consistently, Immunofluorescence assay showed that E-cadherin or β-catenin expression was suppressed in a time dependent manner by gallotannin. Furthermore, silencing of E-cadherin by siRNA transfection method enhanced PAPR cleavage, caspase 3 activation and sub G1 population and attenuated the cell adhesion induced by gallotannin in Hep G2 cells. Overall, our findings demonstrate that the disruption of cell adhesion junction by suppression of E-cadherin mediates gallotannin enhanced apoptosis in Hep G2 liver cancer cells.
PMCID: PMC4007362  PMID: 24795530
gallotannin; Hep G2 cells; apoptosis; PARP; caspase; E-cadherin.
10.  The optimal follow-up period in patients with above 5-year disease-free survival after curative liver resection for hepatocellular carcinoma 
Although many patients with hepatocellular carcinoma experience recurrence within 2 years after hepatectomy, some patients with T1 and T2 hepatocellular carcinoma show recurrence-free survival for more than 5 years after surgery. This study was designed to analyze the optimal follow-up period on patients with T1 and T2 hepatocellular carcinoma (HCC) showing recurrence-free survival 5 years after surgery.
One hundred seventy patients underwent hepatectomy from January 1995 to December 1999. Numbers of patients with T1 and T2 HCC were 76 and 73, respectively. The recurrence patterns of patients experiencing recurrence more than 5 years after liver resection were analyzed in aspect of clinicopathological features and follow-up period.
Thirteen patients experienced recurrence more than 5 years after surgery. Only age was found as a significant factor for recurrence. Eight patients were checked regularly with 6-month intervals and the others were checked with 12-month or more intervals. The size of the recurrent tumors in the 6-month interval group had a median of 1.1 cm (range, 1 to 4.2 cm) and the size of the recurrent tumors in the 12-month or more interval group had a median of 3 cm (range, 1.6 to 4 cm). The tumor size was significantly smaller in the 6-month interval group.
Though the patients with early stage HCC showed high overall survival, some patients experienced a late recurrence of more than 5 years after surgery. Patients less than 60 years old with early stage HCC should be checked regularly with 6-month intervals even over 5 years after liver resection.
PMCID: PMC3868678  PMID: 24368984
Hepatocellular carcinoma; Recurrence; Surveillance
12.  Essential Oil of Pinus koraiensis Exerts Antiobesic and Hypolipidemic Activity via Inhibition of Peroxisome Proliferator-Activated Receptors Gamma Signaling 
Our group previously reported that essential oil of Pinus koraiensis (EOPK) exerts antihyperlipidemic effects via upregulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A. In the present study, we investigated the antiobesity and hypolipidemic mechanism of EOPK using in vitro 3T3-L1 cells and in vivo HFD-fed rats. EOPK markedly suppressed fat accumulation and intracellular triglyceride associated with downregulation of adipogenic transcription factor expression, including PPARγ and CEBPα in the differentiated 3T3-L1 adipocytes. Additionally, EOPK attenuated the expression levels of FABP and GPDH as target genes of PPARγ during adipocyte differentiation. Furthermore, PPARγ inhibitor GW9662 enhanced the decreased expression of FABP and PPARγ and fat accumulation induced by EOPK. To confirm the in vitro activity of EOPK, animal study was performed by administering normal diet, HFD, and/or EOPK at the dose of 100 or 200 mg/kg for 6 weeks. Consistently, EOPK significantly suppressed body weight gain, serum triglyceride, total cholesterol, LDL cholesterol, and AI value and increased HDL cholesterol in a dose-dependent manner. Immunohistochemistry revealed that EOPK treatment abrogated the expression of PPARγ in the liver tissue sections of EOPK-treated rats. Taken together, our findings suggest that EOPK has the antiobesic and hypolipidemic potential via inhibition of PPARγ-related signaling.
PMCID: PMC3753736  PMID: 23997801
13.  Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells 
Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear. In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3. In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells. Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.
PMCID: PMC3710643  PMID: 23878608
14.  Incidental focal colorectal 18F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography 
AIM: To assess the clinical significance of incidental focal colorectal 18F-fluorodeoxyglucose (18F-FDG) uptake on 18F-FDG-positron emission tomography/computed tomography (PET/CT).
METHODS: The records of all the cases which had undergone colonoscopy after PET/CT within a two weeks interval were reviewed. Adenomas were considered advanced when they were villous, ≥ 10 mm in size, or had high-grade dysplasia. Colorectal cancers and advanced adenomas are collectively referred to as advanced colorectal neoplasms. Receiver-operating characteristic curve analysis was used to determine the significant predictive maximum standardized uptake value (SUVmax) cutoff value for advanced colorectal neoplasms and cancer.
RESULTS: Ninety-five colorectal lesions matched the site of incidental focal colorectal 18F-FDG uptake on PET/CT and 146 did not. Colonoscopy showed advanced colorectal neoplasms corresponding to the site of 18F-FDG uptake in 49 of the 95 (51.5%) lesions with incidental uptake. Of the lesions without incidental uptake, only 6 of 146 (4.1%) had advanced colorectal neoplasms on colonoscopy, indicating a statistically significant difference between the two groups (P < 0.001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of incidental focal 18F-FDG uptake in identifying advanced colorectal neoplasms were 89.1%, 75.3%, 51.6%, 95.9%, and 78.4%, respectively. In detecting only CRC, these values were 89.2%, 69.6%, 34.7%, 97.3%, and 72.6%, respectively. The significant SUVmax cutoff value for advanced colorectal neoplasms (area under the curve 0.755, P < 0.001) was 4.35, with a sensitivity, specificity, PPV, NPV, and accuracy of 75.5%, 65.2%, 69.8%, 71.4% and 70.5%, respectively. For CRC, 5.05 was the significant SUVmax cutoff value (area under the curve 0.817, P < 0.001), with a sensitivity, specificity, PPV, NPV, and accuracy of 84.8%, 71.0%, 80.9%, 89.8%, and 75.8%, respectively.
CONCLUSION: The presence of incidental focal colorectal 18F-FDG uptake on PET/CT with a SUVmax ≥ 4.35 increases the likelihood of an advanced colorectal neoplasm.
PMCID: PMC3683684  PMID: 23801838
Positron emission tomography; Adenomas; Computed tomography; Colorectal cancer; Colonoscopy
15.  Update on the treatment of endometriosis 
Endometriosis is defined as the presence of functional endometrial tissue outside the uterus, causing diverse progressive symptoms such as infertility, pelvic pain, and dysmenorrhea. Although endometriosis has been described since the 1800s, the mechanisms responsible for its pathogenesis and progression remain poorly understood. It is well established that endometriosis grows and regresses in an estrogen-dependent fashion and the disease can be effectively cured by definitive surgery. However, prolonged medical therapy may be needed in most of the cases since conservative surgery is usually performed especially in young women. This treatment modality is often associated with only partial relief and/or recurrence of the disease. In the present review, up-to-date findings on the treatment of endometriosis will be briefly summarized. The outcomes of surgery in patients with endometriosis will be reviewed in terms of pelvic pain relief as well as infertility treatment largely based on recent Cochrane reviews and clinical reports. The efficacy of newer drugs including aromatase inhibitor, anti-tumor necrosis factor-alpha, and dienogest will be also reviewed based on recent clinical studies.
PMCID: PMC3714429  PMID: 23875160
Endometriosis; Pelvic pain; Infertility; Recurrence; Medical treatment
16.  Epigenetic Regulation in the Brain after Spinal Cord Injury : A Comparative Study 
After spinal cord injury (SCI), functional and structural reorganization occurs at multiple levels of brain including motor cortex. However, the underlying mechanism still remains unclear. The current study was performed to investigate the alterations in the expression of the main regulators of neuronal development, survival and death, in the brain following thoracic contusive SCI in a mouse model.
Eight-week-old female imprinting control region mice (n=60; 30-35 g) were used in this study. We analyzed the expression levels of regulators such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and histone deacetylase (HDAC) 1 in the brain following thoracic contusive SCI.
The expression of BDNF levels were elevated significantly compared with control group at 2 weeks after injury (p<0.05). The expression of NGF levels were elevated at 2, 4 weeks compared with control group, but these difference were not significant (p>0.05). The GDNF levels were elevated at 2 week compared with control group, but these differences were not significant (p>0.05). The difference of HDAC1 levels were not significant at 2, 4 and 8 weeks compared with control group (p>0.05).
These results demonstrate that the upregulation of BDNF may play on important role in brain reorganization after SCI.
PMCID: PMC3756125  PMID: 24003367
Spinal cord injury; Regulators; Brain; Brain derived neurotrophic factor; Epigenetic
17.  Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells 
Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells. Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.
PMCID: PMC3684033  PMID: 23818927
18.  Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance 
The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM).
A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281).
The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index β-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group.
Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both β-cell dysfunction and insulin resistance.
PMCID: PMC3654128  PMID: 23682224
Gestational diabetes mellitus; Gestational impaired glucose tolerance; Insulin secretion; Insulin resistance
19.  Melatonin Suppresses the Expression of 45S Preribosomal RNA and Upstream Binding Factor and Enhances the Antitumor Activity of Puromycin in MDA-MB-231 Breast Cancer Cells 
Since the dysregulation of ribosome biogenesis is closely associated with tumor progression, in the current study, the critical role of ribosome biogenesis related signaling was investigated in melatonin and/or puromycin induced apoptosis in MDA-MB-231 breast cancer cells. Despite its weak cytotoxicity, melatonin from 3 mM attenuated the expression of 45S pre-ribosomal RNA (pre-rRNA), UBF as a nucleolar transcription factor, and fibrillarin at mRNA level and consistently downregulated nucleolar proteins such as UBF and fibrillarin at protein level in MDA-MB-231 cells. Furthermore, immunofluorescence assay revealed that UBF was also degraded by melatonin in MDA-MB-231 cells. In contrast, melatonin attenuated the expression of survival genes such as Bcl-xL, Mcl-1, cyclinD1, and cyclin E, suppressed the phosphorylation of AKT, mTOR, and STAT3, and cleaved PARP and activated caspase 3 only at a high concentration of 12 mM. However, combined treatment of melatonin (3 mM) and puromycin (1 μM) synergistically inhibited viability, attenuated the expression of 45S pre-rRNA and UBF, and consistently downregulated UBF, XPO1 and IPO7, procaspase 3, and Bcl-xL in MDA-MB 231 cells. Overall, these findings suggest that melatonin can be a cancer preventive agent by combination with puromycin via the inhibition of 45S pre-rRNA and UBF in MDA-MB 231 breast cancer cells.
PMCID: PMC3638601  PMID: 23690862
20.  Activation of AMP-Activated Protein Kinase α and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells 
Here, antitumor mechanism of cinnamaldehyde derivative CB-PIC was elucidated in human SW620 colon cancer cells. CB-PIC significantly exerted cytotoxicity, increased sub-G1 accumulation, and cleaved PARP with apoptotic features, while it enhanced the phosphorylation of AMPK alpha and ACC as well as activated the ERK in hypoxic SW620 cells. Furthermore, CB-PIC suppressed the expression of HIF1 alpha, Akt, and mTOR and activated the AMPK phosphorylation in hypoxic SW620 cells. Conversely, silencing of AMPKα blocked PARP cleavage and ERK activation induced by CB-PIC, while ERK inhibitor PD 98059 attenuated the phosphorylation of AMPKα in hypoxic SW620 cells, implying cross-talk between ERK and AMPKα. Furthermore, cotreatment of CB-PIC and metformin enhanced the inhibition of HIF1α and Akt/mTOR and the activation of AMPKα and pACC in hypoxic SW620 cells. In addition, CB-PIC suppressed the growth of SW620 cells inoculated in BALB/c athymic nude mice, and immunohistochemistry revealed that CB-PIC treatment attenuated the expression of Ki-67, CD34, and CAIX and increased the expression of pAMPKα in CB-PIC-treated group. Interestingly, CP-PIC showed better antitumor activity in SW620 colon cancer cells under hypoxia than under normoxia, since it may be applied to chemoresistance. Overall, our findings suggest that activation of AMPKα and ERK mediates CB-PIC-induced apoptosis in hypoxic SW620 colon cancer cells.
PMCID: PMC3622407  PMID: 23589723
21.  Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells 
Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(−) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(−) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA down-regulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide, LNCaP cell culture assays did not detect agonist activity of GBA. GBA and bicalutamide exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D1 without the causal involvement of CDK inhibitory proteins P21Cip1 and P27Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and bicalutamide with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multi-targeting drug candidate for the prevention and therapy of PCa.
PMCID: PMC3137900  PMID: 21328348
Galbanic acid; Androgen receptor; Proteasomal degradation; Prostate cancer; G1 arrest
22.  A Study of Snack Consumption, Night-Eating Habits, and Nutrient Intake in Gestational Diabetes Mellitus 
Clinical Nutrition Research  2013;2(1):42-51.
This study was performed to identify dietary behavior such as snack consumption, night-eating and nutrients intake associated with gestational diabetes mellitus (GDM). The study was conducted on 219 normal glucose tolerance (NGT) subjects and 44 GDM subjects by using a questionnaire including dietary behavior, food frequency and 3-day food record. The mean age, OGTT, and delivery weight of GDM subjects were statistically higher than those in NGT. A larger proportion of NGT subjects consumed black coffee (49.8%) while the majority of GDM subjects (61.4%) drank mixed coffee with sugar and cream. Dairy products were the most frequently consumed snack item in NGT subjects (40.7%), while fruits were most frequently consumed food item in GDM subjects (34.4%). Many of NGT subjects (49.8%) answered that they hardly took night-eating snacks whereas most of GDM subjects (61.4%) took night-eating snacks more than once a week. For change of taste preference, the proportion of NGT subjects who showed less preference for salty taste (33.3%) or greasy taste (16.9%) was higher than that of GDM subjects (11.4%). Nutrient intakes of energy, fat, cholesterol, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), carbohydrate, vitamin B1, vitamin B2, vitamin C, and vitamin E in GDM group were significantly higher than those in NGT group. Nutrient densities of SFA and vitamin C in GDM group were higher and nutrient density of calcium was lower than those in NGT group. Taken together, it is recommended to reduce night-eating snack and choose less salty and fatty foods, black-coffee rather than coffee with cream and sugar, and more dairy products to prevent GDM.
PMCID: PMC3572811  PMID: 23431085
Snack consumption; Night-eating; Nutrient intake; Gestational diabetes mellitus
23.  Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells 
Although cryptotanshinone (CT) was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.
PMCID: PMC3519236  PMID: 23243443
24.  Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells 
Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H2O2-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H2O2) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H2O2-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H2O2-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H2O2-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H2O2-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H2O2-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H2O2-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.
PMCID: PMC3518788  PMID: 23243457
25.  Prognostic value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in resectable colorectal cancer 
AIM: To assess the prognostic value of preoperative 18 fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) in patients with resectable colorectal cancer.
METHODS: One hundred sixty-three patients with resectable colorectal cancer who underwent FDG-PET/CT before surgery were included. Patient data including pathologic stage at presentation, histology, treatment, disease-free survival and the maximum standardized uptake value (SUVmax) of the primary tumor on FDG-PET/CT were retrospectively analyzed. Median follow up duration was 756 (range, 419-1355). The primary end point was disease-free survival.
RESULTS: Twenty-five of 163 patients (15.3%) had recurrences. The median SUVmax values of the recurrence and no-recurrence groups were 8.9 (range, 5-24) and 8.2 (range, 0-23, P = 0.998). Receiver operating characteristic (ROC) curve analysis showed no significant association between SUVmax and recurrence (area under the curve = 0.5, P = 0.998, 95% CI: 0.389-0.611). Because a statistically significant value was not found, SUVmax was dichotomized at its median of 8.6. The disease-free survival curve was analyzed using the median SUVmax (8.6) as the cut off. Univariate and multivariate analysis did not provide evidence that disease-free survival rates for the subgroups defined by the median SUVmax were significantly different (P = 0.52, P = 0.25).
CONCLUSION: Our study suggests that the high FDG uptake of primary mass in resectable colorectal cancer doesn’t have a significant relationship with tumor recurrence and disease-free survival.
PMCID: PMC3460334  PMID: 23049216
Positron-emission tomography; Colorectal neoplasms; Disease-free survival; Recurrence; Prognosis

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