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1.  Prevalence of and Risk Factors for Gastrointestinal Diseases in Korean Americans and Native Koreans Undergoing Screening Endoscopy 
Gut and Liver  2013;7(5):539-545.
In South Korea, health check-ups are readily accessible to the public. We aimed to compare the prevalence of upper gastrointestinal (GI) and lower GI diseases in Korean Americans and native Koreans to determine differences and risk factors.
In total, 1,942 subjects who visited Gangnam Severance Hospital from July 2008 to November 2010 for a health check-up were enrolled. Basic characteristics and laboratory data for the subjects were collected. Esophagogastroduodenoscopy and colonoscopy were performed. In total, 940 Korean Americans (group 1) and 1,002 native Koreans (group 2) were enrolled.
The overall prevalence of GI diseases for each group (group 1 vs group 2) were as follows: reflux esophagitis (RE) (9.65% vs 7.9%), gastric ulcer (2.8% vs 3.4%), duodenal ulcer (2.3% vs 3.6%), gastric cancer (0.4% vs 0.3%), colorectal polyp (35.9% vs 35.6%), colorectal cancer (0.5% vs 0.5%), and hemorrhoids (29.4% vs 21.3%). The prevalence of hemorrhoids was significantly higher in group 1 than in group 2 (p=0.001). In the multivariable analysis of group 1, male sex, age over 50 years, hypercholesterolemia and hypertriglyceridemia predicted colorectal polyps. Male sex and high fasting glucose levels were associated with RE.
Our study showed that the prevalence of GI diseases (except hemorrhoids) in Korean Americans was similar to that observed in native Koreans. Therefore, the Korean guidelines for upper and lower screening endoscopy may be applicable to Korean Americans.
PMCID: PMC3782668  PMID: 24073311
Korean Americans; Screening endoscopy
2.  Finite element modeling technique for predicting mechanical behaviors on mandible bone during mastication 
The purpose of this study was to propose finite element (FE) modeling methods for predicting stress distributions on teeth and mandible under chewing action.
For FE model generation, CT images of skull were translated into 3D FE models, and static analysis was performed considering linear material behaviors and nonlinear geometrical effect. To find out proper boundary and loading conditions, parametric studies were performed with various areas and directions of restraints and loading. The loading directions are prescribed to be same as direction of masseter muscle, which was referred from anatomy chart and CT image. From the analysis, strain and stress distributions of teeth and mandible were obtained and compared with experimental data for model validation.
As a result of FE analysis, the optimized boundary condition was chosen such that 8 teeth were fixed in all directions and condyloid process was fixed in all directions except for forward and backward directions. Also, fixing a part of mandible in a lateral direction, where medial pterygoid muscle was attached, gave the more proper analytical results. Loading was prescribed in a same direction as masseter muscle. The tendency of strain distributions between the teeth predicted from the proposed model were compared with experimental results and showed good agreements.
This study proposes cost efficient FE modeling method for predicting stress distributions on teeth and mandible under chewing action. The proposed modeling method is validated with experimental data and can further be used to evaluate structural safety of dental prosthesis.
PMCID: PMC3517960  PMID: 23236574
Mandible; Stress distribution; Mastication; Finite element analysis
3.  Downregulation of Angiotensin II-Induced 12-Lipoxygenase Expression and Cell Proliferation in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats by CCL5 
Angiotensin II (Ang II) plays an important role in vascular hypertension. The role of the chemokine CCL5 on Ang II-induced activities in vascular smooth muscle cells (VSMCs) has not been studied. In this study, we elucidated the effect of CCL5 on Ang II-induced 12-lipoxygenase (LO) expression and cell proliferation in spontaneously hypertensive rats (SHR) VSMCs. CCL5 decreased Ang II-induced 12-LO mRNA expression and protein production, and it increased Ang II type 2 (AT2) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the AT2 receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an AT2 receptor antagonist, blocked the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation. Phosphorylation of p38 was detected in VSMCs treated with Ang II or CCL5 alone. But, decrease of p38 phosphorylation was detected in VSMCs treated with Ang II and CCL5 simultaneously (Ang II/CCL5) and PD123,319 increased p38 phosphorylation in VSMCs treated with Ang II/CCL5. Therefore, these results suggest that the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation is mediated by the AT2 receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.
PMCID: PMC2776900  PMID: 19915702
Angiotensin II; Angiotensin II type 2 receptor; Cell proliferation; Chemokine CCL5; 12-lipoxygenase
4.  Glial Cell-Specific Regulation of the JC Virus Early Promoter by Histone Deacetylase Inhibitors 
Journal of Virology  2003;77(6):3394-3401.
The human polyomavirus JC virus is the etiologic agent of the fatal disease demyelinating progressive multifocal leukoencephalopathy. Although multiple transcription factors have been shown to interact with the JC virus promoter and regulate transcriptional activity, their relevance to cell specificity remains elusive. To investigate whether chromatin structure controls glial cell-specific expression of JC virus early genes, glial and nonglial cells were transfected with a reporter plasmid containing the JC virus early promoter and then treated with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate. TSA and butyrate induced 20- to 30-fold activation of the JC virus promoter in nonglial cells, whereas less than 2-fold induction was observed in glial cells. These results indicate that the JC virus early promoter might be highly suppressed in nonglial cells by hypoacetylated chromatin and activated by hyperacetylation. In support of this, chromatin immunoprecipitation assays demonstrated acetylation of the JC virus promoter region in U87MG cells but no acetylation in HeLa cells. In addition, treatment of HeLa cells with TSA induced hyperacetylation of the JC virus promoter, whereas minimal induction was seen in U87MG cells. Deletional and site-directed mutational analyses revealed that the enhancer region and Sp1 binding site upstream of the TATA box were important for TSA-mediated activation. We confirmed TSA-mediated activation of the JC virus promoter in the context of natural chromatin structure in stable cell lines. Thus, it appears that chromatin structure may control JC virus transcription in a cell-specific manner.
PMCID: PMC149517  PMID: 12610114
5.  Arctigenin Increases Hemeoxygenase-1 Gene Expression by Modulating PI3K/AKT Signaling Pathway in Rat Primary Astrocytes 
Biomolecules & Therapeutics  2014;22(6):497-502.
In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-induced reactive oxygen species (ROS) production in rat primary astrocytes. Since hemeoxygenase-1 (HO-1) plays a critical role as an antioxidant defense factor in the brain, we examined the effect of arctigenin on HO-1 expression in rat primary astrocytes. We found that arctigenin increased HO-1 mRNA and protein levels. Arctigenin also increases the nuclear translocation and DNA binding of Nrf2/c-Jun to the antioxidant response element (ARE) on HO-1 promoter. In addition, arctigenin increased ARE-mediated transcriptional activities in rat primary astrocytes. Further mechanistic studies revealed that arctigenin increased the phosphorylation of AKT, a downstream substrate of phosphatidylinositol 3-kinase (PI3K). Treatment of cells with a PI3K-specific inhibitor, LY294002, suppressed the HO-1 expression, Nrf2 DNA binding and ARE-mediated transcriptional activities in arctigenin-treated astrocyte cells. The results collectively suggest that PI3K/AKT signaling pathway is at least partly involved in HO-1 expression by arctigenin via modulation of Nrf2/ARE axis in rat primary astrocytes.
PMCID: PMC4256028  PMID: 25489416
Arctigenin; Astrocyte; Hemeoxygenase-1; PI3K/AKT; Nrf2/ARE axis
6.  A Preliminary Validity Study of the Cambridge Neuropsychological Test Automated Battery for the Assessment of Executive Function in Schizophrenia and Bipolar Disorder 
Psychiatry Investigation  2014;11(4):394-401.
Although the executive function subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) have been used to assess cognitive function in diverse psychiatric illnesses, few studies have verified the validity of this battery for Korean psychiatric patients. Therefore, this preliminary study evaluated the construct and concurrent validity of the executive function subtests of the CANTAB for Korean psychiatric patients by comparing it with subtests of the Computerized Neuropsychological Test (CNT).
Three subtests of the CANTAB and three subtests of the CNT were administered to 36 patients diagnosed with either schizophrenia or bipolar disorder. Subtests of the CANTAB included the Intra/Extra-Dimensional Set Shift (IED), Stockings of Cambridge (SOC), and Spatial Working Memory (SWM). Differences between groups on each subtest as well as correlations between the subtests of the CANTAB and the CNT were assessed.
The schizophrenia group performed significantly more poorly on the IED and the Wisconsin Card Sorting Test (WCST) compared with the bipolar disorder group. Additionally, correlation analyses revealed a significant correlation between the IED and the WCST; a positive correlation between the SOC and the Trail Making Test, Part B and the Stroop test; and a significant correlation between the SWM and the Stroop test.
This study verified the construct and concurrent validity of the executive function subtests of the CANTAB for Korean psychiatric patients and suggests that the subtests of this battery would be useful and appropriate for assessing deficits in executive function in Korean clinical settings.
PMCID: PMC4225203  PMID: 25395970
Cambridge Neuropsychological Test Automated Battery (CANTAB); Computerized neuropsychological test; Executive function; Validity
7.  The significance of placental ratios in pregnancies complicated by small for gestational age, preeclampsia, and gestational diabetes mellitus 
Obstetrics & Gynecology Science  2014;57(5):358-366.
This study aimed to evaluate the placental weight, volume, and density, and investigate the significance of placental ratios in pregnancies complicated by small for gestational age (SGA), preeclampsia (PE), and gestational diabetes mellitus (GDM).
Two hundred and fifty-four pregnant women were enrolled from August 2005 through July 2013. Participants were divided into four groups: control (n=82), SGA (n=37), PE (n=102), and GDM (n=33). The PE group was classified as PE without intrauterine growth restriction (n=65) and PE with intrauterine growth restriction (n=37). Birth weight, placental weight, placental volume, placental density, and placental ratios including birth weight/placental weight ratio (BPW) and birth weight/placental volume ratio (BPV) were compared between groups.
Birth weight, placental weight, and placental volume were lower in the SGA group than in the control group. However, the BPW and BPV did not differ between the two groups. Birth weight, placental weight, placental volume, BPW, and BPV were all significantly lower in the PE group than in the control group. Compared with the control group, birth weight, BPW, and BPV were higher in the GDM group, whereas placental weight and volume did not differ in the two groups. Placental density was not significantly different among the four groups.
Placental ratios based on placental weight, placental volume, placental density, and birth weight are helpful in understanding the pathophysiology of complicated pregnancies. Moreover, they can be used as predictors of pregnancy complications.
PMCID: PMC4175595  PMID: 25264525
Birth weight/placental weight ratio; Complicated pregnancies; Placental volume
8.  Comparison of the Effects of Matrix Metalloproteinase Inhibitors on TNF-α Release from Activated Microglia and TNF-α Converting Enzyme Activity 
Biomolecules & Therapeutics  2014;22(5):414-419.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-α activity. We found that the MMP inhibitors suppressed TNF-α secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-α inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-α secretion. A subsequent pro-TNF-α cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-α, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.
PMCID: PMC4201218  PMID: 25414771
Microglia; Inflammation; MMP inhibitor; TNF-α; TACE
9.  The anti-inflammatory role of tissue inhibitor of metalloproteinase-2 in lipopolysaccharide-stimulated microglia 
Tissue inhibitors of metalloproteinases (TIMPs) are known to be endogenous inhibitors of matrix metalloproteinases (MMPs). Our preliminary study showed that TIMP-2 is constitutively expressed in microglia but significantly inhibited by lipopolysaccharide (LPS) treatment. The current study was undertaken to investigate the role of TIMP-2 in microglia.
The expression of TIMP-2 was evaluated in the BV2 mouse microglial cell line and rat primary cultured microglia. To investigate the role of TIMP-2, a TIMP-2 expression plasmid or small interfering RNA (siRNA) was introduced into BV2 cells by transient transfection, and their effects on LPS-induced inflammatory reactions were examined. We further analyzed the molecular mechanism underlying the anti-inflammatory effects of TIMP-2 by electrophoretic mobility shift assay (EMSA), a reporter gene assay and Western blot analysis.
Overexpression of TIMP-2 significantly inhibited the production of nitric oxide (NO), TNF-α, IL-1β, and reactive oxygen species (ROS), while increasing anti-inflammatory IL-10 production. On the other hand, knockdown of TIMP-2 augmented the production of pro-inflammatory molecules and downregulated IL-10 in LPS-stimulated BV2 cells. The results suggest that endogenously expressed TIMP-2 plays an anti-inflammatory role. Further mechanistic studies revealed that overexpression of TIMP-2 suppresses microglial activation via inhibition of the activity of mitogen-activated protein kinases (MAPKs) and NF-κB with enhancement of the activity of anti-inflammatory Nrf2 and cAMP-response element binding protein (CREB) transcription factors. TIMP-2 also inhibited the activity and expression of LPS-induced MMP-3, -8, and -9. Finally, we demonstrated that TIMP-2 exerts a neuroprotective effect via the inhibition of microglial activation.
Enhancement of TIMP-2 expression may be a potential therapeutic target for neuroinflammatory disorders.
PMCID: PMC4091675  PMID: 24970341
TIMP-2; MMP; microglia; neuroinflammation; neuroprotection
10.  Anti-Inflammatory Effects of α-Galactosylceramide Analogs in Activated Microglia: Involvement of the p38 MAPK Signaling Pathway 
PLoS ONE  2014;9(2):e87030.
Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.
PMCID: PMC3921125  PMID: 24523867
11.  Radioprotection of mice by lactoferrin against irradiation with sublethal X-rays 
Journal of Radiation Research  2014;55(2):277-282.
The influence of a host defense protein, lactoferrin (LF), contained in exocrine secretions such as milk, on radiation disorder was investigated. A total of 25 C3H/He mice in each of two groups were maintained with 0.1% LF-added and LF-free diets, respectively, for one month. The mice were then treated with single whole-body X-ray irradiation at a sublethal dose (6.8 Gy), and the survival rate after irradiation was investigated. The survival rate at 30 d after irradiation was relatively higher in the LF group than in the control group (LF-free), (85 and 62%, respectively). The body weight 15 d after X-ray irradiation was also significantly greater in the LF group than in the control group. The hemoglobin level and hematocrit value were higher in the LF group at 5 d before X-ray irradiation. Another 52 mice underwent whole-body X-ray irradiation at the sublethal dose (6.8 Gy), and then LF was intraperitoneally injected once at 4 mg/animal to half of them. The survival rate in LF-treated mice 30 d after irradiation was 92%, significantly higher than in mice treated with saline (50%) (P = 0.0012). In addition, LF showed hydroxyl radical scavenger activity in vitro. These findings suggest that LF may inhibit radiation damage.
PMCID: PMC3951079  PMID: 24508645
lactoferrin; radioprotection; sub-lethal X-ray irradiation; mice
12.  Successful treatment of myelodysplastic syndrome and Behcet colitis after allogeneic hematopoietic stem cell transplantation 
PMCID: PMC3932385  PMID: 24574844
Myelodysplastic syndromes; Behcet syndrome; Hematopoietic stem cell transplantation
13.  Kalopanaxsaponin A Exerts Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated Microglia via Inhibition of JNK and NF-κB/AP-1 Pathways 
Biomolecules & Therapeutics  2013;21(5):332-337.
Microglial activation plays an important role in the development and progression of various neurological disorders such as cerebral ischemia, multiple sclerosis, and Alzheimer’s disease. Thus, controlling microglial activation can serve as a promising therapeutic strategy for such brain diseases. In the present study, we showed that kalopanaxsaponin A, a triterpenoid saponin isolated from Kalopanax pictus, inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated microglia, while kalopanaxsaponin A increased anti-inflammatory cytokine interleukin (IL)-10 expression. Subsequent mechanistic studies revealed that kalopanaxsaponin A inhibited LPS-induced DNA binding activities of NF-κB and AP-1, and the phosphorylation of JNK without affecting other MAP kinases. Furthermore, kalopanaxsaponin A inhibited the intracellular ROS production with upregulation of anti-inflammatory hemeoxygenase-1 (HO-1) expression. Based on the previous reports that JNK pathway is largely involved in iNOS and proinflammatory cytokine gene expression via modulating NF-κB/AP-1 and ROS, our data collectively suggest that inhibition of JNK pathway plays a key role in anti-inflammatory effects of kalopanaxsaponin A in LPS-stimulated microglia.
PMCID: PMC3825195  PMID: 24244819
Microglia; Kalopanaxsaponin A; Anti-inflammation; JNK; NF-κB; AP-1
14.  Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice 
Journal of Veterinary Science  2013;14(3):271-279.
We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.
PMCID: PMC3788152  PMID: 23820165
AKR/J mice; DNA repair genes; low-dose-rate radiation; thymic lymphoma
15.  Effect of silane activation on shear bond strength of fiber-reinforced composite post to resin cement 
Among the surface treatment methods suggested to enhance the adhesion of resin cement to fiber-reinforced composite posts, conflicting results have been obtained with silanization. In this study, the effects of silanization, heat activation after silanization, on the bond strength between fiber-reinforced composite post and resin cement were determined.
Six groups (n=7) were established to evaluate two types of fiber post (FRC Postec Plus, D.T. Light Post) and three surface treatments (no treatment; air drying; drying at 38℃). Every specimen were bonded with dual-curing resin cement (Variolink N) and stored in distilled water for 24 hours at 37℃. Shear-bond strength (MPa) between the fiber post and the resin cement were measured using universal testing device. The data were analyzed with 1-way ANOVA and by multiple comparisons according to Tukey's HSD (α=0.05). The effect of surface treatment, fiber post type, and the interactions between these two factors were analyzed using 2-way ANOVA and independent sample T-tests.
Silanization of the FRC Postec Plus significantly increased bond strength compared with the respective non-treated control, whereas no effect was determined for the D.T. Light Post. Heat drying the silane coupling agent on to the fiber-reinforced post did not significantly improve bond strength compared to air-syringe drying.
The bond strength between the fiber-reinforced post and the resin cement was significantly increased with silanization in regards to the FRC Postec Plus post. Bond strength was not significantly improved by heat activation of the silane coupling agent.
PMCID: PMC3675281  PMID: 23755334
Post and core technique; Silane; Resin cements; Shear strength; Heat treatment
16.  Anti-Inflammatory Effect of Ginsenoside Rg5 in Lipopolysaccharide-Stimulated BV2 Microglial Cells 
Microglia are resident immune cells in the central nervous system. They play a role in normal brain development and neuronal recovery. However, overactivation of microglia causes neuronal death, which is associated with neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Therefore, controlling microglial activation has been suggested as an important target for treatment of neurodegenerative diseases. In the present study, we investigated the anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia. The data showed that Rg5 suppressed LPS-induced nitric oxide (NO) production and proinflammatory TNF-α secretion. In addition, Rg5 inhibited the mRNA expressions of iNOS, TNF-α, IL-1β, COX-2 and MMP-9 induced by LPS. Further mechanistic studies revealed that Rg5 inhibited the phophorylations of PI3K/Akt and MAPKs and the DNA binding activities of NF-κB and AP-1, which are upstream molecules controlling inflammatory reactions. Moreover, Rg5 suppressed ROS production with upregulation of hemeoxygenase-1 (HO-1) expression in LPS-stimulated BV2 cells. Overall, microglial inactivation by ginsenoside Rg5 may provide a therapeutic potential for various neuroinflammatory disorders.
PMCID: PMC3676815  PMID: 23698769
ginsenoside Rg5; microglia; neuroinflammation; iNOS; cytokine; signaling pathway
17.  Inorganic sulfur reduces cell proliferation by inhibiting of ErbB2 and ErbB3 protein and mRNA expression in MDA-MB-231 human breast cancer cells 
Dietary inorganic sulfur is the minor component in our diet, but some studies suggested that inorganic sulfur is maybe effective to treat cancer related illness. Therefore, this study aims to examine the effects of inorganic sulfur on cell proliferation and gene expression in MDA-MB-231 human breast cancer cells. MDA-MB-231 cells were cultured the absence or presence of various concentrations (12.5, 25, or 50 µmol/L) of inorganic sulfur. Inorganic sulfur significantly decreased proliferation after 72 h of incubation (P < 0.05). The protein expression of ErbB2 and its active form, pErbB2, were significantly reduced at inorganic sulfur concentrations of 50 µmol/L and greater than 25 µmol/L, respectively (P < 0.05). The mRNA expression of ErbB2 was significantly reduced at an inorganic sulfur concentration of 50 µmol/L (P < 0.05). The protein expression of ErbB3 and its active form, pErbB3, and the mRNA expression of ErbB3 were significantly reduced at inorganic sulfur concentrations greater than 25 µmol/L (P < 0.05). The protein and mRNA expression of Akt were significantly reduced at an inorganic sulfur concentration of 50 µmol/L (P < 0.05), but pAkt was not affected by inorganic sulfur treatment. The protein and mRNA expression of Bax were significantly increased with the addition of inorganic sulfur concentration of 50 µmol/L (P < 0.05). In conclusion, cell proliferation was suppressed by inorganic sulfur treatment through the ErbB-Akt pathway in MDA-MB-231 cells.
PMCID: PMC3627935  PMID: 23610600
Inorganic sulfur; epidermal growth factor receptor; apoptosis; cell proliferation; MDA-MB-231 cell
18.  Hypoxia Antagonizes Glucose Deprivation on Interleukin 6 Expression in an Akt Dependent, but HIF-1/2α Independent Manner 
PLoS ONE  2013;8(3):e58662.
Although both glucose deprivation and hypoxia have been reported to promote cascades of biological alterations that lead to induction of inflammatory mediators, we hypothesized that glucose deprivation and hypoxia might show neutral, synergistic or antagonistic effects to each other on gene expression of inflammatory mediators depending on the regulatory components in their promoters. Gene expression of interleukin 6 (IL-6) was analyzed by real-time PCR, ELISA, or Western blot. Effects of glucose deprivation and/or hypoxia on activation of signaling pathways were analyzed by time-dependent phosphorylation patterns of signaling molecules. We demonstrate that hypoxia antagonized the effects of glucose deprivation on induction of IL-6 gene expression in microglia, macrophages, and monocytes. Hypoxia also antagonized thapsigargin-induced IL-6 gene expression. Hypoxia enhanced phosphorylation of Akt, and inhibition of Akt was able to reverse the effects of hypoxia on IL-6 gene expression. However, inhibition of HIF-1/2α did not reverse the effects of hypoxia on IL-6 gene expression. In addition, phosphorylation of p38, but not JNK, was responsible for the effects of glucose deprivation on IL-6 gene expression.
PMCID: PMC3592797  PMID: 23520526
19.  The utility of sperm DNA damage assay using toluidine blue and aniline blue staining in routine semen analysis 
The aim of the present study was to examine the relationship among male age, strict morphology, and sperm chromatin structure and condensation.
Sperm samples from a total of 100 men underwent semen analysis, and sperm chromatin structure and condensation were assessed with toluidine blue (TB) and aniline blue (AB) tests.
Prevalence of strict morphology of less than 4%, and abnormal sperm chromatin structure and condensation did not show any statistically significant differences according to male age (p=0.605, p=0.235, and p=0.080). No significant correlation was demonstrated among age of male partners, strict morphology, and abnormal sperm chromatin structure using TB and AB tests. However, abnormal sperm chromatin condensation was positively associated with sperm chromatin structure (r=0.594, p=0.000) and showed negative correlation with strict morphology (r=-0.219, p=0.029).
The tests for sperm chromatin condensation showed a significant association with strict morphology. Further study is needed to elucidate the relationship between clinical outcome and sperm chromatin tests.
PMCID: PMC3630289  PMID: 23614112
Toluidine blue; Aniline blue; Semen analysis; DNA damage; Human
20.  Successful birth with preimplantation genetic diagnosis using single-cell allele-specific PCR and sequencing in a woman with hypochondroplasia due to FGFR3 mutation (c.1620C>A, p.N540K) 
Hypochondroplasia (HCH) is an autosomal dominant inherited skeletal dysplasia, usually caused by a heterozygous mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A 27-year-old HCH woman with a history of two consecutive abortions of HCH-affected fetuses visited our clinic for preimplantation genetic diagnosis (PGD). We confirmed the mutation in the proband (FGFR3:c.1620C>A, p.N540K), and established a nested allele-specific PCR and sequence analysis for PGD using single lymphocyte cells. We performed this molecular genetic analysis to detect the presence of mutation among 20 blastomeres from 18 different embryos, and selected 9 embryos with the wild-type sequence (FGFR3:c.1620C). A successful pregnancy was achieved through a frozen-thawed cycle and resulted in the full-term birth of a normal neonate. To the best of our knowledge, this is the first report of a successful pregnancy and birth using single-cell allele-specific PCR and sequencing for PGD in an HCH patient.
PMCID: PMC3630293  PMID: 23614116
Hypochondroplasia; Preimplantation genetic diagnosis; Receptor, fibroblast growth factor, type 3
21.  The Effect of Red Ginseng Extract on Inflammatory Cytokines after Chemotherapy in Children 
Journal of Ginseng Research  2012;36(4):383-390.
Ginseng has been used as an herbal medicine, widely used in Asian countries, for long time. Recently, beneficial effects for immune functions of Korean red ginseng (KRG) have been reported in adults. This study was performed to investigate the effects of ginseng on immune functions in children after cessation of chemotherapy or stem cell transplantation for advanced cancer. Thirty patients, who were diagnosed and treated for leukemia and solid cancer at the department of pediatrics and adolescence of the Yeungnam University Hospital from June 2004 to June 2009, were enrolled for the study. The study group consisted of 19 patients who received KRG extract (60 mg/kg/d) for 1 yr and 11 patients who did not receive KRG extract were the control group. Blood samples were collected every 6 mo. Immune assays included circulating lymphocyte subpopulation, serum cytokines (IL- 2, IL-10, IL-12, TNF-alpha, and IFN-gamma), and total concentrations of serum IgG, IgA, and IgM subclasses. Age at diagnosis ranged from 2 mo to 15 yr (median 5 yr). Nine patients received stem cell transplantation. The cytokines of the KRG treated group were decreasing more rapidly than that of the control group. Lymphocyte subpopulations (T cell, B cell, NK cell, T4, T8, and T4/ T8 ratio) and serum immunoglobulin subclasses (IgG, IgA, and IgM) did not show significant differences between the study and the control groups. This study suggests that KRG extract might have a stabilizing effect on the inflammatory cytokines in children with cancer after chemotherapy.
PMCID: PMC3659604  PMID: 23717140
Panax ginseng; Korean red ginseng; Cytokine; Childhood cancer
22.  Augmentation of natural cytotoxicity by chronic low-dose ionizing radiation in murine natural killer cells primed by IL-2 
Journal of Radiation Research  2012;53(6):823-829.
The possible beneficial effects of chronic low-dose irradiation (LDR) and its mechanism of action in a variety of pathophysiological processes such as cancer are a subject of intense investigation. While animal studies involving long-term exposure to LDR have yielded encouraging results, the influence of LDR at the cellular level has been less well defined. We reasoned that since natural killer (NK) cells constitute an early responder to exogenous stress, NK cells may reveal sentinel alterations in function upon exposure to LDR. When purified NK cells received LDR at 4.2 mGy/h for a total of 0.2 Gy in vitro, no significant difference in cell viability was observed. Likewise, no functional changes were detected in LDR-exposed NK cells, demonstrating that LDR alone was insufficient to generate changes at the cellular level. Nonetheless, significant augmentation of cytotoxic, but not proliferative, function was detected when NK cells were stimulated with low-dose IL-2 prior to irradiation. This enhancement of NK cytotoxicity was not due to alterations in NK-activating receptors, NK1.1, NKG2D, CD69 and 2B4, or changes in the rate of early or late apoptosis. Therefore, LDR, in the presence of suboptimal cytokine levels, can facilitate anti-tumor cytotoxicity of NK cells without influencing cellular proliferation or apoptosis. Whether these results translate to in vivo consequences remains to be seen; however, our data provide initial evidence that exposure to LDR can lead to subtle immune-enhancing effects on NK cells and may explain, in part, the functional basis underlying, diverse beneficial effects seen in the animals chronically exposed to LDR.
PMCID: PMC3483842  PMID: 22915781
Low-dose radiation; natural killer cells; natural cytotoxicity; innate immunity
23.  Protein Kinase C-Dependent Dephosphorylation of Tyrosine Hydroxylase Requires the B56δ Heterotrimeric Form of Protein Phosphatase 2A 
PLoS ONE  2011;6(10):e26292.
Tyrosine hydroxylase, which plays a critical role in regulation of dopamine synthesis, is known to be controlled by phosphorylation at several critical sites. One of these sites, Ser40, is phosphorylated by a number of protein kinases, including protein kinase A. The major protein phosphatase that dephosphorylates Ser40 is protein phosphatase-2A (PP2A). A recent study has also linked protein kinase C to the dephosphorylation of Ser40 [1], but the mechanism is unclear. PP2A isoforms are comprised of catalytic, scaffold, and regulatory subunits, the regulatory B subunits being able to influence cellular localization and substrate selection. In the current study, we find that protein kinase C is able to phosphorylate a key regulatory site in the B56δ subunit leading to activation of PP2A. In turn, activation of the B56δ-containing heterotrimeric form of PP2A is responsible for enhanced dephosphorylation of Ser40 of tyrosine hydroylase in response to stimulation of PKC. In support of this mechanism, down-regulation of B56δ expression in N27 cells using RNAi was found to increase dopamine synthesis. Together these studies reveal molecular details of how protein kinase C is linked to reduced tyrosine hydroxylase activity via control of PP2A, and also add to the complexity of protein kinase/protein phosphatase interactions.
PMCID: PMC3198769  PMID: 22046270
24.  Inorganic sulfur reduces the motility and invasion of MDA-MB-231 human breast cancer cells 
Nutrition Research and Practice  2011;5(5):375-380.
This study investigated the effects of inorganic sulfur on metastasis in MDA-MB-231 human breast cancer cells. MDA-MB-231 cells were cultured in the absence or presence of various concentrations (12.5, 25, or 50 µmol/L) of inorganic sulfur. Cell motility, invasion, and the activity and mRNA expression of matrix metalloproteases (MMPs) were examined. Numbers of viable MDA-MB-231 cells did not differ by inorganic sulfur treatment from 0 to 50 µmol/L within 48 h. Inorganic sulfur significantly decreased cell motility and invasion in the MDA-MB-231 cells in a dose-dependent manner (P < 0.05), as determined using a Boyden chamber assay and a Matrigel chamber. The activities of MMP-2 and MMP-9 were significantly reduced by inorganic sulfur in a dose-dependent manner (P < 0.05). The inorganic sulfur also significantly inhibited MMP-2 and MMP-9 expression in the cells (P < 0.05). These data suggest that inorganic sulfur can suppress cancer cell motility and invasion by inhibiting MMP-2 and MMP-9 activity and gene expression in MDA-MB-231 cells.
PMCID: PMC3221821  PMID: 22125673
Inorganic sulfur; invasion; motility; matrix metalloprotease; MDA-MB-231 cells
25.  Cilostazol Inhibits Vascular Smooth Muscle Cell Proliferation and Reactive Oxygen Species Production through Activation of AMP-activated Protein Kinase Induced by Heme Oxygenase-1 
Cilostazol is a selective inhibitor of phosphodiesterase 3 that increases intracellular cAMP levels and activates protein kinase A, thereby inhibiting vascular smooth muscle cell (VSMC) proliferation. We investigated whether AMP-activated protein kinase (AMPK) activation induced by heme oxygenase-1 (HO-1) is a mediator of the beneficial effects of cilostazol and whether cilostazol may prevent cell proliferation and reactive oxygen species (ROS) production by activating AMPK in VSMC. In the present study, we investigated VSMC with various concentrations of cilostazol. Treatment with cilostazol increased HO-1 expression and phosphorylation of AMPK in a dose- and time-dependent manner. Cilostazol also significantly decreased platelet-derived growth factor (PDGF)-induced VSMC proliferation and ROS production by activating AMPK induced by HO-1. Pharmacological and genetic inhibition of HO-1 and AMPK blocked the cilostazol-induced inhibition of cell proliferation and ROS production.These data suggest that cilostazol-induced HO-1 expression and AMPK activation might attenuate PDGF-induced VSMC proliferation and ROS production.
PMCID: PMC3186921  PMID: 21994478
Cilostazol; Proliferation; ROS; AMPK; HO-1

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