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1.  Diagnostic Imaging Utilization in Cases of Acute Appendicitis: Multi-Center Experience 
Journal of Korean Medical Science  2014;29(9):1308-1316.
The purpose of this cross-sectional study was to measure imaging utilization rates and the negative appendectomy rate (NAR) in metropolitan Seoul, Korea. The study included 2321 adolescents and adults (≥15 yr; median [interquartile range] age, 37 [27-50] yr; 46.7% female) undergoing appendectomy in 2011 at eight tertiary and three secondary hospitals. Imaging utilization rate was 99.7% (95% confidence interval, 99.4%-99.9%). CT and ultrasonography utilization rates as an initial imaging modality were 93.1% (92.0%-94.1%), and 6.5% (5.6%-7.6%), respectively. The NAR in patients undergoing CT only, complementary ultrasonography following CT, ultrasonography only, and complementary CT following ultrasonography were 3.3% (2.6%-4.1%), 27% (14%-44%), 9% (4%-16%), and 8% (2%-20%), respectively. The use of ultrasonography instead of CT as the initial imaging modality was significantly associated with higher NAR (adjusted odds ratio [AOR], 2.28 [1.22-4.27]; risk difference, 4.4 [0-8.8] percentage points), however, the population attributable risk was 0.3 [0-0.6] percentage points. We observed a very high CT utilization rate and a low NAR in metropolitan Seoul. Although the use of CT was significantly associated with the lower NAR, CT utilization rate already has reached the level that increase in CT utilization from the status quo would hardly decrease the NAR further.
Graphical Abstract
PMCID: PMC4168187  PMID: 25246752
Appendicitis; Tomography, X-ray Computed; Ultrasonography
2.  Influence of reactive species on the modification of biomolecules generated from the soft plasma 
Scientific Reports  2015;5:8221.
Plasma medicine is an upcoming research area that has attracted the scientists to explore more deeply the utility of plasma. So, apart from the treating biomaterials and tissues with plasma, we have studied the effect of soft plasma with different feeding gases such as Air, N2 and Ar on modification of biomolecules. Hence, in this work we have used the soft plasma on biomolecules such as proteins ((Hemoglobin (Hb) and Myoglobin (Mb)), calf thymus DNA and amino acids. The structural changes or structural modification of proteins and DNA have been studied using circular dichroism (CD), fluorescence spectroscopy, protein oxidation test, gel electrophoresis, UV-vis spectroscopy, dynamic light scattering (DLS) and 1D NMR, while Liquid Chromatograph/Capillary Electrophoresis-Mass Spectrometer (LC/CE-MS) based on qualitative and quantitative bio-analysis have been used to study the modification of amino acids. Further, the thermal analysis of the protein has been studied with differential scanning calorimetry (DSC) and CD. Additionally, we have performed docking studies of H2O2 with Hb and Mb, which reveals that H2O2 molecules preferably attack the amino acids near heme group. We have also shown that N2 gas plasma has strong deformation action on biomolecules and compared to other gases plasma.
PMCID: PMC4316168  PMID: 25649786
3.  Erratum: Correction of 1.3 Investigators in Supplementary Materials 
PMCID: PMC4278020  PMID: 25547240
4.  Effects of Polydeoxyribonucleotide in the Treatment of Pressure Ulcers 
Journal of Korean Medical Science  2014;29(Suppl 3):S222-S227.
This study aimed to examine the positive effects of polydeoxyribonucleotide (PDRN) on the wound-healing process in pressure ulcers. In this randomized controlled trial, the effects of PDRN were compared over time between an experimental group (n=11) and a control group (n=12). The former was administered the same dose of PDRN intramuscularly (1 ampule, 3 mL, 5.625 mg, for 5 days) for 2 weeks and perilesionally (1 ampule, 3 mL, 5.625 mg, twice a week) for 4 weeks. The primary endpoint for determining efficacy was wound healing in the pressure ulcers, which was reflected by the wound surface area determined using VISITRAK Digital (Smith & Nephew, Largo, FL). The secondary endpoint was the pressure ulcer scale for healing score, determined using pressure ulcer scale for healing (PUSH Tool 3.0 developed by the National Pressure Ulcer Advisory Panel). After the 4-week treatment period, PDRN therapy was found to significantly reduce the wound size and PUSH score, without adverse effect during the treatment. The findings indicate that PDRN can positively modify the wound healing process in pressure ulcers, and its use could improve the clinical outcomes of patients and lower the need for additional therapies or hospital stay.
Graphical Abstract
PMCID: PMC4248009  PMID: 25473213
Pressure Ulcers; Polydeoxyribonucleotides; Re-epithelialization
5.  Docosahexaenoic acid-induced apoptosis is mediated by activation of mitogen-activated protein kinases in human cancer cells 
BMC Cancer  2014;14:481.
The role of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in cancer prevention has been demonstrated; however, the exact molecular mechanisms underlying the anticancer activity of ω3-PUFAs are not fully understood. Here, we investigated the relationship between the anticancer action of a specific ω3-PUFA docosahexaenoic acid (DHA), and the conventional mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 whose dysregulation has been implicated in human cancers.
MTT assays were carried out to determine cell viability of cancer cell lines (PA-1, H1299, D54MG and SiHa) from different origins. Apoptosis was confirmed by TUNEL staining, DNA fragmentation analysis and caspase activity assays. Activities of the conventional MAPKs were monitored by their phosphorylation levels using immunoblotting and immunocytochemistry analysis. Reactive oxygen species (ROS) production was measured by flow cytometry and microscopy using fluorescent probes for general ROS and mitochondrial superoxide.
DHA treatment decreased cell viability and induced apoptotic cell death in all four studied cell lines. DHA-induced apoptosis was coupled to the activation of the conventional MAPKs, and knockdown of ERK/JNK/p38 by small interfering RNAs reduced the apoptosis induced by DHA, indicating that the pro-apoptotic effect of DHA is mediated by MAPKs activation. Further study revealed that the DHA-induced MAPKs activation and apoptosis was associated with mitochondrial ROS overproduction and malfunction, and that ROS inhibition remarkably reversed these effects of DHA.
Together, these results indicate that DHA-induced MAPKs activation is dependent on its capacity to provoke mitochondrial ROS generation, and accounts for its cytotoxic effect in human cancer cells.
PMCID: PMC4094407  PMID: 24993937
Docosahexaenoic acid; Reactive oxygen species; Mitogen-activated protein kinases; Apoptosis; Cancer
6.  An Indole Derivative Protects Against Acetaminophen-Induced Liver Injury by Directly Binding to N-Acetyl-p-Benzoquinone Imine in Mice 
Antioxidants & Redox Signaling  2013;18(14):1713-1722.
Aims: Acetaminophen (APAP)-induced liver injury is mainly due to the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the formation of a reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), in both humans and rodents. Here, we show that the indole-derived synthetic compound has a protective effect against APAP-induced liver injury in C57Bl/6 mice model. Results: NecroX-7 decreased tert-butylhydroperoxide (t-BHP)- and APAP-induced cell death and ROS/RNS formation in HepG2 human hepatocarcinoma and primary mouse hepatocytes. In mice, NecroX-7 decreased APAP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and 3-nitrotyrosine (3-NT) formation, and also protected mice from APAP-induced liver injury and lethality by binding directly to NAPQI. The binding of NecroX-7 to NAPQI did not require any of cofactors or proteins. NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low. Innovation: NecroX-7 is an indole-derived potent antioxidant molecule, which can be bound to some types of radicals and especially NAPQI. It is well known that the NAPQI is a major intermediate of APAP, which causes necrosis of hepatocytes in rodents and humans. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategies for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment. Conclusion: Our data suggest that the indole-derivative, NecroX-7, directly binds to NAPQI when hepatic GSH levels are very low and the NAPQI–NecroX-7 complex is secreted to the blood from the liver. NecroX-7 shows more preventive and similar therapeutic effects against APAP-induced liver injury when compared to the effect of N-acetylcysteine in C57Bl/6 mice. Antioxid. Redox Signal. 18, 1713–1722.
PMCID: PMC3619205  PMID: 23121402
7.  Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy 
Neurogenetics  2014;15(3):171-182.
Recessive mutations in chromosome 10 open reading frame 2 (C10orf2) are relevant in infantile-onset spinocerebellar ataxia (IOSCA). In this study, we investigated the causative mutation in a Korean family with combined phenotypes of IOSCA, sensorimotor polyneuropathy, and myopathy. We investigated recessive mutations in a Korean family with two individuals affected by IOSCA. Causative mutations were investigated using whole exome sequencing. Electrophysiological analyses and muscle and nerve biopsies were performed, along with magnetic resonance imaging (MRI) of the brain and lower extremities. Compound heterozygous mutations c.1460C>T and c.1485-1G>A in C10orf2 were identified as causative of IOSCA. Skeletal muscle showed mitochondrial DNA (mtDNA) deletions. Both patients showed a period of normal development until 12–15 months, followed by ataxia, athetosis, hearing loss, and intellectual disability. Electrophysiological findings indicated motor and sensory polyneuropathies. Muscle biopsy revealed variations in the size and shape of myofibers with scattered, small, and angulated degenerating myofibers containing abnormal mitochondria; these observations are consistent with myopathy and may be the result of mtDNA deletions. Sural nerve biopsy revealed an axonal neuropathy. High-signal-intensity lesions in the middle cerebellar peduncles were correlated with clinical severity, and MRI of the lower legs was compatible with the hypothesis of length-dependent axonal degeneration. We identified novel compound heterozygous mutations of the C10orf2 gene as the cause of IOSCA with sensorimotor polyneuropathy and myopathy. Signs of motor neuropathy and myopathy were discovered for the first time in IOSCA patients with C10orf2 mutations. These results suggest that the clinical spectrum of IOSCA caused by C10orf2 mutations may be more variable than previously reported.
Electronic supplementary material
The online version of this article (doi:10.1007/s10048-014-0405-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4102772  PMID: 24816431
C10orf2; Whole exome sequencing (WES); Infantile-onset spinocerebellar ataxia (IOSCA); Neuropathy; Myopathy; Mitochondria
8.  Does Diabetes Mellitus Influence Standardized Uptake Values of Fluorodeoxyglucose Positron Emission Tomography in Colorectal Cancer? 
Intestinal Research  2014;12(2):146-152.
Hyperglycemia is associated with decreased 2-18[F]fluoro-2-deoxy-D-glucose (FDG) uptake by tumors assessed by positron emission tomography (PET). In this retrospective study we investigated a comparison of standardized uptake values (SUVs) in patients with primary colorectal cancers who either had diabetes mellitus (DM) or were otherwise healthy.
The medical records of 397 patients who were diagnosed with colorectal cancer and underwent PET-CT between January 2006 and December 2012 were analyzed. Eighty patients with DM and 317 patients without DM were included. Clinical characteristics were reviewed and maximal standardized uptake values (SUVmax) were calculated in the primary colorectal lesions.
There was no significant difference between tumor SUVmax in DM patients (10.60±5.78) and those without DM (10.92±5.44). In addition, no significant difference was detected between tumor SUVmax in DM patients with glycated hemoglobin (HbA1c) levels <8% (10.34±5.17) and those with HbA1c levels ≥8% (10.61±7.27). The maximum size of the primary colorectal tumor was associated with SUVmax in a linear regression analysis.
The results of this study showed that DM did not influence FDG uptake values in colorectal cancer patients regardless of glucose levels.
PMCID: PMC4204697  PMID: 25349582
Diabetes mellitus; Positron emission tomography; Colorectal neoplasms
9.  PMA synergistically enhances apicularen A-induced cytotoxicity by disrupting microtubule networks in HeLa cells 
BMC Cancer  2014;14:36.
Combination therapy is key to improving cancer treatment efficacy. Phorbol 12-myristate 13-acetate (PMA), a well-known PKC activator, increases the cytotoxicity of several anticancer drugs. Apicularen A induces cytotoxicity in tumor cells through disrupting microtubule networks by tubulin down-regulation. In this study, we examined whether PMA increases apicularen A-induced cytotoxicity in HeLa cells.
Cell viability was examined by thiazolyl blue tetrazolium (MTT) assays. To investigate apoptotic potential of apicularen A, DNA fragmentation assays were performed followed by extracting genomic DNA, and caspase-3 activity assays were performed by fluorescence assays using fluorogenic substrate. The cell cycle distribution induced by combination with PMA and apicularen A was examined by flow cytometry after staining with propidium iodide (PI). The expression levels of target proteins were measured by Western blotting analysis using specific antibodies, and α-tubulin mRNA levels were assessed by reverse transcription polymerase chain reaction (RT-PCR). To examine the effect of combination of PMA and apicularen A on the microtubule architecture, α-tubulin protein and nuclei were visualized by immunofluorescence staining using an anti-α-tubulin antibody and PI, respectively.
We found that apicularen A induced caspase-dependent apoptosis in HeLa cells. PMA synergistically increased cytotoxicity and apoptotic sub-G1 population induced by apicularen A. These effects were completely blocked by the PKC inhibitors Ro31-8220 and Go6983, while caspase inhibition by Z-VAD-fmk did not prevent cytotoxicity. RNA interference using siRNA against PKCα, but not PKCβ and PKCγ, inhibited cytotoxicity induced by combination PMA and apicularen A. PMA increased the apicularen A-induced disruption of microtubule networks by further decreasing α- and β-tubulin protein levels in a PKC-dependent manner.
These results suggest that the synergy between PMA and apicularen A is involved by PKCα activation and microtubule disruption, and that may inform the development of novel approaches to treat cancer.
PMCID: PMC3901760  PMID: 24447339
PMA; Apicularen A; PKCα; Cell death; Microtubule disruption
10.  Sentinel Node Mapping of VX2 Carcinoma in Rabbit Thigh with CT Lymphography Using Ethiodized Oil 
Korean Journal of Radiology  2014;15(1):29-36.
To assess the feasibility of computed tomography (CT) lymphography using ethiodized oil for sentinel node mapping in experimentally induced VX2 carcinoma in the rabbit thigh.
Materials and Methods
This experiment received approval from the institutional animal use and care administrative advisory committee. Twenty-three rabbits with VX2 carcinoma in the thigh underwent CT before and after (1 hour, 2 hour) peritumoral injection of 2 mL ethiodized oil. After the CT examination, sentinel nodes were identified by peritumoral injection of methylene blue and subsequently removed. The retrieved sentinel and non-sentinel lymph nodes were investigated with radiographic and pathologic examinations. Based on the comparison of CT findings with those of radiographic and pathologic examinations, the diagnostic performance of CT for sentinel node identification was assessed.
All 23 rabbits showed 53 ethiodized oil retention nodes on post-injection CT and specimen radiography, and 52 methylene blue-stained nodes at the right femoroiliac area. Of the 52 blue-stained sentinel nodes, 50 nodes demonstrated ethiodized oil retention. Thus, the sentinel node detection rate of CT was 96% (50 of 52). On pathologic examination, 28 sentinel nodes in 17 rabbits (nodes/rabbit, mean ± standard deviation, 1.7 ± 0.6) harbored metastasis. Twenty seven of the 28 metastatic sentinel nodes were found to have ethiodized oil retention.
Computed tomography lymphography using ethiodized oil may be feasible for sentinel node mapping in experimentally induced VX2 carcinoma in the rabbit thigh.
PMCID: PMC3909858  PMID: 24497789
Sentinel lymph node; Computed tomography; Lymphography; Lymphatic metastasis; Animal model
12.  MR Imaging in Patients with Suspected Liver Metastases: Value of Liver-Specific Contrast Agent Gadoxetic Acid 
Korean Journal of Radiology  2013;14(6):894-904.
To compare the diagnostic performance of gadoxetic acid-enhanced magnetic resonance (MR) imaging with that of triple-phase multidetector-row computed tomography (MDCT) in the detection of liver metastasis.
Materials and Methods
Our institutional review board approved this retrospective study and waived informed consent. The study population consisted of 51 patients with hepatic metastases and 62 patients with benign hepatic lesions, who underwent triple-phase MDCT and gadoxetic acid-enhanced MRI within one month. Two radiologists independently and randomly reviewed MDCT and MRI images regarding the presence and probability of liver metastasis. In order to determine additional value of hepatobiliary-phase (HBP), the dynamic-MRI set alone and combined dynamic-and-HBP set were evaluated, respectively. The standard of reference was a combination of pathology diagnosis and follow-up imaging. For each reader, diagnostic accuracy was compared using the jackknife alternative free-response receiver-operating-characteristic (JAFROC).
For both readers, average JAFROC figure-of-merit (FOM) was significantly higher on the MR image sets than on the MDCT images: average FOM was 0.582 on the MDCT, 0.788 on the dynamic-MRI set and 0.847 on the combined HBP set, respectively (p < 0.0001). The differences were more prominent for small (≤ 1 cm) lesions: average FOM values were 0.433 on MDCT, 0.711 on the dynamic-MRI set and 0.828 on the combined HBP set, respectively (p < 0.0001). Sensitivity increased significantly with the addition of HBP in gadoxetic acid-enhanced MR imaging (p < 0.0001).
Gadoxetic acid-enhanced MRI shows a better performance than triple-phase MDCT for the detection of hepatic metastasis, especially for small (≤ 1 cm) lesions.
PMCID: PMC3835636  PMID: 24265564
Gadoxetic acid; Magnetic resonance imaging; Computed tomography; Hepatic metastasis
13.  Opening and reversible control of a wide energy gap in uniform monolayer graphene 
Scientific Reports  2013;3:2725.
For graphene to be used in semiconductor applications, a ‘wide energy gap' of at least 0.5 eV at the Dirac energy must be opened without the introduction of atomic defects. However, such a wide energy gap has not been realized in graphene, except in the cases of narrow, chemically terminated graphene nanostructures with inevitable edge defects. Here, we demonstrated that a wide energy gap of 0.74 eV, which is larger than that of germanium, could be opened in uniform monolayer graphene without the introduction of atomic defects into graphene. The wide energy gap was opened through the adsorption of self-assembled twisted sodium nanostrips. Furthermore, the energy gap was reversibly controllable through the alternate adsorption of sodium and oxygen. The opening of such a wide energy gap with minimal degradation of mobility could improve the applicability of graphene in semiconductor devices, which would result in a major advancement in graphene technology.
PMCID: PMC3792418  PMID: 24100763
14.  The Omega-3 Polyunsaturated Fatty Acid DHA Induces Simultaneous Apoptosis and Autophagy via Mitochondrial ROS-Mediated Akt-mTOR Signaling in Prostate Cancer Cells Expressing Mutant p53 
BioMed Research International  2013;2013:568671.
Docosahexaenoic acid (DHA) induces autophagy-associated apoptotic cell death in wild-type p53 cancer cells via regulation of p53. The present study investigated the effects of DHA on PC3 and DU145 prostate cancer cell lines harboring mutant p53. Results show that, in addition to apoptosis, DHA increased the expression levels of lipidated form LC3B and potently stimulated the autophagic flux, suggesting that DHA induces both autophagy and apoptosis in cancer cells expressing mutant p53. DHA led to the generation of mitochondrial reactive oxygen species (ROS), as shown by the mitochondrial ROS-specific probe mitoSOX. Similarly, pretreatment with the antioxidant N-acetyl-cysteine (NAC) markedly inhibited both the autophagy and the apoptosis triggered by DHA, indicating that mitochondrial ROS mediate the cytotoxicity of DHA in mutant p53 cells. Further, DHA reduced the levels of phospho-Akt and phospho-mTOR in a concentration-dependent manner, while NAC almost completely blocked that effect. Collectively, these findings present a novel mechanism of ROS-regulated apoptosis and autophagy that involves Akt-mTOR signaling in prostate cancer cells with mutant p53 exposed to DHA.
PMCID: PMC3691929  PMID: 23841076
15.  T1 Slope and Cervical Sagittal Alignment on Cervical CT Radiographs of Asymptomatic Persons 
We performed a retrospective analysis of medical records and radiographic images of patients who never underwent spinal treatment including diagnosis. The objective of this study is to explain the biomechanical and physiologic characteristics of cervical alignment related to thoracic inlet angle including T1 slope changes in each individual.
We reviewed the cervical CT radiographs of 80 patients who visited ENT outpatient clinic without any symptom, diagnosis and treatment of cervical spine from January 2011 to September 2012. All targeted people were randomized without any prejudice. We assessed the data-T1 slope, Cobb's angle C2-7, neck tilt, sagittal vertical axis (SVA) C2-7 and thoracic inlet angle by the CT radiographs.
The relationships between each value were analyzed and we concluded that Cobb's angle C2-7 gets higher as the T1 slope gets higher, while the SVA C2-7 value decreases.
We propose that the T1 slope is background information in deciding how much angle can be made in the cervical spinal angle of surgical lordotic curvature, especially severe cervical deformity.
PMCID: PMC3756128  PMID: 24003370
T1 slope; Cervical sagittal alignment; Cobb's angle C2-7
16.  Discovery of Cellular Proteins Required for the Early Steps of HCV Infection Using Integrative Genomics 
PLoS ONE  2013;8(4):e60333.
Successful viral infection requires intimate communication between virus and host cell, a process that absolutely requires various host proteins. However, current efforts to discover novel host proteins as therapeutic targets for viral infection are difficult. Here, we developed an integrative-genomics approach to predict human genes involved in the early steps of hepatitis C virus (HCV) infection. By integrating HCV and human protein associations, co-expression data, and tight junction-tetraspanin web specific networks, we identified host proteins required for the early steps in HCV infection. Moreover, we validated the roles of newly identified proteins in HCV infection by knocking down their expression using small interfering RNAs. Specifically, a novel host factor CD63 was shown to directly interact with HCV E2 protein. We further demonstrated that an antibody against CD63 blocked HCV infection, indicating that CD63 may serve as a new therapeutic target for HCV-related diseases. The candidate gene list provides a source for identification of new therapeutic targets.
PMCID: PMC3625227  PMID: 23593195
17.  A Case of Acute Suppurative Thyroiditis with Thyrotoxicosis in an Elderly Patient 
Endocrinology and Metabolism  2013;28(1):50-54.
Acute suppurative thyroiditis (AST) is a rare condition, as the thyroid gland is relatively resistant to infection. Thyroid function tests are usually normal in AST. A few cases of AST associated with thyrotoxicosis have been reported in adults. We report a case of AST that was associated with thyrotoxicosis in a 70-year-old woman. We diagnosed AST with thyroid ultrasonography and fine needle aspiration of pus. The patient improved after surgical intervention and had no anatomical abnormality. Fine needle aspiration is the best method for the difficult task of differentiating malignancy and subacute thyroiditis from AST with thyrotoxicosis. Earlier diagnosis and proper treatment for AST might improve the outcome.
PMCID: PMC3811791  PMID: 24396651
Thyroiditis, suppurative; Biopsy, fine-needle; Thyrotoxicosis
18.  eIF4GI Facilitates the MicroRNA-Mediated Gene Silencing 
PLoS ONE  2013;8(2):e55725.
MicroRNAs (miRNAs) are small noncoding RNAs that mediate post-transcriptional gene silencing by binding to complementary target mRNAs and recruiting the miRNA-containing ribonucleoprotein complexes to the mRNAs. However, the molecular basis of this silencing is unclear. Here, we show that human Ago2 associates with the cap-binding protein complex and this association is mediated by human eIF4GI, a scaffold protein required for the translation initiation. Using a cap photo-crosslinking method, we show that Ago2 closely associates with the cap structure. Taken together, these data suggest that eIF4GI participates in the miRNA-mediated post-transcriptional gene silencing by promoting the association of Ago2 with the cap-binding complex.
PMCID: PMC3567085  PMID: 23409027
19.  Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53 
Autophagy  2011;7(11):1348-1358.
Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here we show that DHA increased both the level of microtubule-associated protein 1 light chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA-induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA-induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53.
PMCID: PMC3242799  PMID: 21811093
DHA; autophagy; apoptosis; p53; cancer; mTOR; AMPK; p27
20.  A Case of Acute Myocarditis as the Initial Presentation of Crohn's Disease 
Gut and Liver  2012;6(4):512-515.
We experienced a case of acute myocarditis as the initial presentation of Crohn's disease. A 19-year-old woman was admitted with impaired consciousness, shock, and respiratory failure. She had suffered from frequent diarrhea and abdominal pain for several years. Cardiac troponin I and creatine kinase-MB fraction levels were elevated to 5.32 and 16.66 ng/mL, respectively. A 12-lead electrocardiogram showed sinus tachycardia, and a chest radiograph revealed interstitial pulmonary edema. An echocardiogram showed dilated ventricles with akinesia of the basal to apical inferoseptal, anteroseptal, anterior, and inferior left ventricular walls and severely impaired systolic function. Intensive care with inotropic support was effective, and her clinical condition gradually improved. Two weeks later, a colonoscopy revealed ulceration with stenosis in the terminal ileum and multiple aphthous ulcers in the rectum. A biopsy of the rectum revealed non-caseating granulomatous inflammation. She was diagnosed with Crohn's disease presenting with acute myocarditis.
PMCID: PMC3493735  PMID: 23170159
Crohn disease; Myocarditis
21.  Korean Red Ginseng Saponin Fraction Downregulates Proinflammatory Mediators in LPS Stimulated RAW264.7 Cells and Protects Mice against Endotoxic Shock 
Journal of Ginseng Research  2012;36(3):263-269.
Korean red ginseng has shown therapeutic effects for a number of disease conditions. However, little is known about the antiinflammatory effect of Korean red ginseng saponin fraction (RGSF) in vitro and in vivo. Therefore, in this study, we showed that RGSF containing 20(S)-protopanaxadiol type saponins inhibited nitric oxide production and attenuated the release of tumor necrotic factor (TNF)-α, interleukin (IL)-6, granulocyte monocyte colony stimulating factor (GMCSF), and macrophage chemo-attractant protein-1 in lipopolysaccharide (LPS) stimulated murine macrophage RAW264.7 cells. Moreover, RGSF down-regulated the mRNA expressions of inducible nitric oxide synthase, cyclooxyginase-2, IL-1β, TNF-α, GMCSF, and IL-6. Furthermore, RGSF reduced the level of TNF-α in the serum and protected mice against LPS mediated endotoxic shock. In conclusion, these results indicated that ginsenosides from RGSF and their metabolites could be potential sources of therapeutic agents against inflammation.
PMCID: PMC3659593  PMID: 23717127
Panax ginseng; 20(S)-protopanaxadiol saponins; Pro-inflammatory cytokines; Endotoxic shock; Macrophages
22.  DJ-1 Null Dopaminergic Neuronal Cells Exhibit Defects in Mitochondrial Function and Structure: Involvement of Mitochondrial Complex I Assembly 
PLoS ONE  2012;7(3):e32629.
DJ-1 is a Parkinson's disease-associated gene whose protein product has a protective role in cellular homeostasis by removing cytosolic reactive oxygen species and maintaining mitochondrial function. However, it is not clear how DJ-1 regulates mitochondrial function and why mitochondrial dysfunction is induced by DJ-1 deficiency. In a previous study we showed that DJ-1 null dopaminergic neuronal cells exhibit defective mitochondrial respiratory chain complex I activity. In the present article we investigated the role of DJ-1 in complex I formation by using blue native-polyacrylamide gel electrophoresis and 2-dimensional gel analysis to assess native complex status. On the basis of these experiments, we concluded that DJ-1 null cells have a defect in the assembly of complex I. Concomitant with abnormal complex I formation, DJ-1 null cells show defective supercomplex formation. It is known that aberrant formation of the supercomplex impairs the flow of electrons through the channels between respiratory chain complexes, resulting in mitochondrial dysfunction. We took two approaches to study these mitochondrial defects. The first approach assessed the structural defect by using both confocal microscopy with MitoTracker staining and electron microscopy. The second approach assessed the functional defect by measuring ATP production, O2 consumption, and mitochondrial membrane potential. Finally, we showed that the assembly defect as well as the structural and functional abnormalities in DJ-1 null cells could be reversed by adenovirus-mediated overexpression of DJ-1, demonstrating the specificity of DJ-1 on these mitochondrial properties. These mitochondrial defects induced by DJ-1mutation may be a pathological mechanism for the degeneration of dopaminergic neurons in Parkinson's disease.
PMCID: PMC3293835  PMID: 22403686
23.  Hepatitis C Virus Infection Is Blocked by HMGB1 Released from Virus-Infected Cells ▿ 
Journal of Virology  2011;85(18):9359-9368.
High-mobility group box 1 (HMGB1), an abundant nuclear protein that triggers host immune responses, is an endogenous danger signal involved in the pathogenesis of various infectious agents. However, its role in hepatitis C virus (HCV) infection is not known. Here, we show that HMGB1 protein is translocated from the nucleus to cytoplasm and subsequently is released into the extracellular milieu by HCV infection. Secreted HMGB1 triggers antiviral responses and blocks HCV infection, a mechanism that may limit HCV propagation in HCV patients. Secreted HMGB1 also may have a role in liver cirrhosis, which is a common comorbidity in HCV patients. Further investigations into the roles of HMGB1 in the diseases caused by HCV infection will shed light on and potentially help prevent these serious and prevalent HCV-related diseases.
PMCID: PMC3165778  PMID: 21752923
24.  80-kVp CT Using Iterative Reconstruction in Image Space Algorithm for the Detection of Hypervascular Hepatocellular Carcinoma: Phantom and Initial Clinical Experience 
Korean Journal of Radiology  2012;13(2):152-164.
To investigate whether the low-tube-voltage (80-kVp), intermediate-tube-current (340-mAs) MDCT using the Iterative Reconstruction in Image Space (IRIS) algorithm improves lesion-to-liver contrast at reduced radiation dosage while maintaining acceptable image noise in the detection of hepatocellular carcinomas (HCC) in thin (mean body mass index, 24 ± 0.4 kg/m2) adults.
Subjects and Methods
A phantom simulating the liver with HCC was scanned at 50-400 mAs for 80, 100, 120 and 140-kVp. In addition, fifty patients with HCC who underwent multiphasic liver CT using dual-energy (80-kVp and 140-kVp) arterial scans were enrolled. Virtual 120-kVP scans (protocol A) and 80-kVp scans (protocol B) of the late arterial phase were reconstructed with filtered back-projection (FBP), while corresponding 80-kVp scans were reconstructed with IRIS (protocol C). Contrast-to-noise ratio (CNR) of HCCs and abdominal organs were assessed quantitatively, whereas lesion conspicuity, image noise, and overall image quality were assessed qualitatively.
IRIS effectively reduced image noise, and yielded 29% higher CNR than the FBP at equivalent tube voltage and current in the phantom study. In the quantitative patient study, protocol C helped improve CNR by 51% and 172% than protocols A and B (p < 0.001), respectively, at equivalent radiation dosage. In the qualitative study, protocol C acquired the highest score for lesion conspicuity albeit with an inferior score to protocol A for overall image quality (p < 0.001). Mean effective dose was 2.63-mSv with protocol A and 1.12-mSv with protocols B and C.
CT using the low-tube-voltage, intermediate-tube-current and IRIS help improve lesion-to-liver CNR of HCC in thin adults during the arterial phase at a lower radiation dose when compared with the standard technique using 120-kVp and FBP.
PMCID: PMC3303898  PMID: 22438682
Hepatocellular carcinoma; Low tube voltage; Iterative reconstruction; 80-kVp; Computed tomography; Image quality
25.  Translation-competent 48S complex formation on HCV IRES requires the RNA-binding protein NSAP1 
Nucleic Acids Research  2011;39(17):7791-7802.
Translation of many cellular and viral mRNAs is directed by internal ribosomal entry sites (IRESs). Several proteins that enhance IRES activity through interactions with IRES elements have been discovered. However, the molecular basis for the IRES-activating function of the IRES-binding proteins remains unknown. Here, we report that NS1-associated protein 1 (NSAP1), which augments several cellular and viral IRES activities, enhances hepatitis C viral (HCV) IRES function by facilitating the formation of translation-competent 48S ribosome–mRNA complex. NSAP1, which is associated with the solvent side of the 40S ribosomal subunit, enhances 80S complex formation through correct positioning of HCV mRNA on the 40S ribosomal subunit. NSAP1 seems to accomplish this positioning function by directly binding to both a specific site in the mRNA downstream of the initiation codon and a 40S ribosomal protein (or proteins).
PMCID: PMC3177222  PMID: 21715376

Results 1-25 (29)