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author:("Lee, In-seen")
1.  Carbon Monoxide Confers Protection in Sepsis by Enhancing Beclin 1-Dependent Autophagy and Phagocytosis 
Antioxidants & Redox Signaling  2014;20(3):432-442.
Abstract
Aims: Sepsis, a systemic inflammatory response to infection, represents the leading cause of death in critically ill patients. However, the pathogenesis of sepsis remains incompletely understood. Carbon monoxide (CO), when administered at low physiologic doses, can modulate cell proliferation, apoptosis, and inflammation in pre-clinical tissue injury models, though its mechanism of action in sepsis remains unclear. Results: CO (250 ppm) inhalation increased the survival of C57BL/6J mice injured by cecal ligation and puncture (CLP) through the induction of autophagy, the down-regulation of pro-inflammatory cytokines, and by decreasing the levels of bacteria in blood and vital organs, such as the lung and liver. Mice deficient in the autophagic protein, Beclin 1 (Becn1+/−) were more susceptible to CLP-induced sepsis, and unresponsive to CO therapy, relative to their corresponding wild-type (Becn1+/+) littermate mice. In contrast, mice deficient in autophagic protein microtubule-associated protein-1 light chain 3B (LC3B) (Map1lc3b−/−) and their corresponding wild-type (Map1lc3b+/+) mice showed no differences in survival or response to CO, during CLP-induced sepsis. CO enhanced bacterial phagocytosis in Becn1+/+ but not Becn1+/− mice in vivo and in corresponding cultured macrophages. CO also enhanced Beclin 1-dependent induction of macrophage protein signaling lymphocyte-activation molecule, a regulator of phagocytosis. Innovation: Our findings demonstrate a novel protective effect of CO in sepsis, dependent on autophagy protein Beclin 1, in a murine model of CLP-induced polymicrobial sepsis. Conclusion: CO increases the survival of mice injured by CLP through systemic enhancement of autophagy and phagocytosis. Taken together, we suggest that CO gas may represent a novel therapy for patients with sepsis. Antioxid. Redox Signal. 20, 432–442.
doi:10.1089/ars.2013.5368
PMCID: PMC3894711  PMID: 23971531
2.  Data Mining of Acupoint Characteristics from the Classical Medical Text: DongUiBoGam of Korean Medicine 
Throughout the history of East Asian medicine, different kinds of acupuncture treatment experiences have been accumulated in classical medical texts. Reexamining knowledge from classical medical texts is expected to provide meaningful information that could be utilized in current medical practices. In this study, we used data mining methods to analyze the association between acupoints and patterns of disorder with the classical medical book DongUiBoGam of Korean medicine. Using the term frequency-inverse document frequency (tf-idf) method, we quantified the significance of acupoints to its targeting patterns and, conversely, the significance of patterns to acupoints. Through these processes, we extracted characteristics of each acupoint based on its treating patterns. We also drew practical information for selecting acupoints on certain patterns according to their association. Data analysis on DongUiBoGam's acupuncture treatment gave us an insight into the main idea of DongUiBoGam. We strongly believe that our approach can provide a novel understanding of unknown characteristics of acupoint and pattern identification from the classical medical text using data mining methods.
doi:10.1155/2014/329563
PMCID: PMC4276123  PMID: 25574179
3.  Isolation and Characterization of the Colletotrichum acutatum ABC Transporter CaABC1 
The Plant Pathology Journal  2014;30(4):375-383.
Fungi tolerate exposure to various abiotic stresses, including cytotoxic compounds and fungicides, via their ATP-driven efflux pumps belonging to ATP-binding cassette (ABC) transporters. To clarify the molecular basis of interaction between the fungus and various abiotic stresses including fungicides, we constructed a cDNA library from germinated conidia of Colletotrichum acutatum, a major anthracnose pathogen of pepper (Capsicum annum L.). Over 1,000 cDNA clones were sequenced, of which single clone exhibited significant nucleotide sequence homology to ABC transporter genes. We isolated three fosmid clones containing the C. acutatum ABC1 (CaABC1) gene in full-length from genomic DNA library screening. The CaABC1 gene consists of 4,059 bp transcript, predicting a 1,353-aa protein. The gene contains the typical ABC signature and Walker A and B motifs. The 5′-flanking region contains a CAAT motif, a TATA box, and a Kozak region. Phylogenetic and structural analysis suggested that the CaABC1 is a typical ABC transporter gene highly conserved in various fungal species, as well as in Chromista, Metazoans, and Viridiplantae. We also found that CaABC1 was up-regulated during conidiation and a minimal medium condition. Moreover, CaABC1 was induced in iprobenfos, kresoxim-methyl, thiophanate-methyl, and hygromycin B. These results demonstrate that CaABC1 is necessary for conidiation, abiotic stress, and various fungicide resistances. These results will provide the basis for further study on the function of ABC transporter genes in C. acutatum.
doi:10.5423/PPJ.OA.08.2014.0077
PMCID: PMC4262290  PMID: 25506302
ABC transporter gene; abiotic stress; Colletotrichum acutatum; expression profiling; fungicide resistance
4.  2014 Clinical Practice Guidelines for Overweight and Obesity in Korea 
Endocrinology and Metabolism  2014;29(4):405-409.
The dramatic increase in the prevalence of obesity and its accompanying comorbidities are major health concerns in Korea. Obesity is defined as a body mass index ≥25 kg/m2 in Korea. Current estimates are that 32.8% of adults are obese: 36.1% of men and 29.7% of women. The prevalence of being overweight and obese in national surveys is increasing steadily. Early detection and the proper management of obesity are urgently needed. Weight loss of 5% to 10% is the standard goal. In obese patients, control of cardiovascular risk factors deserves the same emphasis as weight-loss therapy. Since obesity is multifactorial, proper care of obesity requires a coordinated multidisciplinary treatment team, as a single intervention is unlikely to modify the incidence or natural history of obesity.
doi:10.3803/EnM.2014.29.4.405
PMCID: PMC4285036  PMID: 25559568
Clinical practice guidelines; Obesity; Korea
5.  Protective Effects of Black Rice Extracts on Oxidative Stress Induced by tert-Butyl Hydroperoxide in HepG2 Cells 
Black rice contains many biologically active compounds. The aim of this study was to investigate the protective effects of black rice extracts (whole grain extract, WGE and rice bran extract, RBE) on tert-butyl hydroperoxide (TBHP)-induced oxidative injury in HepG2 cells. Cellular reactive oxygen species (ROS), antioxidant enzyme activities, malondialdehyde (MDA) and glutathione (GSH) concentrations were evaluated as biomarkers of cellular oxidative status. Cells pretreated with 50 and 100 μg/mL of WGE or RBE were more resistant to oxidative stress in a dose-dependent manner. The highest WGE and BRE concentrations enhanced GSH concentrations and modulated antioxidant enzyme activities (glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase) compared to TBHP-treated cells. Cells treated with RBE showed higher protective effect compared to cells treated with WGE against oxidative insult. Black rice extracts attenuated oxidative insult by inhibiting cellular ROS and MDA increase and by modulating antioxidant enzyme activities in HepG2 cells.
doi:10.3746/pnf.2014.19.4.348
PMCID: PMC4287329  PMID: 25580401
black rice; oxidative stress; antioxidant enzyme; glutathione; HepG2 cell
6.  Induction of the Viable but Nonculturable State of Ralstonia solanacearum by Low Temperature in the Soil Microcosm and Its Resuscitation by Catalase 
PLoS ONE  2014;9(10):e109792.
Ralstonia solanacearum is the causal agent of bacterial wilt on a wide variety of plants, and enters a viable but nonculturable (VBNC) state under stress conditions in soil and water. Here, we adopted an artificial soil microcosm (ASM) to investigate the VBNC state of R. solanacearum induced by low temperature. The culturability of R. solanacearum strains SL341 and GMI1000 rapidly decreased at 4°C in modified ASM (mASM), while it was stably maintained at 25°C in mASM. We hypothesized that bacterial cells at 4°C in mASM are viable but nonculturable. Total protein profiles of SL341 cells at 4°C in mASM did not differ from those of SL341 culturable cells at 25°C in mASM. Moreover, the VBNC cells maintained in the mASM retained respiration activity. Catalase treatment effectively restored the culturability of nonculturable cells in mASM, while temperature increase or other treatments used for resuscitation of other bacteria were not effective. The resuscitated R. solanacearum from VBNC state displayed normal level of bacterial virulence on tomato plants compared with its original culturable bacteria. Expression of omp, oxyR, rpoS, dps, and the 16S rRNA gene quantified by RT-qPCR did not differ significantly between the culturable and VBNC states of R. solanacearum. Our results suggested that the VBNC bacterial cells in mASM induced by low temperature exist in a physiologically unique state.
doi:10.1371/journal.pone.0109792
PMCID: PMC4190316  PMID: 25296177
7.  A practical method for the detection of freezing of gait in patients with Parkinson’s disease 
Purpose
Freezing of gait (FOG), increasing the fall risk and limiting the quality of life, is common at the advanced stage of Parkinson’s disease, typically in old ages. A simple and unobtrusive FOG detection system with a small calculation load would make a fast presentation of on-demand cueing possible. The purpose of this study was to find a practical FOG detection system.
Patients and methods
A sole-mounted sensor system was developed for an unobtrusive measurement of acceleration during gait. Twenty patients with Parkinson’s disease participated in this study. A simple and fast time-domain method for the FOG detection was suggested and compared with the conventional frequency-domain method. The parameters used in the FOG detection were optimized for each patient.
Results
The calculation load was 1,154 times less in the time-domain method than the conventional method, and the FOG detection performance was comparable between the two domains (P=0.79) and depended on the window length (P<0.01) and dimension of sensor information (P=0.03).
Conclusion
A minimally constraining sole-mounted sensor system was developed, and the suggested time-domain method showed comparable FOG detection performance to that of the conventional frequency-domain method. Three-dimensional sensor information and 3–4-second window length were desirable. The suggested system is expected to have more practical clinical applications.
doi:10.2147/CIA.S69773
PMCID: PMC4199977  PMID: 25336936
Parkinson’s disease; freezing of gait; acceleration; detection system; time-domain; frequency-domain
8.  Decreased Peripheral and Central Responses to Acupuncture Stimulation following Modification of Body Ownership 
PLoS ONE  2014;9(10):e109489.
Acupuncture stimulation increases local blood flow around the site of stimulation and induces signal changes in brain regions related to the body matrix. The rubber hand illusion (RHI) is an experimental paradigm that manipulates important aspects of bodily self-awareness. The present study aimed to investigate how modifications of body ownership using the RHI affect local blood flow and cerebral responses during acupuncture needle stimulation. During the RHI, acupuncture needle stimulation was applied to the real left hand while measuring blood microcirculation with a LASER Doppler imager (Experiment 1, N = 28) and concurrent brain signal changes using functional magnetic resonance imaging (fMRI; Experiment 2, N = 17). When the body ownership of participants was altered by the RHI, acupuncture stimulation resulted in a significantly lower increase in local blood flow (Experiment 1), and significantly less brain activation was detected in the right insula (Experiment 2). This study found changes in both local blood flow and brain responses during acupuncture needle stimulation following modification of body ownership. These findings suggest that physiological responses during acupuncture stimulation can be influenced by the modification of body ownership.
doi:10.1371/journal.pone.0109489
PMCID: PMC4186833  PMID: 25285620
9.  Total Knee Arthroplasty Using a Posterior Cruciate Ligament Sacrificing Medial Pivot Knee: Minimum 5-year Follow-up Results 
Knee Surgery & Related Research  2014;26(3):135-140.
Purpose
To evaluate minimum 5-year follow-up clinical and radiological results of total knee arthroplasty (TKA) using a posterior cruciate ligament sacrificing (PS), non-substituting Advance Medial Pivot Knee.
Materials and Methods
One hundred and twenty knees in 80 patients who could be followed up for more than 5 years after TKA using the PS Advance Medial Pivot Knee were evaluated retrospectively. The evaluations included the preoperative and postoperative range of motion (ROM), tibiofemoral angle, Knee Society (KS) knee and function scores, and Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. The Kaplan-Meier method was used for survival analysis.
Results
The ROM increased from a preoperative mean flexion contracture of 7.6° and further flexion of 115.1° to a postoperative mean flexion contracture of 1.5° and further flexion of 120.5°. The tibiofemoral angle was changed from 4.6° varus preoperatively to 5.8° valgus postoperatively. The KS knee and function scores as well as WOMAC score significantly improved after surgery (p<0.05). Complications developed in 4 cases (3.3%): 2 cases of periprosthetic patellar fracture (1.7%) and 2 cases of aseptic loosening (1.7%). The seven-year survival rate was 98.1% in the Kaplan-Meier survival analysis.
Conclusions
The minimum 5-year follow-up results of TKA using the PS Medial Pivot Knee were satisfactory.
doi:10.5792/ksrr.2014.26.3.135
PMCID: PMC4163570  PMID: 25229042
Knee; Arthroplasty; Medial Pivot
10.  Prasugrel-Induced Hypersensitivity Skin Reaction 
Korean Circulation Journal  2014;44(5):355-357.
We report a case of hypersensitivity skin reaction to prasugrel. The patient exhibited a generalized skin rash after treatment with prasugrel, which was resolved after discontinuation of prasugrel and substitution to clopidogrel. Clopidogrel was successfully administered as an alternative to prasugrel without any signs of further hypersensitivity.
doi:10.4070/kcj.2014.44.5.355
PMCID: PMC4180615  PMID: 25278991
Prasugrel; Clopidogrel; Thienopyridine; Hypersensitivity; Exanthema
11.  Histologic Findings and Inflammatory Reactions After Long-term Colonization of Helicobacter felis in C57BL/6 Mice 
Journal of Cancer Prevention  2014;19(3):224-230.
Background:
The Helicobacter felis (H. felis) mouse model has been developed for the research regarding pathogenesis of chronic gastritis and gastric cancer. The aim of this study was to investigate long-term H. felis colonization in the stomachs of C57BL/6 mice and subsequent histologic findings and inflammatory reactions including pro-inflammatory cytokines.
Methods:
Twenty-three female C57BL/6 mice at 4 weeks of age were gavaged with H. felis, and 13 control mice served as vehicle only. The mice were sacrificed at 4, 24, and 52 weeks after inoculation. The infection status and degree of inflammation were determined by culture and histopathology. The level of gastric mucosal myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-α), and interleukin-1beta (IL-1β) were measured by ELISA.
Results:
The overall infection rate was 100%, as determined by the culture and histology. At 4, 24, and 52 weeks, the neutrophil and monocyte scores were significantly higher in infected mice than in control mice. At 24 weeks after inoculation, most of the infected mice showed mucosal atrophy with or without metaplasia, and a few showed focal dysplasia. Adenocarcinoma was observed in one mouse at 52 week post-infection. Gastric mucosal MPO and IL-1β levels were significantly higher in infected mice than those in control mice at 24 and 52 weeks. However, the expression of gastric mucosal TNF-α was not significantly different between the infected and control mice at any time-point.
Conclusions:
Long-term H. felis-infection in C57BL/6 mice provoked a severe inflammatory reaction and it progressed into atrophy, metaplasia, dysplasia and cancer. IL-1β might play an important role in the inflammatory response of mice to Helicobacter species.
doi:10.15430/JCP.2014.19.3.224
PMCID: PMC4189513  PMID: 25337592
Helicobacter felis; Inflammation; Interleukin-1beta; Tumor necrosis factor-alpha
12.  Metformin Attenuates Experimental Autoimmune Arthritis through Reciprocal Regulation of Th17/Treg Balance and Osteoclastogenesis 
Mediators of Inflammation  2014;2014:973986.
Metformin is widely used to suppress certain functions of the cells found in diseases including diabetes and obesity. In this study, the effects of metformin on downregulating IL-17-producing T (Th17) cells, activating and upregulating regulatory T (Treg) cells, suppressing osteoclastogenesis, and clinically scoring collagen-induced arthritis (CIA) were investigated. To evaluate the effect of metformin on CIA, mice were orally fed with either metformin or saline as control three times a week for nine weeks. Histological analysis of the joints was performed using immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. Metformin mitigated the severity of CIA, reduced serum immunoglobulin concentrations, and reciprocally regulated Th17/Treg axis. Also, metformin treatment of normal cells cultured in Th17 conditions decreased the number of Th17 cells and increased the number of Treg cells. Metformin decreased gene expression and osteoclastogenic activity in CIA and normal mice. These results indicate that metformin had immunomodulatory actions influencing anti-inflammatory action on CIA through the inhibition of Th17 cell differentiation and the upregulation of Treg cell differentiation along with the suppression of osteoclast differentiation. Our results suggest that metformin may be a potential therapeutic for rheumatoid arthritis.
doi:10.1155/2014/973986
PMCID: PMC4158168  PMID: 25214721
13.  Caveolin-1 mediates Fas–BID signaling in hyperoxia-induced apoptosis 
Free radical biology & medicine  2011;50(10):1252-1262.
Fas-mediated apoptosis is a crucial cellular event. Fas, the Fas-associated death domain, and caspase 8 form the death-inducing signaling complex (DISC). Activated caspase 8 mediates the extrinsic pathways and cleaves cytosolic BID. Truncated BID (tBID) translocates to the mitochondria, facilitates the release of cytochrome c, and activates the intrinsic pathways. However, the mechanism causing these DISC components to aggregate and form the complex remains unclear. We found that Cav-1 regulated Fas signaling and mediated the communication between extrinsic and intrinsic pathways. Shortly after hyperoxia (4 h), the colocalization and interaction of Cav-1 and Fas increased, followed by Fas multimer and DISC formation. Deletion of Cav-1 (Cav-1−/−) disrupted DISC formation. Further, Cav-1 interacted with BID. Mutation of Cav-1 Y14 tyrosine to phenylalanine (Y14F) disrupted the hyperoxia-induced interaction between BID and Cav-1 and subsequently yielded a decreased level of tBID and resistance to hyperoxia-induced apoptosis. The reactive oxygen species (ROS) scavenger N-acetylcysteine decreased the Cav-1–Fas interaction. Deletion of glutathione peroxidase-2 using siRNA aggravated the BID–Cav-1 interaction and tBID formation. Taken together, these results indicate that Cav-1 regulates hyperoxia/ROS-induced apoptosis through interactions with Fas and BID, probably via Fas palmitoylation and Cav-1 Y14 phosphorylation, respectively.
doi:10.1016/j.freeradbiomed.2011.02.031
PMCID: PMC4134776  PMID: 21382479
Hyperoxia; Fas; Caveolin-1; Apoptosis; Free radicals
14.  Targeted chiral lipidomics analysis of bioactive eicosanoid lipids in cellular systems 
BMB reports  2009;42(7):401-410.
We have developed a targeted lipidomics approach that makes it possible to directly analyze chiral eicosanoid lipids generated in cellular systems. The eicosanoids, including prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and alcohols (HETEs), have been implicated as potent lipid mediators of various biological processes. Enzymatic formations of eicosanoids are regioselective and enantioselective, whereas reactive oxygen species (ROS)-mediated formation proceeds with no stereo-selectivity. To distinguish between enzymatic and non-enzymatic pathways of eicosanoid formation, it is necessary to resolve enantiomeric forms as well as regioisomers. High sensitivity is also required to analyze the eicosanoid lipids that are usually present as trace amounts (pM level) in biological fluids. A discovery of liquid chromatography-electron capture atmospheric pressure chemical ionization/mass spectrometry (LC- ECAPCI/MS) allows us to couple normal phase chiral chromatography without loss of sensitivity. Analytical specificity was obtained by the use of collision-induced dissociation (CID) and tandem MS (MS/MS). With combination of stable isotope dilution methodology, complex mixtures of regioisomeric and enantiomeric eicosanoids have been resolved and quantified in biological samples with high sensitivity and specificity. Targeted chiral lipidomics profiles of bioactive eicosanoid lipids obtained from various cell systems and their biological implications have been discussed.
PMCID: PMC4063125  PMID: 19643036
Bioactive lipids; Cellular systems; Cyclooxygenase; Eicosanoids; LC-ECAPCI/MS; Lipoxygenase; Targeted chiral lipidomics
15.  Pharmacopuncture for Cancer Care: A Systematic Review 
Background. Pharmacopuncture, injection to acupoints with pharmacological medication or herbal medicine, is a new acupuncture therapy widely available in Korea and China for cancer-related symptoms. However, the evidence is yet to be clear. Objective. To determine pharmacopuncture's effectiveness on cancer-related symptoms. Methods. Eleven databases were searched for randomized controlled trials of pharmacopuncture in cancer patients. The Cochrane risk of bias (ROB) assessment tool was used for quality assessment. Results. Twenty-two studies involving 2,459 patients were included. Five trials of chemotherapy-induced nausea and vomiting (CINV) underwent meta-analysis. Pharmacopuncture significantly relieved severity of CINV compared with control group (3 trials, risk ratio (RR) 1.28, 95% confidence interval (CI) = 1.14–1.44). The frequency of CINV was also significantly reduced with pharmacopuncture (2 trials, RR 2.47, 95% CI = 2.12–2.89). Seventeen trials studied various symptoms, and in most studies, pharmacopuncture significantly relieved pain, ileus, hiccup, fever, and gastrointestinal symptoms and improved quality of life in various cancer patients. ROB was generally high. Conclusion. It may be suggested with caution that pharmacopuncture may help various symptom relief in cancer patients, but it is hard to draw a firm conclusion due to clinical heterogeneity and high ROB of the included studies, hence warranting further investigation.
doi:10.1155/2014/804746
PMCID: PMC4036607  PMID: 24899911
16.  Echinochrome A Protects Mitochondrial Function in Cardiomyocytes against Cardiotoxic Drugs 
Marine Drugs  2014;12(5):2922-2936.
Echinochrome A (Ech A) is a naphthoquinoid pigment from sea urchins that possesses antioxidant, antimicrobial, anti-inflammatory and chelating abilities. Although Ech A is the active substance in the ophthalmic and cardiac drug Histochrome®, its underlying cardioprotective mechanisms are not well understood. In this study, we investigated the protective role of Ech A against toxic agents that induce death of rat cardiac myoblast H9c2 cells and isolated rat cardiomyocytes. We found that the cardiotoxic agents tert-Butyl hydroperoxide (tBHP, organic reactive oxygen species (ROS) inducer), sodium nitroprusside (SNP; anti-hypertension drug), and doxorubicin (anti-cancer drug) caused mitochondrial dysfunction such as increased ROS level and decreased mitochondrial membrane potential. Co-treatment with Ech A, however, prevented this decrease in membrane potential and increase in ROS level. Co-treatment of Ech A also reduced the effects of these cardiotoxic agents on mitochondrial oxidative phosphorylation and adenosine triphosphate level. These findings indicate the therapeutic potential of Ech A for reducing cardiotoxic agent-induced damage.
doi:10.3390/md12052922
PMCID: PMC4052324  PMID: 24828295
echinochrome A; mitochondrial function; cardiotoxic drugs; SNP; tBHP; doxorubicin
17.  The EF-hand calcium-binding protein tescalcin is a potential oncotarget in colorectal cancer 
Oncotarget  2014;5(8):2149-2160.
Tescalcin (TESC) is an EF-hand calcium binding protein that is differentially expressed in several tissues, however it is not reported that the expression and functional roles of TESC in colorectal cancer. Levels of messenger RNA (mRNA) and protein expression of TESC in colorectal cancer tissues were assessed using RT-PCR, real time PCR, immunohistochemistry, and clinicopathologic analyses. Quantitative analysis of TESC levels in serum specimens was performed using sandwich ELISA. Colorectal cancer cells transfected with TESC small interfering RNA and short hairpin RNA were examined in cell proliferation assays, phospho-MAPK array, and mouse xenograft models. Here we demonstrated that TESC is overexpressed in colorectal cancer (CRC), but was not expressed in normal mucosa and premalignant dysplastic lesions. Furthermore, serum TESC levels were elevated in patients with CRC. Knockdown of TESC inhibited the Akt-dependent NF-κB pathway and decreased cell survival in vitro. Depletion of TESC reduced tumor growth in a CRC xenograft model. Thus, TESC is a potential diagnostic marker and oncotarget in colorectal cancer.
PMCID: PMC4039152  PMID: 24811141
Tescalcin; colorectal cancer; cell growth; tumor growth, NF-κB
18.  p62 Sequestosome 1/Light Chain 3b Complex Confers Cytoprotection on Lung Epithelial Cells after Hyperoxia 
Lung epithelial cell death is a prominent feature of hyperoxic lung injury, and has been considered a very important underlying mechanism of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Here we report on a novel mechanism involved in epithelial cytoprotection and homeostasis after oxidative stress. p62 (sequestosome 1; SQSTM1) is a ubiquitously expressed cellular protein. It interacts with ubiquitinated proteins and autophagic marker light chain 3b (LC3b), thus mediating the degradation of selective targets. In this study, we explored the role of p62 in mitochondria-mediated cell death after hyperoxia. Lung alveolar epithelial cells demonstrate abundant p62 expression, and p62 concentrations are up-regulated by oxidative stress at both the protein and mRNA levels. The p62/LC3b complex interacts with Fas and truncated BID (tBID) physically. These interactions abruptly diminish after hyperoxia. The deletion of p62 robustly increases tBID and cleaved caspase-3, implying an antiapoptotic effect. This antiapoptotic effect of p62 is further confirmed by measuring caspase activities, cleaved poly ADP ribose polymerase, and cell viability. The deletion of the p62 PBI domain or the ubiquitin-associated domain both lead to elevated tBID, cleaved caspase-3, and significantly more cell death after hyperoxia. Moreover, p62 traffics in an opposite direction with LC3b after hyperoxia, leading to the dissociation of the p62/Cav-1/LC3b/BID complex. Subsequently, the LC3b-mediated lysosomal degradation of tBID is eliminated. Taken together, our data suggest that the p62/LC3b complex regulates lung alveolar epithelial cell homeostasis and cytoprotection after hyperoxia.
doi:10.1165/rcmb.2012-0017OC
PMCID: PMC3653608  PMID: 23333919
p62/SQSTM1; hyperoxia; tBid; LC3b; apoptosis
19.  Abnormal Neural Processing during Emotional Salience Attribution of Affective Asymmetry in Patients with Schizophrenia 
PLoS ONE  2014;9(3):e90792.
Aberrant emotional salience attribution has been reported to be an important clinical feature in patients with schizophrenia. Real life stimuli that incorporate both positive and negative emotional traits lead to affective asymmetry such as negativity bias and positivity offset. In this study, we investigated the neural correlates of emotional salience attribution in patients with schizophrenia when affective asymmetry was processed. Fifteen patients with schizophrenia and 14 healthy controls were scanned using functional magnetic resonance imaging (fMRI) while performing an emotion judgment task in which two pictures were juxtaposed. The task consisted of responding to affective asymmetry condition (ambivalent and neutral) and affective symmetry conditions (positive and negative), and group comparisons were performed for each condition. Significantly higher activity in the medial prefrontal cortex and inferior frontal gyrus was observed for the ambivalent condition than for the other conditions in controls, but not in patients. Compared with controls, patients showed decreased activities in the dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, insula, and putamen for the ambivalent condition, but no changes were observed for the neutral condition. Multiple prefrontal hypoactivities during salience attribution of negativity bias in schizophrenia may underlie deficits in the integrative processing of emotional information. Regional abnormalities in the salience network may be the basis of defective emotional salience attribution in schizophrenia, which is likely involved in symptom formation and social dysfunction.
doi:10.1371/journal.pone.0090792
PMCID: PMC3949688  PMID: 24619004
20.  Favorable Vocal Fold Wound Healing Induced by Platelet-Rich Plasma Injection 
Objectives
To introduce a new injection material for vocal fold diseases, which could be readily translated to clinical practice, we investigated the effectiveness of platelet-rich plasma (PRP) injection on the injured vocal fold in terms of histological recovery.
Methods
Blood samples were drawn from New Zealand White rabbits and PRP was isolated through centrifugation and separation of the samples. Using a CO2 laser, we made a linear wound in the 24 vocal fold sides of 12 rabbits and injected each wound with PRP on one vocal fold side and normal saline (NS) on the other. Morphologic analyses were conducted at 2, 4, and 12 weeks after injection, and inflammatory response, collagen deposit, and changes in growth factors were assessed using H&E and masson trichrome (MT) staining and western blot assay.
Results
PRP was prepared in approximately 40 minutes. The mean platelet concentration was 1,315,000 platelets/mm3. In morphological analyses, decreased granulation was observed in the PRP-injected vocal folds (P<0.05). However, the irregular surface and atrophic change were not difference. Histological findings revealed significant inflammation and collagen deposition in NS-injected vocal folds, whereas the PRP-injected vocal folds exhibited less (P<0.05). However, the inflammatory reaction and fibrosis were not difference. In western blot assay, increased amounts of growth factors were observed in PRP-injected vocal folds.
Conclusion
Injection of injured rabbit vocal folds with PRP led to improved wound healing and fewer signs of scarring as demonstrated by decreased inflammation and collagen deposition. The increased vocal fold regeneration may be due to the growth factors associated with PRP.
doi:10.3342/ceo.2014.7.1.47
PMCID: PMC3932349  PMID: 24587881
Vocal fold; Scar; Wound healing; Growth factor; Platelet-rich plasma
21.  Antioxidant Effects of Spinach (Spinacia oleracea L.) Supplementation in Hyperlipidemic Rats 
Increased consumption of fresh vegetables that are high in polyphenols has been associated with a reduced risk of oxidative stress-induced disease. The present study aimed to evaluate the antioxidant effects of spinach in vitro and in vivo in hyperlipidemic rats. For measurement of in vitro antioxidant activity, spinach was subjected to hot water extraction (WE) or ethanol extraction (EE) and examined for total polyphenol content (TPC), oxygen radical absorbance capacity (ORAC), cellular antioxidant activity (CAA), and antigenotoxic activity. The in vivo antioxidant activity of spinach was assessed using blood and liver lipid profiles and antioxidant status in rats fed a high fat-cholesterol diet (HFCD) for 6 weeks. The TPC of WE and EE were shown as 1.5±0.0 and 0.5±0.0 mg GAE/g, respectively. Increasing the concentration of the extracts resulted in increased ORAC value, CAA, and antigenotoxic activity for all extracts tested. HFCD-fed rats displayed hyperlipidemia and increased oxidative stress, as indicated by a significant rise in blood and liver lipid profiles, an increase in plasma conjugated diene concentration, an increase in liver thiobarbituric acid reactive substances (TBARS) level, and a significant decrease in manganese superoxide dismutase (Mn-SOD) activity compared with rats fed normal diet. However, administration of 5% spinach showed a beneficial effect in HFCD rats, as indicated by decreased liver TBARS level and DNA damage in leukocyte and increased plasma conjugated dienes and Mn-SOD activity. Thus, the antioxidant activity of spinach may be an effective way to ameliorate high fat and cholesterol diet-induced oxidative stress.
doi:10.3746/pnf.2014.19.1.019
PMCID: PMC3999804  PMID: 24772405
spinach; comet assay; liver TBARS; tail DNA; hyperlipidemic rat
22.  EGCG Attenuates Autoimmune Arthritis by Inhibition of STAT3 and HIF-1α with Th17/Treg Control 
PLoS ONE  2014;9(2):e86062.
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705) and p-STAT3 (S727), mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3+ Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.
doi:10.1371/journal.pone.0086062
PMCID: PMC3928092  PMID: 24558360
23.  Collagen Triple Helix Repeat Containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells 
Oncotarget  2014;5(2):519-529.
Collagen triple helix repeat-containing 1 (CTHRC1) is known to be aberrantly upregulated in most human solid tumors, although the functional roles of CTHRC1 in colorectal cancer remain unclear. In this study, we investigated the occurrence of CTHRC1 upregulation and its role in vivo and in vitro. The expression profile and clinical importance of CTHRC1 were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses in normal and tumor patient samples. CTHRC1 was detectable in normal tissues, but also was highly expressed in tumor specimens. CTHRC1 upregulation was significantly associated with demethylation of the CTHRC1 promoter in colon cancer cell lines and tumor tissues. Clinicopathologic analyses showed that nodal status and expression of CTHRC1 (95% CI 0.999–3.984, p=0.05) were significant prognostic factors for disease-free survival. Promoter CpG methylation and hypermethylation status were measured by bisulfite sequencing and pyrosequencing analysis. Furthermore, we showed that overexpression of CTHRC1 in the SW480 and HT-29 cell lines increased invasiveness, an effect mediated by extracellular signal-regulated kinase (ERK)-dependent upregulation of matrix metalloproteinase 9 (MMP9). Consistent with this, we found that knockdown of CTHRC1 attenuated ERK activation and cancer cell invasivity. These results demonstrate that CTHRC1 expression is elevated in human colon cancer cell lines and clinical specimens, and promotes cancer cell invasivity through ERK-dependent induction of MMP9 expression. Our results further suggest that high levels of CTHRC1 expression are associated with poor clinical outcomes.
PMCID: PMC3964226  PMID: 24504172
CTHRC1; ERK; MMP9; Invasion; Colorectal cancer
24.  The Use of High Performance Liquid Chromatography to Speciate and Characterize the Epidemiology of Mycobacteria 
Laboratory medicine  2011;42(10):612-617.
Objective
We evaluated high-performance liquid chromatography (HPLC) for species identification of mycobacteria from various clinical specimens in an urban hospital in South Korea between January 2005 and December 2009.
Methods
In the study period 24,774 cultures were completed, yielding the 3215 clinical isolates cultivated for mycobacteria and positive cultures that had mycolic acid investigated by HPLC. For species identification, we compared HPLC patterns of clinical isolates with 33 standard Mycobacterium species.
Results
There were 3 different HPLC groups with single, double, and triple-cluster patterns representing 9, 20, and 4 mycobacterial species, respectively. Species identification rates of HPLC for Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM) were found to be 100% and 95.6%, respectively. Among mycobacterial isolates, 12.1% were NTM-positive. There were 20 different NTM species with frequencies of 0.3%~15.5%.
Conclusion
The HPLC method was highly sensitive identifying NTM isolated from clinical specimens.
doi:10.1309/LMDDEHPSYE6ZDM3C
PMCID: PMC3892985  PMID: 24443588
mycobacteria; Mycobacterium tuberculosis; nontuberculous mycobacteria; HPLC
25.  Extramedullary Plasmacytoma of the Pancreas Diagnosed Using Endoscopic Ultrasonography-Guided Fine Needle Aspiration 
Clinical Endoscopy  2014;47(1):115-118.
Extramedullary plasmacytoma involves organs outside the bone marrow; however, involvement of the pancreas is rare. We recently experienced a case of extramedullary plasmacytoma of the pancreas that was diagnosed by endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). EUS-FNA, which has a high diagnostic accuracy and an excellent safety profile, is the modality of choice for establishing tissue diagnosis. We report a case of extramedullary plasmacytoma of the pancreas diagnosed using EUS-FNA.
doi:10.5946/ce.2014.47.1.115
PMCID: PMC3928484  PMID: 24570894
Extramedullary plasmacytoma; Pancreas; Endosonography; Biopsy, fine-needle

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