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2.  Suppression of PTRF Alleviates the Polymicrobial Sepsis Induced by Cecal Ligation and Puncture in Mice 
The Journal of Infectious Diseases  2013;208(11):1803-1812.
Background. Sepsis and sepsis-associated organ failure are devastating conditions. Understanding the detailed cellular/molecular mechanisms involved in sepsis should lead to the identification of novel therapeutic targets.
Methods. Cecal ligation and puncture (CLP) was used as a polymicrobial sepsis model in vivo to determine mortality and end-organ damage. Macrophages were adopted as the cellular model in vitro for mechanistic studies.
Results. PTRF+/− mice survived longer and suffered less organ damage after CLP. Reductions in nitric oxide (NO) and iNOS biosynthesis were observed in plasma, macrophages, and vital organs in the PTRF+/− mice. Using an acute sepsis model after CLP, we found that iNOS−/− mice had a comparable level of survival as the PTRF+/− mice. Similarly, polymerase I transcript release factor (PTRF) deficiency resulted in decreased iNOS and NO/ROS production in macrophages in vitro. Mechanistically, lipopolysaccharide (LPS) enhanced the co-localization and interaction between PTRF and TLR4 in lipid rafts. Deletion of PTRF blocked formation of the TLR4/Myd88 complex after LPS. Consistent with this, lack of PTRF impaired the TLR4 signaling, as shown by the decreased p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS transcription.
Conclusion. PTRF is a crucial regulator of TLR4 signaling in the development of sepsis.
doi:10.1093/infdis/jit364
PMCID: PMC3814834  PMID: 23908488
PTRF; sepsis; macrophage; CLP; nitric oxide; ROS; TLR4
3.  Lyn mitigates mouse airway remodeling by down-regulating the TGF-β3 isoform in house dust mite models 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(11):10.4049/jimmunol.1301596.
Chronic airway remodeling is a serious consequence of asthma, which is caused by complex but largely unknown mechanisms. Despite versatile functions, the role of Lyn in chronic airway remodeling remains undefined. Using Lyn−/− mice, we show that continual exposure (for 8 weeks) of house dust mite (HDM) extracts induced a severe phenotype of chronic airway remodeling including exacerbated mucus production, collagen deposition, dysregulated cytokine secretion, and elevated inflammation. Strikingly, a significant increase in TGF-β3 rather than TGF-β1 was observed in Lyn−/− mouse lungs compared to wild-type mice. Furthermore, TGF-β3 neutralizing antibodies not only inhibited the expression of STAT6 and Smad2/3, but also decreased phosphorylation of Smad2 and NFκB in Lyn−/− mouse lungs. In addition, both recombinant and adenoviral TGF-β3 significantly promoted epithelial to mesenchymal transition (EMT) and intensified collagen I production and MUC5AC expression. Further examining chronic asthma patients showed that a decreased Lyn correlated with the severity of airway inflammation and mucus hypersecretion. Finally, Lyn may critically regulate airway remodeling by directly interacting with TGF-β3. Collectively, these findings revealed that Lyn regulates TGF-β3 isoform and modulates the development of airway remodeling, which may have therapeutic indications for severe chronic asthma.
doi:10.4049/jimmunol.1301596
PMCID: PMC3863691  PMID: 24127553
knockout mice; Th2 cytokines; HDM extracts; oxidative stress; airway remodeling; EMT
4.  Prevalence of Isolates of Streptococcus pneumoniae Putative Serotype 6E in South Korea 
Journal of Clinical Microbiology  2014;52(6):2096-2099.
The prevalence of serogroup 6 among 1,206 Streptococcus pneumoniae clinical isolates collected from Korean hospitals over three periods (1996 to 2001, 2004 to 2006, and 2008 to 2009) was investigated. The number of serogroup 6 isolates increased from 9.7 to 17.5% over the three periods. While the proportion of serotype 6A and 6D isolates increased significantly, that of serotype 6B isolates decreased. Twenty-four isolates (2.0%) were typed as the recently identified putative serotype 6E or genetic variants of serotype 6B. The results suggest that the lack of change in frequency of serotype 6B, in spite of the introduction of the PCV7 vaccine as seen in previous studies in South Korea, might be due mainly to the improper inclusion of putative serotype 6E in serotype 6B. All but three serotype 6E isolates belonged to CC90, indicating their clonal expansion.
doi:10.1128/JCM.00228-14
PMCID: PMC4042748  PMID: 24719436
5.  Cigarette Smoking Promotes Inflammation in Patients with COPD by Affecting the Polarization and Survival of Th/Tregs through Up-Regulation of Muscarinic Receptor 3 and 5 Expression 
PLoS ONE  2014;9(11):e112350.
Background
CD4+ T cells in the lung are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), although CD4+ T cell subsets and the direct effect of smoking on these cells, especially the expression of MRs, have not been comprehensively examined.
Methods
First, circulating CD4+ T cell subsets in healthy nonsmokers, patients with SCOPD and patients with AECOPD were evaluated by flow cytometry. Then, differentiation experiments were carried out using RT-PCR, and Ki-67/Annexin V antibodies were used to measure proliferation and apoptosis. We also explored the impact of CSE on the differentiation and survival of CD4+Th/Tregs and examined the expression of MRs in healthy nonsmokers and patients with SCOPD.
Results
We found the percentages of circulating Th1 and Th17 cells were increased in patients with AECOPD, while the percentage of Th2 cells was decreased in patients with SCOPD. The percentages of Th10 cells were decreased in both patients with SCOPD and patients with AECOPD, while the percentages of Tregs were increased. In addition, the percentages of CD4+α-7+ T cells were decreased in patients with SCOPD and patients with AECOPD. However, only the decrease observed in patients with AECOPD was significant. In vitro studies also revealed MR expression affected the polarization of T cells, with different CD4+ T cell subtypes acquiring different MR expression profiles. The addition of CSE facilitated CD4+ T cell polarization towards pro-inflammatory subsets (Th1 and Th17) and affected the survival of CD4+ T cells and Treg cells by up-regulating the expression of MR3 and 5, resulting in an imbalance of CD4+ T cell subsets.
Conclusions
Our findings suggest an imbalance of circulating CD4+ T cell subsets is involved in COPD pathogenesis in smokers. Cigarette smoking may contribute to this imbalance by affecting the polarization and survival of Th/Tregs through the up-regulation of MR3 and MR5.
doi:10.1371/journal.pone.0112350
PMCID: PMC4223024  PMID: 25375131
6.  Treg/IL-17 Ratio and Treg Differentiation in Patients with COPD 
PLoS ONE  2014;9(10):e111044.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by chronic pulmonary and systematic inflammation. An abnormal adaptive immune response leads to an imbalance between pro- and anti-inflammatory processes. T-helper (Th), T-cytotoxic (Tc) and T-regulatory (Treg) cells may play important roles in immune and inflammatory responses. This study was conducted to clarify the changes and imbalance of cytokines and T lymphocyte subsets in patients with COPD, especially during acute exacerbations (AECOPD).
Methods
Twenty-three patients with stable COPD (SCOPD) and 21 patients with AECOPD were enrolled in the present study. In addition, 20 age-, sex- and weight-matched non-smoking healthy volunteers were included as controls. The serum levels of selected cytokines (TGF-β, IL-10, TNF-α, IL-17 and IL-9) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, the T lymphocyte subsets collected from peripheral blood samples were evaluated by flow cytometry after staining with anti-CD3-APC, anti-CD4-PerCP, anti-CD8- PerCP, anti-CD25-FITC and anti-FoxP3-PE monoclonal antibodies. Importantly, to remove the confounding effects of inflammatory factors, the authors introduced a concept of “inflammation adjustment” and corrected each measured value using representative inflammatory markers, such as TNF-α and IL-17.
Results
Unlike the other cytokines, serum TGF-β levels were considerably higher in patients with AECOPD relative to the control group regardless of adjustment. There were no significant differences in the percentages of either CD4+ or CD8+ T cells among the three groups. Although Tregs were relatively upregulated during acute exacerbations, their capacities of generation and differentiation were far from sufficient. Finally, the authors noted that the ratios of Treg/IL-17 were similar among groups.
Conclusions
These observations suggest that in patients with COPD, especially during acute exacerbations, both pro-inflammatory and anti-inflammatory reactions are strengthened, with the pro-inflammatory reactions dominating. Although the Treg/IL-17 ratios were normal, the regulatory T cells were still insufficient to suppress the accompanying increases in inflammation. All of these changes suggest a complicated mechanism of pro- and anti-inflammatory imbalance which needs to be further investigated.
doi:10.1371/journal.pone.0111044
PMCID: PMC4199736  PMID: 25329073
7.  Clinico-radiological Characteristics of Spontaneous Basal Ganglia Hemorrhage, According to Regional Classification 
Objective
The clinico-radiologic features of the spontaneous basal ganglia hemorrhage (BGH) may often differ one from another, according to its regional location. Therefore, we attempted to classify the BGH into regional subgroups, and to extrapolate the distinct characteristics of each group of BGH.
Materials and Methods
A total of 103 BGHs were analyzed by retrospective review of medical records. BGH was classified according to four subgroups; anterior BGH; posterior BGH; lateral BGH; massive BGH.
Results
The most common BGH was the posterior BGH (56, 54.4%), followed by the lateral BGH (26, 25.2%), the massive BGH (12, 11.7%), and the anterior BGH (9, 8.7%). The shape of hemorrhage tended to be round in anterior, irregular in posterior, and ovoid in lateral BGH. A layered density of hematoma on initial computed tomography showed correlation with hematoma expansion (p = 0.016), which was observed more often in the postero-lateral group of BGH than in the anterior BGH group. Relatively better recovery from the initial insult was observed in the lateral BGH group than in the other regional BGH groups. The proportion of poor outcome (modified Rankin scale 4, 5, 6) was 100% in the massive, 41.1% in the posterior, 34.6% in the lateral, and 0% in the anterior BGH group.
Conclusion
We observed that BGH can be grouped according to its regional location and each group may have distinct characteristics. Thus, a more sophisticated clinical strategy tailored to each group of BGHs can be implemented.
doi:10.7461/jcen.2014.16.3.216
PMCID: PMC4205247  PMID: 25340023
Basal Ganglia; Hemorrhage; Outcome; Classification
8.  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
9.  Extensively Drug-Resistant Streptococcus pneumoniae, South Korea, 2011–2012 
Emerging Infectious Diseases  2014;20(5):869-871.
To better understand extensively drug resistant Streptococcus pneumoniae, we assessed clinical and microbiological characteristics of 5 extensively drug-resistant pneumococcal isolates. We concluded that long-term care facility residents who had undergone tracheostomy might be reservoirs of these pneumococci; 13- and 23-valent pneumococcal vaccines should be considered for high-risk persons; and antimicrobial drugs should be used judiciously.
doi:10.3201/eid2005.131371
PMCID: PMC4012805  PMID: 24750694
Streptococcus pneumoniae; extensively drug-resistant; bacteria; South Korea; antimicrobial drug resistance
10.  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
11.  Capsular Gene Sequences and Genotypes of “Serotype 6E” Streptococcus pneumoniae Isolates 
Journal of Clinical Microbiology  2013;51(10):3395-3399.
To characterize Streptococcus pneumoniae “serotype 6E,” complete cps loci were sequenced. The capsular genes of “serotype 6E” isolates differed much from those of serotypes 6A and 6B. We identified 10 additional “serotype 6E” isolates, which are not confined to a restricted geographic locality. Most of these “serotype 6E” isolates belonged to sequence type 90 and its single-locus variants. The homogeneity of their genetic background and cps loci suggests a recent origin of the “serotype 6E” isolates.
doi:10.1128/JCM.01645-13
PMCID: PMC3811659  PMID: 23824778
12.  Beneficial effects of natural Jeju groundwaters on lipid metabolism in high-fat diet-induced hyperlipidemic rats 
Nutrition Research and Practice  2014;8(2):165-171.
BACKGROUND
Groundwater is believed to possess many beneficial effects due to its natural source of various minerals. In this study, we examined the effects of natural Jeju groundwater S1 (Samdasoo™), S2 and S3 pumped up from different locations of Jeju Island, Korea, along with local tap water, on body weight gain, serum lipids and lipoproteins, and liver histopathology in high-fat diet-induced hyperlipidemic rats.
MATERIALS/METHODS
Rats were randomly and equally divided into 6 groups. Different water samples were supplied to the hyperlipidemic rats as their daily drinking water and the widely-used anti-hyperlipidemic drug simvastatin was used as a positive control. Body weight, serum lipids and lipoproteins were measured weekly. Liver weight, liver index and liver histopathology were examined after the execution of the rats.
RESULTS
After drinking Jeju groundwaters for two months, S2 but not S3 significantly reduced weight growth and serum triglycerides levels and increased high density lipoprotein-C (HDL-C) without affecting total cholesterol or LDL-C. S1 and particularly S2 significantly reduced the severity of liver hypertrophy and steatosis. All Groundwaters had much higher contents of vanadium (S3>S2>S1>>tap water) whereas S1 and S2 but not S3 markedly blocked autoxidation of ferrous ions.
CONCLUSION
Jeju Groundwater S1 and particularly S2 exhibit protective effects against hyperlipidemia and fatty liver and hypothesize that the beneficial effect of Jeju Groundwaters may be contributed from blockade of autoxidation of ferrous ions rather than their high contents of vanadium.
doi:10.4162/nrp.2014.8.2.165
PMCID: PMC3988505  PMID: 24741400
Jeju groundwaters; fatty liver; hyperlipidemia; vanadium; ferrous ion autoxidation
13.  Long-Term Clinical and Angiographic Outcomes of Wrap-Clipping Strategies for Unclippable Cerebral Aneurysms 
Yonsei Medical Journal  2014;55(2):401-409.
Purpose
To evaluate the efficacy and stability of the wrap-clipping methods as a reconstructive strategy in the treatment of unclippable cerebral aneurysms.
Materials and Methods
Twenty four patients who had undergone wrap-clipping microsurgery were retrospectively reviewed. Type and morphology of the treated aneurysm, utilized technique for wrap-clip procedure, and clinical outcome with angiographic results at their last follow-up were evaluated.
Results
Of 24 patients, eleven patients had internal carotid artery (ICA) blister-like aneurysms, three had dissecting type aneurysms, and ten had fusiform aneurysms. The follow-up period for the late clinical and angiographic results ranged from 10 to 75 months (mean 35 months). Wrap-clipping was performed in eleven, wrap-holding clipping was in ten, and combination of wrap-clip and wrap-holding clip was in three cases. At the last angiographic follow-up study, twelve aneurysms (50%) were found to have completely healed, and nine aneurysms (38%) were at least stable. However, wrap-holding clip for the elongated blister type of ICA aneurysm was found failed, leading to fatal rebleeding in one case, and two cases of combination of wrap-clip-wrap-holding clip revealed delayed branch occlusion and marked regrowing, respectively.
Conclusion
Wrap-clipping strategy could be an easy and safe alternative for unclippable aneurysms. The wrapped aneurysm mostly disappeared, or at least remained stationary, after a long-term period. However, surgeons should be aware of that the wrapped aneurysm might become worse. Therefore, follow-up surveillance for an extended period should be mandatory.
doi:10.3349/ymj.2014.55.2.401
PMCID: PMC3936646  PMID: 24532510
Cerebral aneurysms; unclippable; wrap-clipping; follow-up
14.  One-stage surgical management for tuberculosis of the upper cervical spine by posterior debridement, short-segment fusion, and posterior instrumentation in children 
European Spine Journal  2012;22(1):72-78.
Purpose
To evaluate the clinical study efficacy and feasibility of 11 children with tuberculosis of the upper cervical spine treated by one-stage posterior debridement, short-segment fusion, and posterior instrumentation.
Methods
Eleven children who suffered from tuberculosis of the upper cervical spine were admitted to our hospital between June 2005 and December 2010. All of them were treated by one-stage posterior debridement, short-segment fusion, and posterior instrumentation. Then, the clinical efficacy was evaluated using statistical analysis based on the materials about the visual analogue scale (VAS) scores of pain, JOA scores of nerve function and erythrocyte sedimentation rate (ESR), which were collected at certain time.
Results
The average follow-up period was 28.1 ± 10.5 months (13–42 months). In the 11 cases, no postoperative complications related to instrumentation occurred and neurologic function was improved in various degrees. The average pretreatment ESR was 58.4 ± 4.9 mm/h (53–69 mm/h), which got normal (8.9 ± 6.5 mm/h) within 3 months in all patients. The average preoperative VAS was 7.4 ± 2.2, which decreased to 1.6 ± 1.8 postoperatively. Mean preoperative JOA was 11.2 ± 3.8, and the JOA at the last visit was 16.3 ± 1.0. All patients got bony fusion within 3–8 months after surgery.
Conclusions
One-stage posterior debridement, short-segment fusion, and posterior instrumentation can be an effective treatment method for the treatment of tuberculosis of the upper cervical spine in children.
doi:10.1007/s00586-012-2544-0
PMCID: PMC3540302  PMID: 23085858
Tuberculosis; Upper cervical spine; Children; Posterior instrumentation; Short-segment fusion
15.  Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells*  
Orthotopic liver transplantation (OLT) is the only proven effective treatment for both end-stage and metabolic liver diseases. Hepatocyte transplantation is a promising alternative for OLT, but the lack of available donor livers has hampered its clinical application. Hepatocyte-like cells (HLCs) differentiated from many multi-potential stem cells can help repair damaged liver tissue. Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures. Recently, a novel mesenchymal stem cell derived from human menstrual blood (MenSC) has been discovered and obtained easily and repeatedly. In this study, we examined whether the MenSCs are able to differentiate into functional HLCs in vitro. After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor (HGF), fibroblast growth factor-4 (FGF-4), and oncostain M (OSM), cuboidal HLCs were observed, and cells also expressed hepatocyte-specific marker genes including albumin (ALB), α-fetoprotein (AFP), cytokeratin 18/19 (CK18/19), and cytochrome P450 1A1/3A4 (CYP1A1/3A4). Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis, glycogen storage, and indocyanine green (ICG) uptake. After intrasplenic transplantation into mice with 2/3 partial hepatectomy, the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein. We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals. In conclusion, MenSCs may serve as an ideal, easily accessible source of material for tissue engineering and cell therapy of liver tissues.
doi:10.1631/jzus.B1300081
PMCID: PMC3829645  PMID: 24190442
Menstrual blood-derived mesenchymal stem cell (MenSC); Differentiation; Hepatocyte; Intrasplenic transplantation; Partial hepatectomy
16.  Traditional Chinese Medicine Tang-Luo-Ning Ameliorates Sciatic Nerve Injuries in Streptozotocin-Induced Diabetic Rats 
Diabetic peripheral neuropathy (DPN) is a common microvascular complication of diabetes associated with high disability rate and low quality of life. Tang-Luo-Ning (TLN) is an effective traditional Chinese medicine for the treatment of DPN. To illustrate the underlying neural protection mechanisms of TLN, the effect of TLN on electrophysiology and sciatic nerve morphology was investigated in a model of streptozotocin-induced DPN, as well as the underlying mechanism. Sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced in DPN and were significantly improved by TLN or α-lipoic acid at 10 and 20 weeks after streptozotocin injection. It was demonstrated that TLN intervention for 20 weeks significantly alleviated pathological injury as well as increased the phosphorylation of ErbB2, Erk, Bad (Ser112), and the mRNA expression of neuregulin 1 (Nrg1), GRB2-associated binding protein 1 (Gab1), and mammalian target of rapamycin (Mtor) in injured sciatic nerve. These novel therapeutic properties of TLN to promote Schwann cell survival may offer a promising alternative medicine for the patients to delay the progression of DPN. The underlying mechanism may be that TLN exerts neural protection effect after sciatic nerve injury through Nrg1/ErbB2→Erk/Bad Schwann cell survival signaling pathway.
doi:10.1155/2013/989670
PMCID: PMC3830865  PMID: 24288572
17.  Flotillin-2 Modulates Fas Signaling Mediated Apoptosis after Hyperoxia in Lung Epithelial Cells 
PLoS ONE  2013;8(10):e77519.
Lipid rafts are subdomains of the cell membrane with distinct protein composition and high concentrations of cholesterol and glycosphingolipids. Raft proteins are thought to mediate diverse cellular processes including signal transduction. However, its cellular mechanisms remain unclear. Caveolin-1 (cav-1, marker protein of caveolae) has been thought as a switchboard between extracellular matrix (ECM) stimuli and intracellular signals. Flotillin-2/reggie-1(Flot-2) is another ubiquitously expressed raft protein which defines non-caveolar raft microdomains (planar raft). Its cellular function is largely uncharacterized. Our novel studies demonstrated that Flot-2, in conjunction with cav-1, played important functions on controlling cell death via regulating Fas pathways. Using Beas2B epithelial cells, we found that in contrast to cav-1, Flot-2 conferred cytoprotection via preventing Fas mediated death-inducing signaling complex (DISC) formation, subsequently suppressed caspase-8 mediated extrinsic apoptosis. Moreover, Flot-2 reduced the mitochondria mediated intrinsic apoptosis by regulating the Bcl-2 family and suppressing cytochrome C release from mitochondria to cytosol. Flot-2 further modulated the common apoptosis pathway and inhibited caspase-3 activation via up-regulating the members in the inhibitor of apoptosis (IAP) family. Last, Flot-2 interacted with cav-1 and limited its expression. Taken together, we found that Flot-2 protected cells from Fas induced apoptosis and counterbalanced the pro-apoptotic effects of cav-1. Thus, Flot-2 played crucial functions in cellular homeostasis and cell survival, suggesting a differential role of individual raft proteins.
doi:10.1371/journal.pone.0077519
PMCID: PMC3799625  PMID: 24204853
18.  Global expression profiling reveals genetic programs underlying the developmental divergence between mouse and human embryogenesis 
BMC Genomics  2013;14:568.
Background
Mouse has served as an excellent model for studying human development and diseases due to its similarity to human. Advances in transgenic and knockout studies in mouse have dramatically strengthened the use of this model and significantly improved our understanding of gene function during development in the past few decades. More recently, global gene expression analyses have revealed novel features in early embryogenesis up to gastrulation stages and have indeed provided molecular evidence supporting the conservation in early development in human and mouse. On the other hand, little information is known about the gene regulatory networks governing the subsequent organogenesis. Importantly, mouse and human development diverges during organogenesis. For instance, the mouse embryo is born around the end of organogenesis while in human the subsequent fetal period of ongoing growth and maturation of most organs spans more than 2/3 of human embryogenesis. While two recent studies reported the gene expression profiles during human organogenesis, no global gene expression analysis had been done for mouse organogenesis.
Results
Here we report a detailed analysis of the global gene expression profiles from egg to the end of organogenesis in mouse. Our studies have revealed distinct temporal regulation patterns for genes belonging to different functional (Gene Ontology or GO) categories that support their roles during organogenesis. More importantly, comparative analyses identify both conserved and divergent gene regulation programs in mouse and human organogenesis, with the latter likely responsible for the developmental divergence between the two species, and further suggest a novel developmental strategy during vertebrate evolution.
Conclusions
We have reported here the first genome-wide gene expression analysis of the entire mouse embryogenesis and compared the transcriptome atlas during mouse and human embryogenesis. Given our earlier observation that genes function in a given process tends to be developmentally co-regulated during organogenesis, our microarray data here should help to identify genes associated with mouse development and/or infer the developmental functions of unknown genes. In addition, our study might be useful for invesgtigating the molecular basis of vertebrate evolution.
doi:10.1186/1471-2164-14-568
PMCID: PMC3924405  PMID: 23961710
Microarray; Mouse embryogenesis; Human embryogenesis; Organogenesis; Evolution; Protein interaction network
19.  CCN1 Secretion Induced by Cigarette Smoking Extracts Augments IL-8 Release from Bronchial Epithelial Cells 
PLoS ONE  2013;8(7):e68199.
Inflammation involves in many cigarette smoke (CS) related diseases including the chronic obstructive pulmonary disease (COPD). Lung epithelial cell released IL-8 plays a crucial role in CS induced lung inflammation. CS and cigarette smoke extracts (CSE) both induce IL-8 secretion and subsequently, IL-8 recruits inflammatory cells into the lung parenchyma. However, the molecular and cellular mechanisms by which CSE triggers IL-8 release remain not completely understood. In this study, we identified a novel extracellular matrix (ECM) molecule, CCN1, which mediated CSE induced IL-8 secretion by lung epithelial cells. We first found that CS and CSE up-regulated CCN1 expression and secretion in lung epithelial cells in vivo and in vitro. CSE up-regulated CCN1 via induction of reactive oxygen spices (ROS) and endoplasmic reticulum (ER) stress. p38 MAPK and JNK activation were also found to mediate the signal pathways in CSE induced CCN1. CCN1 was secreted into ECM via Golgi and membrane channel receptor aquaporin4. After CSE exposure, elevated ECM CCN1 functioned via an autocrine or paracrine manner. Importantly, CCN1 activated Wnt pathway receptor LRP6, subsequently stimulated Wnt pathway component Dvl2 and triggered beta-catenin translocation from cell membrane to cytosol and nucleus. Treatment of Wnt pathway inhibitor suppressed CCN1 induced IL-8 secretion from lung epithelial cells. Taken together, CSE increased CCN1 expression and secretion in lung epithelial cells via induction of ROS and ER stress. Increased ECM CCN1 resulted in augmented IL-8 release through the activation of Wnt pathway.
doi:10.1371/journal.pone.0068199
PMCID: PMC3706594  PMID: 23874538
20.  First Imported Case of Skin Infection Caused by PVL-positive ST30 Community-Associated Methicillin-Resistant Staphylococcus aureus Clone in a Returning Korean Traveler from the Philippines 
Journal of Korean Medical Science  2013;28(7):1100-1102.
Although pandemic community-associated (CA-) methicillin-resistant Staphylococcus aureus (MRSA) ST30 clone has successfully spread into many Asian countries, there has been no case in Korea. We report the first imported case of infection caused by this clone in a Korean traveler returning from the Philippines. A previously healthy 30-yr-old Korean woman developed a buttock carbuncle while traveling in the Philippines. After coming back to Korea, oral cephalosporin was given by a primary physician without any improvement. Abscess was drained and MRSA strain isolated from her carbuncle was molecularly characterized and it was confirmed as ST30-MRSA-IV. She was successfully treated with vancomycin and surgery. Frequent international travel and migration have increased the risk of international spread of CA-MRSA clones. The efforts to understand the changing epidemiology of CA-MRSA should be continued, and we should raise suspicion of CA-MRSA infection in travelers with skin infections returning from CA-MRSA-endemic countries.
doi:10.3346/jkms.2013.28.7.1100
PMCID: PMC3708085  PMID: 23853497
Staphylococcus aureus; Methicillin Resistance; Community-Acquired Infections; Carbuncle; Travel
21.  In Intact Islets Interstitial GABA Activates GABAA Receptors That Generate Tonic Currents in α-Cells 
PLoS ONE  2013;8(6):e67228.
In the rat islets γ-aminobutyric acid (GABA) is produced by the β-cells and, at least, the α-cells express the GABAA receptors (GABAA channels). In this study, we examined in intact islets if the interstitial GABA activated the GABAA receptors. We used the patch-clamp technique to record whole-cell and single-channel currents and single-cell RT-PCR to identify the cell-type we recorded from, in the intact rat islets. We further identified which GABAA receptor subunits were expressed. We determined the cell-type of 43 cells we recorded from and of these 49%, 28% and 7% were α, β and δ-cells, respectively. In the remaining 16% of the cells, mRNA transcripts of more than one hormone gene were detected. The results show that in rat islets interstitial GABA activates tonic current in the α-cells but not in the β-cells. Seventeen different GABAA receptor subunits are expressed with high expression of α1, α2, α4, α6, β3, γ1, δ, ρ1, ρ2 and ρ3 subunits whereas no expression was detected for α5 or ε subunits. The abundance of the GABAA receptor subunits detected suggests that a number of GABAA receptor subtypes are formed in the islets. The single-channel and tonic currents were enhanced by pentobarbital and inhibited by the GABAA receptor antagonist SR-95531. The single-channel conductance ranged from 24 to 105 pS. Whether the single-channel conductance is related to subtypes of the GABAA receptor or variable interstitial GABA concentrations remains to be determined. Our results reveal that GABA is an extracellular signaling molecule in rat pancreatic islets and reaches concentration levels that activate GABAA receptors on the glucagon-releasing α-cells.
doi:10.1371/journal.pone.0067228
PMCID: PMC3691163  PMID: 23826240
22.  Bacteremic Pneumonia Caused by Extensively Drug-Resistant Streptococcus pneumoniae 
Journal of Clinical Microbiology  2012;50(12):4175-4177.
The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region.
doi:10.1128/JCM.01642-12
PMCID: PMC3502956  PMID: 23052301
23.  Hyperoxia-Induced LC3B Interacts with the Fas Apoptotic Pathway in Epithelial Cell Death 
Epithelial cell death plays a critical role in hyperoxia-induced lung injury. We investigated the involvement of the autophagic marker microtubule-associated protein-1 light chain-3B (LC3B) in epithelial cell apoptosis after hyperoxia. Prolonged hyperoxia (>95% O2), which causes characteristic lung injury in mice, activated morphological and biochemical markers of autophagy. Hyperoxia induced the time-dependent expression and conversion of LC3B-I to LC3B-II in mouse lung in vivo and in cultured epithelial cells (Beas-2B, human bronchial epithelial cells) in vitro. Hyperoxia increased autophagosome formation in Beas-2B cells, as evidenced by electron microscopy and increased GFP-LC3 puncta. The augmented LC3B level after hyperoxia was transcriptionally regulated and dependent in part on the c-Jun N-terminal kinase pathway. We hypothesized that LC3B plays a regulatory role in hyperoxia-induced epithelial apoptosis. LC3B siRNA promoted hyperoxia-induced cell death in epithelial cells, whereas overexpression of LC3B conferred cytoprotection after hyperoxia. The autophagic protein LC3B cross-regulated the Fas apoptotic pathway by physically interacting with the components of death-inducing signaling complex. This interaction was mediated by caveolin-1 tyrosine 14, which is a known target of phosphorylation induced by hyperoxia. Taken together, hyperoxia-induced LC3B activation regulates the Fas apoptotic pathway and thus confers cytoprotection in lung epithelial cells. The interaction of LC3B and Fas pathways requires cav-1.
doi:10.1165/rcmb.2009-0415OC
PMCID: PMC3359946  PMID: 22095627
apoptosis; autophagy; hyperoxia; lung injury; caveolin-1
24.  Autophagic proteins 
Autophagy  2012;8(3):426-428.
Oxygen (O2), while essential for aerobic life, can also cause metabolic toxicity through the excess generation of reactive oxygen species (ROS). Pathological changes in ROS production can originate through the partial reduction of O2 during mitochondrial electron transport, as well as from enzymatic sources. This phenomenon, termed the oxygen paradox, has been implicated in aging and disease, and is especially evident in critical care medicine. Whereas high O2 concentrations are utilized as a life-sustaining therapeutic for respiratory insufficiency, they in turn can cause acute lung injury. Alveolar epithelial cells represent a primary target of hyperoxia-induced lung injury. Recent studies have indicated that epithelial cells exposed to high O2 concentrations die by apoptosis, or necrosis, and can also exhibit mixed-phenotypes of cell death (aponecrosis). Autophagy, a cellular homeostatic process responsible for the lysosomal turnover of organelles and proteins, has been implicated as a general response to oxidative stress in cells and tissues. This evolutionarily conserved process is finely regulated by a complex interplay of protein factors. During autophagy, senescent organelles and cellular proteins are sequestered in autophagic vacuoles (autophagosomes) and subsequently targeted to the lysosome, where they are degraded by lysosomal hydrolases, and the breakdown products released for reutilization in anabolic pathways. Autophagy has been implicated as a cell survival mechanism during nutrient-deficiency states, and more generally, as a determinant of cell fate. However, the mechanisms by which autophagy and/or autophagic proteins potentially interact with and/or regulate cell death pathways during high oxygen stress, remain only partially understood.
doi:10.4161/auto.19258
PMCID: PMC3337844  PMID: 22302001
acute lung injury; Apoptosis; autophagy; caveolin-1; Fas; hyperoxia; LC3B
25.  A third case of USA300 community-associated methicillin-resistant Staphylococcus aureus infection in Korea 
doi:10.3904/kjim.2013.28.2.258
PMCID: PMC3604620  PMID: 23524494
Staphylococcus aureus; Methicillin resistance; Community-acquired infections; Genotype

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