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1.  CCN1 suppresses pulmonary vascular smooth muscle contraction in response to hypoxia 
Pulmonary Circulation  2015;5(4):716-722.
Pulmonary vasoconstriction and increased vascular resistance are common features in pulmonary hypertension (PH). One of the contributing factors in the development of pulmonary vasoconstriction is increased pulmonary artery smooth muscle cell (PASMC) contraction. Here we report that CCN1, an extracellular matrix molecule, suppressed PASMC contraction in response to hypoxia. CCN1 (Cyr61), discovered in past decade, belongs to the Cyr61-CTGF-Nov (CCN) family. It carries a variety of cellular functions, including angiogenesis and cell adhesion, death, and proliferation. Hypoxia robustly upregulated the expression of CCN1 in the pulmonary vessels and lung parenchyma. Given that CCN1 is a secreted protein and functions in a paracine manner, we examined the potential effects of CCN1 on the adjacent smooth muscle cells. Interestingly, bioactive recombinant CCN1 significantly suppressed hypoxia-induced contraction in human PASMCs in vitro. Consistently, in the in vivo functional studies, administration of bioactive CCN1 protein significantly decreased right ventricular pressure in three different PH animal models. Mechanistically, protein kinase A–pathway inhibitors abolished the effects of CCN1 in suppressing PASMC contraction. Furthermore, CCN1-inhibited smooth muscle contraction was independent of the known vasodilators, such as nitric oxide. Taken together, our studies indicated a novel cellular function of CCN1, potentially regulating the pathogenesis of PH.
doi:10.1086/683812
PMCID: PMC4671746  PMID: 26697179
CCN1; pulmonary hypertension; hypoxia; pulmonary artery smooth muscle cell
2.  miR-15a/16 Regulates Macrophage Phagocytosis After Bacterial Infection 
Bacterial infection and its associated sepsis are devastating clinical entities which lead to high mortality and morbidity in critically ill patients. Phagocytosis, along with other innate immune responses, exerts crucial impacts on the outcomes of these patients. MicroRNAs (miRNAs) are a novel class of regulatory noncoding RNAs targeting specific mRNAs for modulation of translation and expression of a targeted protein. The roles of miRNAs in host defense against bacterial sepsis remain unclear. We found that bacterial infections and/or bacterial-derived LPS enhanced the level of miR-15a/16 in bone marrow derived macrophages (BMDMs). Deletion of miR-15a/16 (miR-15a/16-/-) in myeloid cells significantly decreased the bacterial infection associated mortality in sepsis mouse models. Moreover, miR-15a/16 deficiency (miR-15a/16-/-) resulted in augmented phagocytosis and generation of mitochondrial reactive oxygen species (ROS) in BMDMs. Supportively, over-expression of miR-15a/16 using miRNA mimics led to decreased phagocytosis and decreased generation of mitochondrial ROS. Mechanistically, deletion of miR-15a/16 up-regulated the expression of toll-like receptor 4 (TLR4) via targeting the principle transcriptional regulator PU.1 locating on the promoter region of TLR4, and further modulated TLR4's downstream signaling molecules, including Rho GTPase Cdc 42 and TRAF6. Additionally, deficiency of miR-15a/16 also facilitated TLR4-mediated pro-inflammatory cytokine/chemokine release from BMDMs at the initial phase of infections. Taken together, miR-15a/16 altered phagocytosis and bacterial clearance by targeting, at least partially, on the TLR4-associated pathways, subsequently affecting the survival of septic mice.
doi:10.4049/jimmunol.1401372
PMCID: PMC4216178  PMID: 25261473
miR-15a/16; bacterial infection; macrophage; phagocytosis
3.  Deep Intracerebral Hemorrhage Caused by Rupture of Distal Lenticulostriate Artery Aneurysm : A Report of Two Cases and a Literature Review 
Intracerebral hemorrhage (ICH) is common among various types of storkes; however, it is rare in young patients and patients who do not have any risk factors. In such cases, ICH is generally caused by vascular malformations, tumors, vasculitis, or drug abuse. Basal ganglia ICH is rarely related with distal lenticulostriate artery (LSA) aneurysm. Since the 1960s, a total of 29 distal LSA aneurysm cases causing ICH have been reported in the English literature. Despite of the small number of cases, various treatment methods have been attempted : surgical clipping, endovascular treatment, conservative treatment, superficial temporal artery-middle cerebral artery anastomosis, and gamma-knife radiosurgery. Here, we report two additional cases and review the literature. Thereupon, we discerned that young patients with deep ICH are in need of conventional cerebral angiography. Moreover, initial conservative treatment with follow-up cerebral angiography might be a good treatment option except for cases with a large amount of hematoma that necessitates emergency evacuation. If the LSA aneurysm still persists or enlarges on follow-up angiography, it should be treated surgically or endovascularly.
doi:10.3340/jkns.2015.58.5.471
PMCID: PMC4688318  PMID: 26713149
Aneurysm ruptured; Basal ganglia hemorrhage; Lenticulostriate artery
4.  Effects of Prophylactic Antiepileptic Drugs on Clinical Outcomes in Patients with a Good Clinical Grade Suffering from Aneurysmal Subarachnoid Hemorrhage 
Objective
Routine use of prophylactic antiepileptic drugs (AED) has been debated. We retrospectively evaluated the effects of prophylactic AED on clinical outcomes in patients with a good clinical grade suffering from aneurysmal subarachnoid hemorrhage (aSAH).
Materials and Methods
Between September 2012 and December 2014, 84 patients who met the following criteria were included: (1) presence of a ruptured aneurysm; (2) Hunt-Hess grade 1, 2, or 3; and (3) without seizure presentation. Patients were divided into two groups; the AED group (n = 44) and the no AED group (n = 40). Clinical data and outcomes were compared between the two groups.
Results
Prophylactic AEDs were used more frequently in patients who underwent microsurgery (84.1%) compared to those who underwent endovascular surgery (15.9%, p < 0.001). Regardless of prophylactic AED use, seizure episodes were not observed during the six-month follow-up period. No statistical difference in clinical outcomes at discharge (p = 0.607) and after six months of follow-up (p = 0.178) were between the two groups. After six months, however, favorable outcomes in the no AED group tended to increase and poor outcomes tended to decrease.
Conclusion
No difference in the clinical outcomes and systemic complications at discharge and after six months of follow-up was observed between the two groups. However, favorable outcomes in the no AED group showed a slight increase after six months. These findings suggest that discontinuation of the current practice of using prophylactic AED might be recommended in patients with a good clinical grade.
doi:10.7461/jcen.2015.17.3.166
PMCID: PMC4626338  PMID: 26526008
Antiepileptic drug; Clinical outcome; Intracranial aneurysm; Seizure; Subarachnoid hemorrhage
5.  Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis 
Mucosal immunology  2014;8(2):243-253.
Summary
To defend against pulmonary infections, lung epithelial cells are equipped with complex innate immunity closely linked to inflammation. Dysregulated innate immunity / inflammation leads to self-perpetuating lung injury. The CpG motif in bacterial DNA is one of the factors involved in bacterial infection-associated inflammation. Bacterial DNA and synthetic CpG oligonucleotide (ODN) induced CCN1 secretion from lung epithelial cells, functioning as a potential “braking” signal to prevent uncontrolled inflammatory responses. CpG ODN-induced ER stress resulted in Src-Y527 phosphorylation (pY527) and Src/CCN1 vWF domain dissociation. Src-Y527 activated caveolin-1 (cav-1) phosphorylation at Y14 and then modulated CCN1 secretion via pCav-1 interaction with CCN1 IGFbp domain. Functionally, secreted CCN1 promoted anti-inflammatory cytokine IL-10 release from epithelial cells via integrin αVβ6 PKC, and this subsequently suppressed TNF-α, MIP-2 secretion and neutrophil infiltration in the lungs. Collectively, bacterial DNA/CpG ODN-stimulated CCN1 secretion via BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway and CpG-induced CCN1 conferred anti-inflammatory roles. Our studies suggested a novel paradigm by which the lung epithelium maintains innate immune homeostasis after bacterial infection.
doi:10.1038/mi.2014.62
PMCID: PMC4289128  PMID: 25005359
CCN1; CpG motif; Bacterial DNA; inflammation
6.  Enhancement of absorption and bioavailability of echinacoside by verapamil or clove oil 
Purpose
This present study investigated the absorption kinetics of echinacoside (ECH) in situ and in vitro and its oral bioavailability in rats. Additional aim was to find an agent(s) to promote ECH absorption and oral bioavailability among two efflux proteins and three absorption promoters.
Methods
ECH absorption behaviors were investigated by everted gut sac model in vitro and single-pass intestinal perfusion model in situ. Pharmacokinetics study was performed to investigate the influences of verapamil and clove oil on ECH bioavailability in vivo. All samples were measured at different time intervals by high performance liquid chromatography.
Results
The results showed that the effective permeability coefficient (Peff) and apparent permeability coefficient of ECH were 0.83×10−6–3.23×10−6 cm/s and 2.99×10−6–9.86×10−6 cm/s, respectively. The Peff among duodenum, jejunum, and ileum were not statistically different, but they were higher than colon (P<0.01), which demonstrated that intestinal ECH absorption was poor and site dependent. Additionally, verapamil and clove oil significantly increased the jejunal Peff of ECH both in situ and in vitro. Moreover, the bioavailability of ECH in combination with verapamil and clove oil were increased by 1.37-fold (P<0.05) and 2.36-fold (P<0.001), respectively, when compared to ECH group. Overall, verapamil and clove oil facilitated ECH absorption and oral bioavailability.
Conclusion
The absorption and bioavailability of ECH were enhanced by verapamil and clove oil, respectively, both in vitro and in vivo. Consequently, the combination of verapamil and clove oil with ECH will be a promising and effective approach to promote intestinal absorption and oral bioavailability of ECH.
doi:10.2147/DDDT.S87581
PMCID: PMC4544722  PMID: 26316707
intestinal absorption; efflux protein inhibitor; absorption promoter
7.  Clinical Risk Factors Affecting Procedure-Related Major Neurological Complications in Unruptured Intracranial Aneurysms 
Yonsei Medical Journal  2015;56(4):987-992.
Purpose
The operative risk and natural history rupture risk for the treatment of unruptured intracranial aneurysms (UIAs) should be evaluated. The purpose of this study was to report our experience with treating UIAs and to outline clinical risk factors associated with procedure-related major neurological complications.
Materials and Methods
We treated 1158 UIAs in 998 patients over the last 14 years. All patients underwent operation performed by a single microvascular surgeon and two interventionists at a single institution. Patient factors, aneurysm factors, and clinical outcomes were analyzed in relation to procedure-related complications.
Results
The total complication rate was 22 (2.2%) out of 998 patients. Among them, complications developed in 14 (2.3%) out of 612 patients who underwent microsurgery and in 8 (2.1%) out of 386 patients who underwent endovascular procedures. One patient died due to intraoperative rupture during an endovascular procedure. The procedure-related complication was highly correlated with age (p=0.004), hypertension (p=0.002), and history of ischemic stroke (p<0.001) in univariate analysis. The multivariate analysis revealed previous history of ischemic stroke (p=0.001) to be strongly correlated with procedure-related complications.
Conclusion
A history of ischemic stroke was strongly correlated with procedure-related major neurological complications when treating UIAs. Accordingly, patients with UIAs who have a previous history of ischemic stroke might be at risk of procedure-related major neurological complications.
doi:10.3349/ymj.2015.56.4.987
PMCID: PMC4479867  PMID: 26069121
Unruptured intracranial aneurysm; procedure; complication; ischemic stroke
8.  Resveratrol Upregulates Cardiac SDF-1 in Mice with Acute Myocardial Infarction through the Deacetylation of Cardiac p53 
PLoS ONE  2015;10(6):e0128978.
Aims
We previously demonstrated that resveratrol (RSV) administration causes cardiac stromal cell-derived factor (SDF)-1 upregulation and can enhance the mobilization of stem cells in mice with acute myocardial infarction (AMI). However, the upstream signal transduction involved in SDF-1 regulation in the setting of AMI and RSV administration remains unclear. Because RSV is a sirtuin 1 (SIRT1) activator and SIRT proteins act as deacetylases, we investigated the role of SIRT1 in SDF-1 upregulation and its subsequent effects.
Methods and Results
In vitro experiments with H9C2 cardiomyocytes under hypoxia and serum-deprivation conditions showed that p53 acted upstream of SDF-1. RSV could not regulate SDF-1 effectively after SIRT1 silencing, indicating that it is dependent on SIRT1. Subsequently, male C57BL/6 mice were divided into four groups: 1) sham, 2) MI, 3) MI+RSV, and 4) MI+RSV plus nicotinamide, an inhibitor of the deacetylase activity of SIRT (MI+RSV+NAM). Compared with the sham mice, AMI caused a slight increase in the cardiac p53 level and resulted in significant SIRT1 downregulation and p53 acetylation or activation. Compared with the MI mice, MI+RSV administration improved the cardiac SDF-1 level and reversed the reduction of SIRT1 and the activation of p53. Furthermore, we observed less cardiac dysfunction in MI+RSV mice and determined that NAM abolished the effects of RSV.
Conclusions
RSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway.
doi:10.1371/journal.pone.0128978
PMCID: PMC4459949  PMID: 26053177
9.  Klebsiella pneumoniae Co-Producing NDM-5 and OXA-181 Carbapenemases, South Korea 
Emerging Infectious Diseases  2015;21(6):1088-1089.
doi:10.3201/eid2106.150048
PMCID: PMC4451906  PMID: 25988911
Klebsiella pneumoniae; carbapenemase; Enterobacteriaceae; South Korea; antimicrobial resistance; bacteria; New Delhi metallo-β-lactamase; NDM-5; oxacillinase 181
10.  Divergent androgen regulation of unfolded protein response pathways drives prostate cancer 
EMBO Molecular Medicine  2015;7(6):788-801.
The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.
doi:10.15252/emmm.201404509
PMCID: PMC4459818  PMID: 25864123
androgen receptor; androgens; ER stress; prostate cancer; UPR
11.  Protein Drugs Related to Allergic Reaction 
BioMed Research International  2015;2015:614048.
doi:10.1155/2015/614048
PMCID: PMC4442276  PMID: 26078957
12.  Incidence and Risk Factors for Rebleeding during Cerebral Angiography for Ruptured Intracranial Aneurysms 
Yonsei Medical Journal  2015;56(2):403-409.
Purpose
The purpose was to evaluate the incidence and risk factors for rebleeding during cerebral angiography in ruptured intracranial aneurysms.
Materials and Methods
Among 1896 patients with ruptured intracranial aneurysms between September 2006 and December 2013, a total of 11 patients who experienced rebleeding of the ruptured aneurysms during digital subtraction angiography (DSA) were recruited in this study.
Results
There were 184 patients (9.7%) who had suffered rebleeding prior to the securing procedure. Among them, 11 patients experienced rebleeding during DSA and other 173 patients at a time other than DSA. Eight (72.7%) of the 11 patients experienced rebleeding during three-dimensional rotational angiography (3DRA). The incidence of rebleeding during DSA was 0.6% in patients with ruptured intracranial aneurysms. Multivariate logistic regression analysis showed that aneurysm location in anterior circulation [odds ratio=14.286; 95% confidence interval (CI), 1.877 to 250.0; p=0.048] and higher aspect ratio (odds ratio=3.040; 95% CI, 1.896 to 10.309; p=0.041) remained independent risk factors for rebleeding during DSA.
Conclusion
Ruptured aneurysms located in anterior circulation with a high aspect ratio might have the risk of rebleeding during DSA, especially during 3DRA.
doi:10.3349/ymj.2015.56.2.403
PMCID: PMC4329351  PMID: 25683988
Cerebral angiography; intracranial aneurysm; rebleeding; subarachnoid hemorrhage
13.  STAMP2 increases oxidative stress and is critical for prostate cancer 
EMBO Molecular Medicine  2015;7(3):315-331.
The six transmembrane protein of prostate 2 (STAMP2) is an androgen-regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage-independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target.
doi:10.15252/emmm.201404181
PMCID: PMC4364948  PMID: 25680860
activating transcription factor 4; iron reductase; prostate cancer; reactive oxygen species; six transmembrane protein of prostate 2
14.  Serum miR-122 correlates with short-term mortality in sepsis patients 
Critical Care  2014;18(6):704.
doi:10.1186/s13054-014-0704-9
PMCID: PMC4262971  PMID: 25672224
15.  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
16.  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
17.  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
18.  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
19.  Interleukin-22 exacerbates airway inflammation induced by short-term exposure to cigarette smoke in mice 
Acta Pharmacologica Sinica  2014;35(11):1393-1401.
Aim:
Interleukin-22 (IL-22) exhibits both proinflammatory and anti-inflammatory properties in various biological processes. In this study we explored the effects of exogenous recombinant IL-22 (rIL-22) on cigarette smoke (CS)-induced airway inflammation in mice.
Methods:
Male C57BL/6 mice were divided into groups: (1) CS group exposed to tobacco smoke for 3 consecutive days, (2) rIL-22 group received rIL-22 (100 mg/kg, ip), and (3) CS plus rIL-22 group, received rIL-22 (100 mg/kg, ip) before the CS exposure. The airway resistance (Rn), lung morphology, inflammatory cells in the airways, and inflammatory cytokines and CXCR3 ligands in both bronchoalveolar lavage (BAL) fluids and lung tissues were analyzed.
Results:
CS alone significantly elevated IL-22 level in the BAL fluid. Both CS and rIL-22 significantly augmented airway resistance, an influx of inflammatory cells into the airways and lung parenchyma, and significantly elevated levels of pro-inflammatory cytokines (TGFβ1 and IL-17A) and CXCR3 chemokines (particularly CXCL10) at the mRNA and/or protein levels. Furthermore, the effects of rIL-22 on airway resistance and inflammation were synergistic with those of CS, as demonstrated by a further increased Rn value, infiltration of greater numbers of inflammatory cells into the lung, higher levels of inflammatory cytokines and chemokines, and more severe pathological changes in CS plus rIL-22 group as compared to those in CS group.
Conclusion:
Exogenous rIL-22 exacerbates the airway inflammatory responses to CS exposure in part by inducing expression of several proinflammatory cytokines and CXCR3 ligands.
doi:10.1038/aps.2014.91
PMCID: PMC4220081  PMID: 25345745
cigarette smoke; lung; airway inflammation; cytokine; IL-22; IL-17A; TGFβ1; CXCR3 chemokine
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

Results 1-25 (75)