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1.  Recurrent Tracheoinnominate Artery Fistula due to Stent Graft Fracture 
Tracheoinnominate artery fistula (TIF) is one of the most dangerous complications after tracheostomy, and fetal even after surgical repair. Recently, endovascular stent has been introduced as an option for the treatment of TIF. Unfortunately, endovascular stent repair could not replace the surgery due to rare clinical reports about the long-term follow-up and complications of stent graft. More collection of clinical data are necessary for the evaluation of long-term results. We report a rare case of recurrent TIF due to stent graft fracture after endovascular stent graft insertion in the treatment of TIF, and reviewed the world literature.
doi:10.1055/s-0034-1370775
PMCID: PMC4487119  PMID: 26171307
tracheoinnominate artery fistula (TIF); endovascular stent graft repair; stent graft fracture
2.  House Dust Mite Allergen Regulates Constitutive Apoptosis of Normal and Asthmatic Neutrophils via Toll-Like Receptor 4 
PLoS ONE  2015;10(5):e0125983.
House dust mites (HDMs) induce allergic diseases such as asthma. Neutrophil apoptosis is an important process of innate immunity, and its dysregulation is associated with asthma. In this study, we examined the effects of HDM on constitutive apoptosis of normal and asthmatic neutrophils. Extract of Dermatophagoides pteronissinus (DP) inhibited neutrophil apoptosis, but Dermatophagoides farinae extract had no effect. Anti-apoptotic signaling mediated by DP involves in TLR4, Lyn, PI3K, Akt, ERK, and NF-κB in normal neutrophils. DP delayed cleavage of procaspase 9 and procaspase 3 and the decrease in Mcl-1 expression. Supernatant collected from DP-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils, and S100A8 and S100A9 were identified as anti-apoptotic proteins in the supernatant. S100A8 and S100A9 transduced the anti-apoptotic signal via TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. DP also suppressed asthmatic neutrophil apoptosis and induced secretion of S100A8 and S100A9, which delayed the constitutive apoptosis. The anti-apoptotic effects of DP, S100A8 and S100A9 in asthmatic neutrophils are associated with TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. The concentrations of S100A8 and S100A9 were significantly elevated in asthmatic bronchoalveolar lavage fluid (BALF) when compared to normal BALF (p<0.01), but not in serum. S100A8 concentration in BALF was positively correlated with the number of BALF neutrophils and negatively correlated with FEV1(%). These findings improve our understanding of the role of HDM in regulation of neutrophil apoptosis in normal individuals and asthmatics and will enable elucidation of asthma pathogenesis.
doi:10.1371/journal.pone.0125983
PMCID: PMC4431853  PMID: 25973752
3.  Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes 
Autophagy  2013;9(12):2103-2114.
ULK1 (unc-51 like kinase 1) is a serine/threonine protein kinase that plays a key role in regulating the induction of autophagy. Recent studies using autophagy-defective mouse models, such as atg5- or atg7-deficient mice, revealed an important function of autophagy in adipocyte differentiation. Suppression of adipogenesis in autophagy-defective conditions has made it difficult to study the roles of autophagy in metabolism of differentiated adipocytes. In this study, we established autophagy defective-differentiated 3T3-L1 adipocytes, and investigated the roles of Ulk1 and its close homolog Ulk2 in lipid and glucose metabolism using the established adipocytes. Through knockdown approaches, we determined that Ulk1 and Ulk2 are important for basal and MTORC1 inhibition-induced autophagy, basal lipolysis, and mitochondrial respiration. However, unlike other autophagy genes (Atg5, Atg13, Rb1cc1/Fip200, and Becn1) Ulk1 was dispensable for adipogenesis without affecting the expression of CCAAT/enhancer binding protein α (CEBPA) and peroxisome proliferation-activated receptor gamma (PPARG). Ulk1 knockdown reduced fatty acid oxidation and enhanced fatty acid uptake, the metabolic changes that could contribute to adipogenesis, whereas Ulk2 knockdown had opposing effects. We also found that the expression levels of insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (SLC2A4/GLUT4) were increased in Ulk1-silenced adipocytes, which was accompanied by upregulation of insulin-stimulated glucose uptake. These results suggest that ULK1, albeit its important autophagic role, regulates lipid metabolism and glucose uptake in adipocytes distinctly from other autophagy proteins.
doi:10.4161/auto.26563
PMCID: PMC4028344  PMID: 24135897
ULK1; ULK2; mTORC1; adipogenesis; adipocytes; lipid metabolism
4.  Induced airway obstruction under extracorporeal membrane oxygenation during treatment of life-threatening massive hemoptysis due to severe blunt chest trauma 
Journal of Thoracic Disease  2014;6(12):E255-E258.
Simultaneous improvement in respiratory maintenance and bleeding control increases survival of patients with life-threatening hemoptysis. Endobronchial blockade is an effective method and is preferred for emergency hemostasis. However, when the volume of hemoptysis is high, emergency hemostasis and airway maintenance are impossible due to flooding of blood into the airway. We used extracorporeal membrane oxygenation (ECMO) to overcome these limitations in a patient with massive hemoptysis due to severe blunt trauma and succeeded in saving the life by inducing a near-total airway obstruction.
doi:10.3978/j.issn.2072-1439.2014.10.22
PMCID: PMC4283295  PMID: 25590003
Hemoptysis; extracorporeal membrane oxygenation (ECMO); hemostasis; trauma
5.  SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling 
Molecular Cell  2012;46(6):833-846.
SUMMARY
Amino acids stimulate cell growth and suppress autophagy through activation of mTORC1. The activation of mTORC1 by amino acids is mediated by Rag guanosine triphosphatase (GTPase) heterodimers on the lysosome. The molecular mechanism by which amino acids regulate the Rag GTPase heterodimers remains to be elucidated. Here, we identify SH3BP4 (SH3 domain-binding protein 4) as a binding protein and a negative regulator of Rag GTPase complex. SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain under conditions of amino acid starvation and inhibits the formation of active Rag GTPase complex. As a consequence, the binding abrogates the interaction of mTORC1 with Rag GTPase complex and the recruitment of mTORC1 to the lysosome, thus inhibiting amino acid-induced mTORC1 activation and cell growth and promoting autophagy. These results demonstrate that SH3BP4 is a negative regulator of the Rag GTPase complex and amino acid-dependent mTORC1 signaling.
doi:10.1016/j.molcel.2012.04.007
PMCID: PMC3389276  PMID: 22575674
6.  Castleman's Disease with Myasthenia Gravis 
Castleman's disease is a rare disorder characterized by benign tumors that may develop in the lymph node tissue throughout the body. Castleman's disease associated with myasthenia gravis is an especially rare disease. Only less than 10 cases have been reported in the world literature. The cause of Castleman's disease is associated with immune mediated reaction, and myasthenia gravis also develops due to an antibody-mediated process. The cause of myasthenia gravis is the immune activity of Castleman's disease, which may be the promoter of the antibody-mediated process. We report here a case of Castleman's disease, which was incidentally found in a patient diagnosed with myasthenia gravis.
doi:10.5090/kjtcs.2012.45.3.199
PMCID: PMC3373980  PMID: 22708092
Myasthenia gravis; Thymectomy; Retroperitoneal neoplasms
7.  Congenital Intercostal Lung Herniation Combined with an Unusual Morgagni's Hernia 
A 70-year-old male visited urgent care due to coughing for 1 month and left chest pain. He had no history of trauma. The initial chest computed tomography (CT) showed the 7th left intercostal lung herniation. A follow-up CT showed an intercostal lung herniation combined with a bowl herniation, which had developed due to a Morgagni's hernia. An emergency operation was performed due to the incarceration of the bowl and lung. The primary repair of the diaphragm was performed and the direct approximation of the 7th intercostal space was determined. We concluded that the defect of the diaphragm and the intercostal muscle was a congenital lesion, and the recurrent coughing was the aggravating factor of herniation.
doi:10.5090/kjtcs.2011.44.6.455
PMCID: PMC3270293  PMID: 22324036
Morgagni's hernia; Hernia, lung
8.  ULK1 inhibits the kinase activity of mTORC1 and cell proliferation 
Autophagy  2011;7(10):1212-1221.
ULK1 (Unc51-like kinase, hATG1) is a Ser/Thr kinase that plays a key role in inducing autophagy in response to starvation. ULK1 is phosphorylated and negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that ULK1 is not only a downstream effector of mTORC1 but also a negative regulator of mTORC1 signaling.1–3 Here, we investigated how ULK1 regulates mTORC1 signaling, and found that ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Deficiency or knockdown of ULK1 or its homolog ULK2 enhanced mTORC1 signaling, cell proliferation rates and accumulation of cell mass, whereas overexpression of ULK1 had the opposite effect. Knockdown of Atg13, the binding partner of ULK1 and ULK2, mimicked the effects of ULK1 or ULK2 deficiency or knockdown. Both insulin and leucine stimulated mTORC1 signaling to a greater extent when ULK1 or ULK2 was deficient or knocked down. In contrast, Atg5 deficiency did not have a significant effect on mTORC1 signaling and cell proliferation. The stimulatory effect of ULK1 knockdown on mTORC1 signaling occurred even in the absence of tuberous sclerosis complex 2 (TSC2), the negative regulator of mTORC1 signaling. In addition, ULK1 was found to bind raptor, induce its phosphorylation, and inhibit the kinase activity of mTORC1. These results demonstrate that ULK1 negatively regulates the kinase activity of mTORC1 and cell proliferation in a manner independent of Atg5 and TSC2. The inhibition of mTORC1 by ULK1 may be important to coordinately regulate cell growth and autophagy with optimized utilization of cellular energy.
doi:10.4161/auto.7.10.16660
PMCID: PMC3210307  PMID: 21795849
ULK1; ULK2; Atg5; raptor; mTOR
9.  mTOR regulation of autophagy 
FEBS letters  2010;584(7):1287-1295.
Nutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target of rapamycin), an evolutionarily-conserved protein kinase. TOR, as a central regulator of cell growth, plays a key role at the interface of the pathways that coordinately regulate the balance between cell growth and autophagy in response to nutritional status, growth factor and stress signals. Although TOR has been known as a key regulator of autophagy for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This review discusses the recent advances in understanding of the mechanism by which TOR regulates autophagy with focus on mammalian TOR (mTOR) and its regulation of the autophagy machinery.
doi:10.1016/j.febslet.2010.01.017
PMCID: PMC2846630  PMID: 20083114
mTOR; Atg1; ULK1; ULK2; Atg13
10.  ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery 
Molecular Biology of the Cell  2009;20(7):1992-2003.
Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.
doi:10.1091/mbc.E08-12-1249
PMCID: PMC2663920  PMID: 19225151
11.  A non-tight junction function of claudin-7—Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment 
Molecular Cancer  2015;14:120.
Background
Claudins are a family of tight junction (TJ) membrane proteins involved in a broad spectrum of human diseases including cancer. Claudin-7 is a unique TJ membrane protein in that it has a strong basolateral membrane distribution in epithelial cells and in tissues. Therefore, this study aims to investigate the functional significance of this non-TJ localization of claudin-7 in human lung cancer cells.
Methods
Claudin-7 expression was suppressed or deleted by lentivirus shRNA or by targeted-gene deletion. Cell cycle analysis and antibody blocking methods were employed to assay cell proliferation and cell attachment, respectively. Electron microscopy and transepthelial electrical resistance measurement were performed to examine the TJ ultrastructure and barrier function. Co-immunolocalization and co-immunoprecipitation was used to study claudin-7 interaction with integrin β1. Tumor growth in vivo were analyzed using athymic nude mice.
Results
Claudin-7 co-localizes and forms a stable complex with integrin β1. Both suppressing claudin-7 expression by lentivirus shRNA in human lung cancer cells (KD cells) and deletion of claudin-7 in mouse lungs lead to the reduction in integrin β1 and phospho-FAK levels. Suppressing claudin-7 expression increases cell growth and cell cycle progression. More significantly, claudin-7 KD cells have severe defects in cell-matrix interactions and adhere poorly to culture plates with a remarkably reduced integrin β1 expression. When cultured on uncoated glass coverslips, claudin-7 KD cells grow on top of each other and form spheroids while the control cells adhere well and grow as a monolayer. Reintroducing claudin-7 reduces cell proliferation, upregulates integrin β1 expression and increases cell-matrix adhesion. Integrin β1 transfection partially rescues the cell attachment defect. When inoculated into nude mice, claudin-7 KD cells produced significantly larger tumors than control cells.
Conclusion
In this study, we identified a previously unrecognized function of claudin-7 in regulating cell proliferation and maintaining epithelial cell attachment through engaging integrin β1.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0387-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-015-0387-0
PMCID: PMC4470020  PMID: 26081244
Claudin-7; Integrin β1; Cell proliferation; Cell-matrix interactions; Lung cancer cells
12.  Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma 
Background
The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma.
Methods
The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse.
Results
Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control.
Conclusion
These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma.
doi:10.2147/DDDT.S80205
PMCID: PMC4404940  PMID: 25931814
streptochlorin; cholangiocarcinoma; chemotherapeutic agent; invasion; metastasis
13.  Conservative extracorporeal membrane oxygenation treatment in a tracheal injury: a case report 
In patients with tracheal injuries, conservative treatment is an alternative approach when surgical treatment is difficult. However, the success rate of conservative treatment is low when a ventilator is used constantly because of underlying lung disease, and successful conservative treatment requires the maintenance of as much self-respiration as possible without a ventilator. Here, we report a case of lower tracheal injury in which both surgical and conservative treatments were difficult, but conservative treatment with extracorporeal membrane oxygenation was successful while maintaining self-respiration without a ventilator.
doi:10.1186/s13019-015-0252-7
PMCID: PMC4487840  PMID: 25885371
Extracorporeal membrane oxygenation; Tracheal injury; Conservative care
14.  Neo-sternum reconstruction using costal cartilage approximation and small Permacol® patch repair in the treatment of Cantrell pentalogy: a case report 
The ideal treatment for pentalogy of Cantrell is neo-sternum reconstruction by using autologous tissues. Although treatment timing varies depending on the degree of deformity and patient’s condition, the principle is performing the procedure at the earliest, to prevent blunt or piercing trauma to the heart. However, the challenge is performing the procedure on a neonate, because feasibility of the procedure is affected by the size of the defect, and limitations in utilizable autologous tissues. We used a small biocompatible patch (Permacol®) and lower costal cartilage to perform curative neo-sternum reconstruction, which is a simple and safe treatment method.
doi:10.1186/s13019-015-0241-x
PMCID: PMC4380113  PMID: 25880424
15.  Antioxidant and Cytoprotective Effects of Lotus (Nelumbo nucifera) Leaves Phenolic Fraction 
Phenolic rich ethyl acetate fraction (EAF) from lotus leaves was prepared and its bioactive components, antioxidant and cytoprotective effects were investigated. EAF showed high total phenolic content and flavonoid content and contained rutin (11,331.3±4.5 mg/100 g EAF), catechin (10,853.8±5.8 mg/100 g EAF), sinapic acid (1,961.3±5.6 mg/100 g EAF), chlorogenic acid (631.9±2.3 mg/100 g EAF), syringic acid (512.3±2.5 mg/100 g EAF), and quercetin (415.0±2.1 mg/100 g EAF). EAF exerted the IC50 of 4.46 μg/mL and 5.35 μg/mL toward DPPH and ABTS cation radicals, respectively, and showed strong reducing power, which was better than that of ascorbic acid, a positive control. Additionally, EAF protected hydroxyl radical-induced DNA damage indicated by the conversion of supercoiled pBR322 plasmid DNA to the open circular form and inhibited lipid peroxidation of polyunsaturated fatty acid in a linoleic acid emulsion. In cultured hepatocytes, EAF exerted a cytoprotective effect against oxidative stress by inhibiting intracellular reactive oxygen species formation and membrane lipid peroxidation. In addition, depletion of glutathione under oxidative stress was remarkably restored by treatment with EAF. The results suggest that EAF have great potential to be used against oxidative stress-induced health conditions.
doi:10.3746/pnf.2015.20.1.22
PMCID: PMC4391537  PMID: 25866746
lotus leaf; antioxidant; DNA damage; cytoprotection
16.  Thrombotic Complications during Interventional Lung Assist: Case Series 
Interventional lung assist (iLA) effectively reduces CO2 retention and allows protective ventilation in cases of life-threatening hypercapnia. Despite the clinical efficacy of iLA, there are a few major limitations associated with the use of this approach, such as bleeding, thrombosis, and catheter-related limb ischemia. We presented two cases in which thrombotic complications developed during iLA. We demonstrated the two possible causes of thrombotic complications during iLA; stasis due to low blood flow and inadequate anticoagulation.
doi:10.4046/trd.2015.78.1.18
PMCID: PMC4311030  PMID: 25653692
Lung; Complications; Thrombosistal
17.  Effect of a neutrophil elastase inhibitor on ventilator-induced lung injury in rats 
Journal of Thoracic Disease  2014;6(12):1681-1689.
Objective
We hypothesized that pretreatment with sivelestat therapy could attenuate ventilator-induced lung injury (VILI) and lung inflammation in a rat model.
Methods
The neutrophil elastase inhibitor was administered intraperitoneally 30 min before and at the initiation of ventilation. The rats were categorized as (I) sham group; (II) VILI group; (III) sivelestat group; (IV) early sivelestat group. Wet-to-dry weight ratio, bronchoalveolar lavage fluid (BALF) neutrophil and protein, tissue malondialdehyde (MDA) and histologic VILI scores were investigated.
Results
The ratio of wet-to-dry weight, BALF neutrophil and protein, tissue MDA and VILI scores were significantly increased in the VILI group compared to the sham group [3.85±0.32 vs. 9.05±1.02, P<0.001; (0.89±0.93)×104 vs. (7.67±1.41)×104 cells/mL, P<0.001; 2.34±0.47 vs. 23.01±3.96 mg/mL, P<0.001; 14.43±1.01 vs. 36.56±5.45 nmol/mg protein, P<0.001; 3.78±0.67 vs. 7.00±1.41, P<0.001]. This increase was attenuated in the early sivelestat group compared with the sivelestat group [wet-to-dry ratio: 6.76±2.01 vs. 7.39±0.32, P=0.032; BALF neutrophil: (5.56±1.13)×104 vs. (3.89±1.05)×104 cells/mL, P=0.021; BALF protein: 15.57±2.32 vs. 18.38±2.00 mg/mL, P=0.024; tissue MDA: 29.16±3.01 vs. 26.31±2.58, P=0.049; VILI scores: 6.33±1.41 vs. 5.00±0.50, P=0.024].
Conclusions
Pretreatment with a neutrophil elastase inhibitor attenuates VILI in a rat model.
doi:10.3978/j.issn.2072-1439.2014.11.10
PMCID: PMC4283296  PMID: 25589960
Ventilator-induced lung injury (VILI); neutrophil elastase
18.  Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate) 
Nanoscale Research Letters  2014;9(1):525.
Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a 1H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a 1H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery.
doi:10.1186/1556-276X-9-525
PMCID: PMC4184469  PMID: 25288916
Nanoparticles; Block copolymer; Poly(3-hydroxyoctanoate); Drug delivery
19.  Defensive mechanism in cholangiocarcinoma cells against oxidative stress induced by chlorin e6-based photodynamic therapy 
In this study, the effect of chlorin e6-based photodynamic therapy (Ce6-PDT) was investigated in human intrahepatic (HuCC-T1) and extrahepatic (SNU1196) cholangiocarcinoma (CCA) cells. The amount of intracellular Ce6 increased with increasing Ce6 concentration administered, or with incubation time, in both cell lines. The ability to take up Ce6 and generate reactive oxygen species after irradiation at 1.0 J/cm2 did not significantly differ between the two CCA cell types. However, after irradiation, marked differences were observed for photodamage and apoptotic/necrotic signals. HuCC-T1 cells are more sensitive to Ce6-PDT than SNU1196 cells. Total glutathione (GSH) levels, glutathione peroxidase and glutathione reductase activities in SNU1196 cells were significantly higher than in HuCC-T1 cells. With inhibition of enzyme activity or addition of GSH, the phototoxic effect could be controlled in CCA cells. The intracellular level of GSH is the most important determining factor in the curative action of Ce6-PDT against tumor cells.
doi:10.2147/DDDT.S62265
PMCID: PMC4174044  PMID: 25258513
cholangiocarcinoma; chlorin e6; photodynamic therapy; reactive oxygen species; glutathione; heme oxygenase-1
20.  Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2 
Oncology Letters  2014;8(6):2769-2775.
Cell cycles, ordered series of events modulating cell growth and division, are tightly regulated by complexes containing cyclin-dependent kinases (CDKs) and cyclins. Cyclin O is a novel cyclin family protein which interacts with CDK2. However, the molecular effects of cyclin O on the activity of CDK2 have not been fully evaluated. In this study, an interaction between cyclin O and CDK2 was identified by co-immunoprecipitation and the effect of cyclin O on the kinase activity of CDK2 was investigated using cyclin O point mutants. Co-immunoprecipitation was achieved using using HEK293 human embryonic kidney cells which were transiently transfected with vectors expressing cyclin O and CDK2, which revealed that cyclin O interacted with CDK2, particularly with the active form of endogenous CDK2. Cyclin O was expressed as several different bands with molecular weights between 45 and 50 kDa, possibly due to different post-translational modifications. When co-expressed with CDK2, cyclin O appeared as a band with a molecular weight of 50 kDa. Treatment with calf intestinal phosphatase reduced the intensity of the uppermost band. Mass spectroscopic analysis of cyclin O co-expressed with CDK2 revealed that the 81st serine residue of cyclin O was phosphorylated. The in vitro kinase activity of CDK2 phosphorylating histone H1 was markedly increased in the cells overexpressing cyclin O. This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O.
doi:10.3892/ol.2014.2530
PMCID: PMC4214489  PMID: 25364462
cyclin-dependent kinase 2; cyclin O; phosphorylation; kinase activity
21.  Epigenetic Regulation of Autophagy by the Methyltransferase G9a 
Molecular and Cellular Biology  2013;33(20):3983-3993.
Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.
doi:10.1128/MCB.00813-13
PMCID: PMC3811684  PMID: 23918802
22.  Life-threatening cardiac tamponade: a rare complication of acupuncture 
Acupuncture as an ancient Chinese treatment has proven effective and is utilized worldwide. Although it is generally believed to be a safe clinical procedure, serious lethal complications including death have been reported. We present a rare case of life-threatening cardiac tamponade due to penetration of an acupuncture needle directly into the right ventricle.
doi:10.1186/1749-8090-9-61
PMCID: PMC4230030  PMID: 24685234
Acupuncture; Complications; Cardiac tamponade
23.  dRAGging Amino Acid-mTORC1 Signaling by SH3BP4 
Molecules and Cells  2012;35(1):1-6.
Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and autophagy. Its activity is regulated by the availability of amino acids and growth factors. The activation of mTORC1 by growth factors, such as insulin and insulin-like growth factor-1 (IGF-1), is mediated by tuberous sclerosis complex (TSC) 1 and 2 and Rheb GTPase. Relative to the growth factor-regulated mTORC1 pathway, the evolutionarily ancient amino acid-mTORC1 pathway remains not yet clearly defined. The amino acid-mTORC1 pathway is mediated by Rag GTPase heterodimers. Several binding proteins of Rag GTPases were discovered in recent studies. Here, we discuss the functions and mechanisms of the newly-identified binders of Rag GTPases. In particular, this review focuses on SH3 binding protein 4 (SH3BP4), the protein recently identifed as a negative regulator of Rag GTPases.
doi:10.1007/s10059-013-2249-1
PMCID: PMC3887856  PMID: 23274731
mTOR; mTORC1; Rag GTPases; SH3BP4
24.  Comparative Study of Heart Rate Variability in Patients with Schizophrenia, Bipolar Disorder, Post-traumatic Stress Disorder, or Major Depressive Disorder 
Objective
Heart rate variability (HRV) changes as a function of psychiatric illness. This study aimed to evaluate HRV among patients with various psychiatric disorders.
Methods
The present study recruited patients with schizophrenia (n=35), bipolar disorder (n=41), post-traumatic stress disorder (PTSD; n=34), or major depressive disorder (n=34) as well as healthy controls (n=27). The time-domain analysis (the standard deviation of all RR intervals [SDNN] and the square root of the mean squared differences of successive normal sinus intervals [RMSSD]), the frequency-domain analysis (very low frequency, low frequency [LF], high frequency [HF], and total power [TP]), and a non-linear complexity measure the approximate entropy were computed.
Results
SDNN and HF were significantly reduced in patients with schizophrenia compared with healthy controls. SDNN, RMSSD, TP, LF, and HF were significantly reduced in bipolar patients compared with healthy controls. HF was significantly reduced in PTSD patients compared with healthy controls.
Conclusion
Our findings indicate that HRV is not sufficiently powerful to discriminate among various psychiatric illnesses. However, our results suggest that HRV, particularly HF, could be used as a tool for discriminating between psychiatric patients and healthy controls.
doi:10.9758/cpn.2013.11.3.137
PMCID: PMC3897762  PMID: 24465250
Heart rate variability; Schizophrenia; Bipolar disorder; Post traumatic stress disorder; Major depressive disorder
25.  Vacuum-Assisted Closure Therapy as an Alternative Treatment of Subcutaneous Emphysema 
Vacuum-assisted closure therapy is an alternative method for a massive subcutaneous emphysema treatment. It is easily applicable and shows rapid effectiveness in massive subcutaneous emphysema, intractable with chest tube drainage.
doi:10.5090/kjtcs.2013.46.5.383
PMCID: PMC3810565  PMID: 24175278
Subcutaneous emphysema; Device; Negative pressure

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