Chronic immobilization stress (CIS) induces low levels of glutamate (Glu) and glutamine (Gln) and hypoactive glutamatergic signaling in the mouse prefrontal cortex (PFC), which is closely related to the Glu-Gln cycle. A Gln-supplemented diet ameliorates CIS-induced deleterious changes. Here, we investigated the effects of CIS and Gln supplementation on Glu-Gln cycle-related proteins to characterize the underlying mechanisms. Using the CIS-induced depression mouse model, we examined the expression of 11 proteins involved in the Glu-Gln cycle in the PFC. CIS decreased levels of glutamate transporter 1 (GLT1) and sodium-coupled neutral amino acid transporter (SNAT) 1, SANT2, SNAT3, and SNAT5. Gln supplementation did not affect the non-stressed group but significantly increased GLT1 and SNATs of the stressed group. By immunohistochemical analysis, we confirmed that SNAT1 and SNAT2 were decreased in neurons and GLT1, SNAT3, and SNAT5 were decreased in astrocytes in the medial PFC of the stressed group, but Gln-supplemented diet ameliorated these decrements. Collectively, these results suggest that CIS may cause depressive-like behaviors by decreasing Glu and Gln transportation in the PFC and that a Gln-supplemented diet could prevent the deleterious effects of CIS.
Amino Acid Transport System X-AG ; Amino Acid Transport Systems ; Animals ; Astrocytes ; Depression ; Depressive Disorder ; Diet ; Glutamic Acid ; Glutamine ; Immobilization ; Mice ; Neurons ; Prefrontal Cortex ; Transportation

PURPOSE: This study aims to investigate the actual compliance with chemotherapy and analyze several factors affecting the compliance in patients with gastric cancer. METHODS: From February 2012 to December 2014, we collected data of patients with gastric cancer who received adjuvant chemotherapy (TS-1 monotherapy or XELOX: capecitabine/oxaliplatin) in Korea. RESULTS: We collected data of 1,089 patients from 31 institutions. The completion rate and dose reduction rate by age (≥60 years vs. <60 years) were 57.5% vs. 76.8% (P < 0.001) and 17.9% vs. 21.3% (P = 0.354); by body mass index (BMI) (≥23 kg/m2 vs. <23 kg/m2) were 70.2% vs. 63.2% (P = 0.019) and 19.2% vs. 19.9% (P = 0.987), respectively. The compliance by American Society of Anesthesiologists physical status (ASA PS) classification was as follows: completion rate was 74.4%, 62.8%, and 60% (P = 0.001) and the dose reduction rate was 18.4%, 20.7%, and 17.8% (P = 0.946) in ASA PS classification I, II, and III, respectively. The completion rate of TS-1 and XELOX was 65.9% vs. 70.3% (P = 0.206) and the dose reduction rate was 15.7% vs. 33.6% (P < 0.001). Furthermore, the completion rate of chemotherapy by surgical oncologists and medical oncologists was 69.5% vs. 63.2% (P = 0.028) and the dose reduction rate was 17.4% vs. 22.3% (P = 0.035), respectively. CONCLUSION: The compliance was lower in patients who were older than 60 years, had BMI <23 kg/m2, and had higher ASA PS classification. Furthermore, the patients showed higher compliance when they received chemotherapy from surgical oncologists rather than from medical oncologists.
Body Mass Index ; Chemotherapy, Adjuvant ; Classification ; Compliance ; Drug Therapy ; Humans ; Korea ; Stomach Neoplasms

BACKGROUND: Several factors contribute to differences in Streptococcus pneumoniae serotype distribution. We investigated the serotype distribution and antimicrobial resistance of S. pneumoniae isolated between 2014 and 2016 in Korea. METHODS: We collected a total of 1,855 S. pneumoniae isolates from 44 hospitals between May 2014 and May 2016, and analyzed the serotypes by sequential multiplex PCR. We investigated the distribution of each serotype by patient age, source of the clinical specimen, and antimicrobial resistance pattern. RESULTS: The most common serotypes were 11A (10.1%), followed by 19A (8.8%), 3 (8.5%), 34 (8.1%), 23A (7.3%), and 35B (6.2%). The major invasive serotypes were 3 (12.6%), 19A (7.8%), 34 (7.8%), 10A (6.8%), and 11A (6.8%). Serotypes 10A, 15B, 19A, and 12F were more common in patients ≤5 years old, while serotype 3 was more common in patients ≥65 years old compared with the other age groups. The coverage rates of pneumococcal conjugate vaccine (PCV)7, PCV10, PCV13, and pneumococcal polysaccharide vaccine 23 were 11.8%, 12.12%, 33.3%, and 53.6%, respectively. Of the 1,855 isolates, 857 (46.2%) were multi-drug resistant (MDR), with serotypes 11A and 19A predominant among the MDR strains. The resistance rates against penicillin, cefotaxime, and levofloxacin were 22.8%, 12.5%, and 9.4%, respectively. CONCLUSIONS: There were significant changes in the major S. pneumoniae serotypes in the community. Non-PCV13 serotypes increased in patients ≤5 years old following the introduction of national immunization programs with the 10- and 13-polyvalent vaccines.
Cefotaxime ; Humans ; Immunization Programs ; Korea ; Levofloxacin ; Multiplex Polymerase Chain Reaction ; Penicillins ; Pneumococcal Vaccines ; Pneumonia ; Serogroup ; Streptococcus pneumoniae ; Streptococcus ; Vaccines

Hyper-O-GlcNAcylation is a general feature of cancer which contributes to various cancer phenotypes, including cell proliferation and cell growth. Quercetin, a naturally occurring dietary flavonoid, has been reported to reduce the proliferation and growth of cancer. Several reports of the anticancer effect of quercetin have been published, but there is no study regarding its effect on O-GlcNAcylation. The aim of this study was to investigate the anticancer effect of quercetin on HeLa cells and compare this with its effect on HaCaT cells. Cell viability and cell death were determined by MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling assays. O-GlcNAcylation of AMP-activated protein kinase (AMPK) was examined by succinylated wheat germ agglutinin pulldown and immunoprecipitation. Immunofluorescence staining was used to detect the immunoreactivitiy of O-linked N-acetylglucosamine transferase (OGT) and sterol regulatory element binding protein 1 (SREBP-1). Quercetin decreased cell proliferation and induced cell death, but its effect on HaCaT cells was lower than that on HeLa cells. O-GlcNAcylation level was higher in HeLa cells than in HaCaT cells. Quercetin decreased the expression of global O-GlcNAcylation and increased AMPK activation by reducing the O-GlcNAcylation of AMPK. AMPK activation due to reduced O-GlcNAcylation of AMPK was confirmed by treatment with 6-diazo-5-oxo-L-norleucine. Our results also demonstrated that quercetin regulated SREBP-1 and its transcriptional targets. Furthermore, immunofluorescence staining showed that quercetin treatment decreased the immunoreactivities of OGT and SREBP-1 in HeLa cells. Our findings demonstrate that quercetin exhibited its anticancer effect by decreasing the O-GlcNAcylation of AMPK. Further studies are needed to explore how quercetin regulates O-GlcNAcylation in cancer.
Adenosine* ; AMP-Activated Protein Kinases ; Cell Death* ; Cell Proliferation ; Cell Survival ; Deoxyuridine ; Diazooxonorleucine ; Fluorescent Antibody Technique ; HeLa Cells ; Humans ; Immunoprecipitation ; Phenotype ; Protein Kinases* ; Quercetin* ; Sterol Regulatory Element Binding Protein 1 ; Transferases ; Triticum ; Uterine Cervical Neoplasms*

Although cell therapy is emerged for cardiac repair, its efficacy is modest by intracoronary infusion. Therefore, we established the intramyocardial delivery technique using a left ventricular (LV) mapping system (NOGA® XP) using 18 pigs. After adipose tissue-derived mesenchymal stem cells (ATSCs) were delivered intramyocardially to porcine infarcted heart, LV ejection fraction (EF) was increased, and LV chamber size was decreased. We proved the therapeutic effect of intramyocardial injection of ATSC through a LV mapping system in the porcine model for the first time in Korea. The adoption of this technique may accelerate the translation into a clinical application in the near future.
Cell- and Tissue-Based Therapy ; Heart ; Heart Failure ; Korea* ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; Myocardial Infarction* ; Stem Cells* ; Swine

BACKGROUND/AIMS: The clinical course after endoscopic management of delayed postpolypectomy bleeding (DPPB) has not been clearly determined. This study aimed to assess clinical outcomes after endoscopic hemostasis of DPPB and evaluate risk factors for rebleeding after initial hemostasis. METHODS: We reviewed medical records of 198 patients who developed DPPB and underwent endoscopic hemostasis between January 2010 and February 2015. The performance of endoscopic hemostasis was assessed. Rebleeding negative and positive patients were compared. RESULTS: DPPB developed 1.4±1.6 days after colonoscopic polypectomy. All patients achieved initial hemostasis. Clipping was the most commonly used technique. Of 198 DPPB patients, 15 (7.6%) had rebleeding 3.3±2.5 days after initial hemostasis. The number of clips required for hemostasis was higher in the rebleeding positive group (3.2±1.6 vs. 4.2±1.9, P=0.047). Combinations of clipping with other modalities such as injection methods were more common in the rebleeding positive group (67/291, 23.0% vs. 12/17, 70.6%; P<0.001). Multivariate analysis showed a large number of clips and combination therapy were independent risk factors for rebleeding. All the rebleeding cases were successfully managed by repeat endoscopic hemostasis. CONCLUSIONS: Endoscopic hemostasis is effective for the management of DPPB because of its high initial hemostasis rate and low rebleeding rate. Endoscopists should carefully observe patients in whom a large number of clips and/or combination therapy have been used to manage DPPB because these may be related to the severity of DPPB and a higher risk of rebleeding.
Colonoscopy ; Hemorrhage* ; Hemostasis ; Hemostasis, Endoscopic ; Humans ; Medical Records ; Multivariate Analysis ; Risk Factors

Colonic perforation may occur as a complication of diagnostic and therapeutic colonoscopy. The risk factors for perforation after colorectal endoscopic submucosal dissection (ESD) include an inexperienced endoscopist, a large tumor size, and submucosal fibrosis. The mechanisms of perforation include unintended endoscopic resection/dissection and severe thermal injury. Here, we report a case of colon perforation that occurred after ESD with snaring of a laterally spreading tumor. The perforation was completely unexpected because there were no colorectal ESD-associated risk factors for perforation, deep dissection, or severe coagulation injury in our patient.
Colon* ; Colonoscopy ; Fibrosis ; Humans ; Risk Factors ; SNARE Proteins*

Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-kappaB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.
Acetylation ; Actins ; Animals ; Collagen ; Connective Tissue Growth Factor ; Diet ; Diet, High-Fat ; Fibrosis ; Glucose ; Inflammation* ; Insulin Resistance ; Liver ; Macrophages ; Metabolism ; Mice* ; NF-kappa B ; Obesity ; Sirtuin 1 ; Sterol Regulatory Element Binding Protein 1 ; Weight Gain

Excessive immune responses induced by ischemia-reperfusion injury (IRI) are known to lead to necrotic and apoptotic cell death, and calcineurin plays a major role in this process. Calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT), permitting its translocation into the nucleus. As a result, calcineurin promotes the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha. The overproduction of pro-inflammatory cytokines causes renal cell death. Calcineurin activity is regulated by calpain, a cysteine protease present in the nucleus. Calpain-mediated proteolysis increases the phosphatase activity of calcineurin, resulting in NFAT dephosphorylation. This process has been studied in cardiomyocytes but its role in renal IRI is unknown. Thus, we examined whether calpain regulates calcineurin in renal tubule nuclei. We established an in vivo renal IRI model in mice and identified the protective role of a calcineurin inhibitor, FK506, in this process. Calcineurin is expressed in the nucleus, where it is present in its calpain-cleaved form. FK506 reduced nuclear expression of calcineurin and prevented calcineurin-mediated NFAT activation. Our study shows clearly that FK506 reduces calpain-mediated calcineurin activity. Consequently, calcineurin could not maintain NFAT activation. FK506 reduced renal cell death by suppressing the transcription of pro-inflammatory cytokine genes. This study provides evidence that FK506 protects against inflammation in a renal IRI mouse model. We also provided a mechanism of calcineurin action in the nucleus. Therefore, FK506 could improve renal function by decreasing calcineurin activity in both the cytoplasm and the nucleus of renal tubule cells.
Animals ; Calcineurin* ; Calpain ; Cell Death ; Cysteine Proteases ; Cytokines ; Cytoplasm* ; Inflammation ; Mice ; Myocytes, Cardiac ; Proteolysis ; Reperfusion Injury ; T-Lymphocytes ; Tacrolimus* ; Tumor Necrosis Factor-alpha

Excessive immune responses induced by ischemia-reperfusion injury (IRI) are known to lead to necrotic and apoptotic cell death, and calcineurin plays a major role in this process. Calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT), permitting its translocation into the nucleus. As a result, calcineurin promotes the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha. The overproduction of pro-inflammatory cytokines causes renal cell death. Calcineurin activity is regulated by calpain, a cysteine protease present in the nucleus. Calpain-mediated proteolysis increases the phosphatase activity of calcineurin, resulting in NFAT dephosphorylation. This process has been studied in cardiomyocytes but its role in renal IRI is unknown. Thus, we examined whether calpain regulates calcineurin in renal tubule nuclei. We established an in vivo renal IRI model in mice and identified the protective role of a calcineurin inhibitor, FK506, in this process. Calcineurin is expressed in the nucleus, where it is present in its calpain-cleaved form. FK506 reduced nuclear expression of calcineurin and prevented calcineurin-mediated NFAT activation. Our study shows clearly that FK506 reduces calpain-mediated calcineurin activity. Consequently, calcineurin could not maintain NFAT activation. FK506 reduced renal cell death by suppressing the transcription of pro-inflammatory cytokine genes. This study provides evidence that FK506 protects against inflammation in a renal IRI mouse model. We also provided a mechanism of calcineurin action in the nucleus. Therefore, FK506 could improve renal function by decreasing calcineurin activity in both the cytoplasm and the nucleus of renal tubule cells.
Animals ; Calcineurin* ; Calpain ; Cell Death ; Cysteine Proteases ; Cytokines ; Cytoplasm* ; Inflammation ; Mice ; Myocytes, Cardiac ; Proteolysis ; Reperfusion Injury ; T-Lymphocytes ; Tacrolimus* ; Tumor Necrosis Factor-alpha