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1.  Efficacy of cap-assisted colonoscopy according to lesion location and endoscopist training level 
AIM: To evaluate the efficacy of cap-assisted colonoscopy (CAC) for detection of colorectal polyps and adenomas according to the lesion location and endoscopist training level.
METHODS: Patients 20 years or older, who underwent their first screening colonoscopy in a single tertiary center from May 2011 to December 2012 were enrolled in this study. All patients underwent either CAC or standard colonoscopy (SC), and all of the procedures were performed by 11 endoscopists (8 trainees and 3 experts). All procedures were performed with high-definition colonoscopes and narrow band imaging. The eight trainees had experiences of performing 150 to 500 colonoscopies, and the three experts had experiences of performing more than 3000 colonoscopies. A 4-mm-long transparent cap was attached to the end of a colonoscope in the CAC group. We retrospectively evaluated the number of polyps and adenomas, polyp detection rate (PDR), and the number of adenomas and adenoma detection rate (ADR) according to the lesion location and endoscopist training level between CAC and SC. We also evaluated the number of polyps and adenomas according to their size between CAC and SC.
RESULTS: Overall, PDR and ADR using CAC were significantly higher than those using SC for both whole colon (48.5% vs 40.7%, P = 0.012; 35.7% vs 28.3%, P = 0.012) and right-side colon (35.3% vs 26.6%, P = 0.002; 27.0% vs 16.9%, P < 0.001). The number of polyps and adenomas per patient using CAC was significantly higher than that using SC for both the whole colon (1.07 ± 1.59 vs 0.82 ± 1.31, P = 0.008; 0.72 ± 1.32 vs 0.50 ± 1.01, P = 0.003) and right-side colon (0.66 ± 1.18 vs 0.41 ± 0.83, P < 0.001; 0.46 ± 0.97 vs 0.25 ± 0.67, P < 0.001). In the trainee group, the PDR and ADR using CAC were significantly higher than those using SC for both the whole colon (46.7% vs 39.7%, P = 0.040; 33.9% vs 26.0%, P =0.012) and right-side colon (34.2% vs 26.5%, P = 0.015; 25.3% vs 15.9%, P = 0.001). In the expert group, the PDR and ADR using CAC were significantly higher than those using SC only for the right-side colon (42.1% vs 27.0%, P =0.035; 36.8% vs 21.0%, P = 0.020).
CONCLUSION: CAC is more effective than SC for detection of colorectal polyps and adenomas, especially when performed by trainees and when the lesions are located in the right-side colon.
PMCID: PMC4445103  PMID: 26034361
Colonoscopy; Cap-assisted colonoscopy; Colonic polyps; Adenoma; Colorectal neoplasm
2.  Ca2+ permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca2+ signaling to sustain muscle function 
Skeletal Muscle  2015;5:4.
Ca2+ influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca2+ permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed.
We generated a mouse with a Ca2+ binding and/or permeation defect in the voltage-dependent Ca2+ channel, CaV1.1, and used Ca2+ imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca2+ imaging techniques to define pathways modulated by Ca2+ binding and/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.
Using mice with a pore mutation in CaV1.1 required for Ca2+ binding and/or permeation (E1014K, EK), we demonstrate that CaV1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca2+ stores during sustained activity. Decreases in these Ca2+-dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca2+ binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.
While not essential for excitation-contraction coupling, Ca2+ binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance.
Electronic supplementary material
The online version of this article (doi:10.1186/s13395-014-0027-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4340672  PMID: 25717360
CaV1.1; CaM kinase II; Fatigue; Fiber type; Protein synthesis and Skeletal muscle
3.  NF-κB/AP-1-Targeted Inhibition of Macrophage-Mediated Inflammatory Responses by Depigmenting Compound AP736 Derived from Natural 1,3-Diphenylpropane Skeleton 
Mediators of Inflammation  2014;2014:354843.
AP736 was identified as an antimelanogenic drug that can be used for the prevention of melasma, freckles, and dark spots in skin by acting as a suppressor of melanin synthesis and tyrosinase expression. Since macrophage-mediated inflammatory responses are critical for skin health, here we investigated the potential anti-inflammatory activity of AP736. The effects of AP736 on various inflammatory events such as nitric oxide (NO)/prostaglandin (PG) E2 production, inflammatory gene expression, phagocytic uptake, and morphological changes were examined in RAW264.7 cells. AP736 was found to strongly inhibit the production of both NO and PGE2 in lipopolysaccharide- (LPS-) treated RAW264.7 cells. In addition, AP736 strongly inhibited both LPS-induced morphological changes and FITC-dextran-induced phagocytic uptake. Furthermore, AP736 also downregulated the expression of multiple inflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase- (COX-) 2, and interleukin- (IL-) 1β in LPS-treated RAW264.7 cells. Transcription factor analysis, including upstream signalling events, revealed that both NF-κB and AP-1 were targeted by AP736 via inhibition of the IKK/IκBα and IRAK1/TAK1 pathways. Therefore, our results strongly suggest that AP736 is a potential anti-inflammatory drug due to its suppression of NF-κB-IKK/IκBα and AP-1-IRAK1/TAK1 signalling, which may make AP736 useful for the treatment of macrophage-mediated skin inflammation.
PMCID: PMC4217328  PMID: 25386046
4.  MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signaling 
Nature communications  2013;4:2354.
Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is a ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme UBE2H. Molecular manipulations that disrupt the E3 ligase function of MG53 abolishes IRS-1 ubiquitination and enhances skeletal myogenesis. Skeletal muscles derived from the MG53−/− mice show an elevated IRS-1 level with enhanced insulin signaling, which protects the MG53−/− mice from developing insulin resistance when challenged with a high fat/high sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.
PMCID: PMC3941707  PMID: 23965929
5.  Interleukin-6 Induces S100A9 Expression in Colonic Epithelial Cells through STAT3 Activation in Experimental Ulcerative Colitis 
PLoS ONE  2012;7(9):e38801.
Intestinal epithelium is essential for maintaining normal intestinal homeostasis; its breakdown leads to chronic inflammatory pathologies, such as inflammatory bowel diseases (IBDs). Although high concentrations of S100A9 protein and interleukin-6 (IL-6) are found in patients with IBD, the expression mechanism of S100A9 in colonic epithelial cells (CECs) remains elusive. We investigated the role of IL-6 in S100A9 expression in CECs using a colitis model.
IL-6 and S100A9 expression, signal transducer and activator of transcription 3 (STAT3) phosphorylation, and infiltration of immune cells were analyzed in mice with dextran sulfate sodium (DSS)-induced colitis. The effects of soluble gp130-Fc protein (sgp130Fc) and S100A9 small interfering (si) RNA (si-S100A9) on DSS-induced colitis were evaluated. The molecular mechanism of S100A9 expression was investigated in an IL-6-treated Caco-2 cell line using chromatin immunoprecipitation assays.
IL-6 concentrations increased significantly in the colon tissues of DSS-treated mice. sgp130Fc or si-S100A9 administration to DSS-treated mice reduced granulocyte infiltration in CECs and induced the down-regulation of S100A9 and colitis disease activity. Treatment with STAT3 inhibitors upon IL-6 stimulation in the Caco-2 cell line demonstrated that IL-6 mediated S100A9 expression through STAT3 activation. Moreover, we found that phospho-STAT3 binds directly to the S100A9 promoter. S100A9 may recruit immune cells into inflamed colon tissues.
Elevated S100A9 expression in CECs mediated by an IL-6/STAT3 signaling cascade may play an important role in the development of colitis.
PMCID: PMC3433486  PMID: 22962574
6.  Effect of Soil Ameliorators on Ectomycorrhizal Fungal Communities that Colonize Seedlings of Pinus densiflora in Abandoned Coal Mine Spoils 
Mycobiology  2012;40(3):168-172.
In this study, the effect of soil ameliorators on ectomycorrhizal (ECM) fungal communities in coal mine spoils was investigated. Organic fertilizers and slaked lime were applied as soil ameliorators in 3 abandoned coal mine spoils. One year after the initial treatment, roots of Pinus densiflora seedlings were collected and the number of ECM species, colonization rate, and species diversity were assessed. The results showed that the soil ameliorators significantly increased ECM colonization on the roots of P. densiflora. The results suggest that soil ameliorators can have a positive effect on ECM fungi in terms of growth of host plants and show the potential use of soil ameliorator treatment for revegetation with ECM-colonized pine seedlings in the coal mine spoils.
PMCID: PMC3483393  PMID: 23115509
Coal mine spoils; Colonization rate; Ectomycorrhizal fungi; Pinus densiflora; Soil ameliorator; Species diversity
7.  AICAR Prevents Heat Induced Sudden Death in RyR1 Mutant Mice Independent of AMPK Activation 
Nature medicine  2012;18(2):244-251.
Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (RyR1) die when exposed to short periods of temperature elevation (≥ 37 °C). We demonstrate that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in Y524S mice. The AICAR protection is independent of AMPK activation and results from a newly identified action on the mutant RyR1 to reduce Ca2+ leak, preventing Ca2+ dependent increases in both reactive oxygen and reactive nitrogen species that act to further increase resting Ca2+ concentrations. If unchecked, the temperature driven increases in resting Ca2+ and ROS/RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents the heat induced death in vivo. Our findings suggest that AICAR is likely to be effective in prophylactic treatment of humans with enhanced susceptibility to exercise/heat-induced sudden death associated with RyR1 mutations.
PMCID: PMC3274651  PMID: 22231556
8.  LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression 
Experimental & Molecular Medicine  2008;40(5):514-522.
Tumor migration/invasion is the main cause of tumor progression and STAT3 is needed to enhance tumor migration/invasion by up-regulating MMP-9. Thus, agents that inhibit STAT3 activation may be used as an anticancer drug. We present herein that 6-methyl-2-propylimino-6, 7-dihydro-5H-benzo [1, 3]-oxathiol-4-one (LYR71) , a derivative of trimeric resveratrol, has an anticancer activity through inhibition of STAT3 activation. We found that LYR71 suppressed STAT3 activation and inhibited the expression and activity of MMP-9 in RANTES-stimulated breast cancer cells. In addition, LYR71 reduced RANTES-induced MMP-9 transcripts by blocking STAT3 recruitment, dissociating p300 and deacetylating histone H3 and H4 on the MMP-9 promoter. Furthermore, LYR71 inhibited tumor migration/invasion in RANTES-treated breast cancer cells and consequently blocked tumor progression in tumor-bearing mice. Taken together, the results of this study suggest that LYR71 can be therapeutically useful due to the inhibition effect of STAT3-mediated MMP-9 expression in breast cancer cells.
PMCID: PMC2679359  PMID: 18985009
chemokine CCL5; LYR71; matrix metalloproteinase 9; neoplasm metastasis; STAT3 transcription factor
9.  STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination 
Experimental & Molecular Medicine  2008;40(5):479-485.
Hypoxia-inducible factor 1α (HIF-1α) is rapidly degraded by the ubiquitin-proteasome pathway under normoxic conditions. Ubiquitination of HIF-1α is mediated by interaction with von Hippel-Lindau tumor suppressor protein (pVHL). In our previous report, we found that hypoxia-induced active signal transducer and activator of transcription3 (STAT3) accelerated the accumulation of HIF-1α protein and prolonged its half-life in solid tumor cells. However, its specific mechanisms are not fully understood. Thus, we examined the role of STAT3 in the mechanism of pVHL-mediated HIF-1α stability. We found that STAT3 interacts with C-terminal domain of HIF-1α and stabilizes HIF-1α by inhibition of pVHL binding to HIF-1α. The binding between HIF-1α and pVHL, negative regulator of HIF-1α stability, was interfered dose-dependently by overexpressed constitutive active STAT3. Moreover, we found that the enhanced HIF-1α protein levels by active STAT3 are due to decrease of poly-ubiquitination of HIF-1α protein via inhibition of interaction between pVHL and HIF-1α. Taken together, our results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1α through competition with pVHL for binding to HIF-1α, and then stabilizes HIF-1α protein levels.
PMCID: PMC2679355  PMID: 18985005
anoxia; hypoxia-inducible factor1, α subunit; neoplasms; STAT3 transcription factor; ubiquitination; von Hippel-Lindau tumor suppressor protein
10.  Secretion of adenylate kinase 1 is required for extracellular ATP synthesis in C2C12 myotubes 
Experimental & Molecular Medicine  2008;40(2):220-228.
Extracellular ATP (exATP) has been known to be a critical ligand regulating skeletal muscle differentiation and contractibility. ExATP synthesis was greatly increased with the high level of adenylate kinase 1 (AK1) and ATP synthase β during C2C12 myogenesis. The exATP synthesis was abolished by the knock-down of AK1 but not by that of ATP synthase β in C2C12 myotubes, suggesting that AK1 is required for exATP synthesis in myotubes. However, membrane-bound AK1β was not involved in exATP synthesis because its expression level was decreased during myogenesis in spite of its localization in the lipid rafts that contain various kinds of receptors and mediate cell signal transduction, cell migration, and differentiation. Interestingly, cytoplasmic AK1 was secreted from C2C12 myotubes but not from C2C12 myoblasts. Taken together all these data, we can conclude that AK1 secretion is required for the exATP generation in myotubes.
PMCID: PMC2679308  PMID: 18446060
adenosine triphosphate; adenylate kinase 1; TP synthase; membrane microdomains; muscle development
11.  In Vitro and In Vivo Activities of LB 10827, a New Oral Cephalosporin, against Respiratory Pathogens 
Antimicrobial Agents and Chemotherapy  2000;44(12):3272-3277.
The in vitro antibacterial activities of LB 10827, a new oral cephalosporin, against common respiratory tract pathogens were compared with those of six β-lactams (cefdinir, cefuroxime, cefprozil, penicillin G, amoxicillin-clavulanate, and ampicillin), two quinolones (trovafloxacin and ciprofloxacin), and one macrolide (clarithromycin). The MIC of LB 10827 at which 90% of the penicillin-resistant strains of Streptococcus pneumoniae tested were inhibited was 0.5 μg/ml, and the drug was 4- to 32-fold more active than the compared β-lactams. The potent activity of LB 10827 against Haemophilus influenzae and Moraxella catarrhalis was retained, and the presence of β-lactamase in both strains had little effect on the in vitro activity of the compound. Time-kill studies revealed that LB 10827 had bactericidal activity against these respiratory pathogens. This agent reduced original counts of all pathogens tested by ≥3 log10 CFU/ml at the MIC, and the regrowth was completely prevented for 12 h. The potent in vitro antibacterial activity of LB 10827 against respiratory pathogens has been proved in both mouse pneumonia and neutropenic rat models. These results strongly suggest that this agent has potential for the treatment of respiratory tract infections.
PMCID: PMC90191  PMID: 11083626

Results 1-11 (11)