Michiro Otaka

Endoscopic submucosal dissection of large colorectal tumors by using a novel spring-action S-O clip for traction (with video)

BACKGROUNDnEndoscopic submucosal dissection (ESD) allows en bloc resection of large GI neoplasms, regardless of their size; however, technical difficulties associated with ESD in the colorectum make it less widely applied in the treatment of tumors in this region. To address this difficulty, we designed a rubber strip-based traction device, called the S-O clip (Sakamoto-Osada clip) and reported previously that ESD with this device was effective for complete resection of large, superficial colorectal neoplasms. In this report, we describe a novel spring-action version of the S-O clip (spring S-O clip) that improves the facility of clip use during ESD of colorectal tumors.nnnOBJECTIVEnTo evaluate the efficacy and safety of the spring S-O clip for ESD of colorectal neoplasms.nnnDESIGNnCase series.nnnSETTINGnJuntendo University Hospital.nnnMAIN OUTCOME MEASUREMENTSnThe efficacy and safety of the spring S-O clip traction device during ESD of colorectal tumors.nnnRESULTSnIn 3 cases, a large, superficial neoplasm in the right side of the colon was removed safely and successfully en bloc without complication. Procedure times for the 3 cases were 44, 27, and 49 minutes, with resected specimens measuring 40, 24, and 35 mm, respectively.nnnLIMITATIONnUncontrolled study.nnnCONCLUSIONnThis limited case series demonstrates that spring S-O clip-assisted ESD is safe and effective for en bloc resection of large superficial neoplasms in the right side of the colon.

Comparison of several activity indices for the evaluation of endoscopic activity in UC: inter- and intraobserver consistency.

Background: This study evaluated inter‐ and intraobserver agreement in the assessment of ulcerative colitis (UC) activity using 4 established indices and a newly designed Modified 6‐point Activity Index. Method: In all, 279 endoscopic pictures of inflammatory lesions from 93 UC patients were displayed twice to 4 expert and 4 trainee endoscopists, at an interval of 1 month. Each picture was assessed for inflammatory changes using established indices (Matts, Schroeder [a.k.a. Mayo Score], Baron, and Blackstone) and our new Modified 6‐point Activity Index. Weighted kappa statistics were used to estimate intra‐ and interobserver variation. Results: The Matts and Schroeder indices gave a “good” degree of concordance for expert endoscopists in terms of inter‐ and intraobserver agreements (0.74–0.78); this was not so evident with the Baron and Blackstone indices (0.61–0.73). For trainee endoscopists, all scores for inter‐ and intraobserver weighted kappa values using established indices (0.41–0.51) were lower than for the experts. The degree of concordance using the Modified 6‐point Activity Index was rated as “good” for inter‐ and intraobserver agreements for expert endoscopists (0.65 and 0.79), and as “moderate” for trainee endoscopists (0.54 and 0.64). Conclusions: Accurate assessment of UC disease activity from endoscopic findings benefited from experience. For expert endoscopists, the Matts and Schroeder indices proved the most reliable of the 4 established indices. Current endoscopic technologies may be adequate for assessing UC activity, particularly if modified to permit a finer classification of disease severity based on 6 grades, as with our newly developed Modified 6‐point Activity Index. (Inflamm Bowel Dis 2009;)

Overexpression of a 60-kDa heat shock protein enhances cytoprotective function of small intestinal epithelial cells.

AIMSnWith the advancement of small intestinal (double balloon and capsule) endoscopy technology, incidence of small intestinal lesion caused by nonsteroidal anti-inflammatory drugs (NSAIDs) has been known to be high. However, therapy for small intestinal mucosal lesion has not yet been developed. Previous studies have shown that heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone. In this study, we examined the effect of HSP60 or HSP70 overexpression on hydrogen peroxide-induced (H2O2) or indomethacin-induced cell damage in the small intestinal epithelial cells.nnnMAIN METHODSncDNA of human HSP60 or HSP70 was transfected to rat small intestinal (IEC-6) cells, and HSP60- or HSP70-overexpressing cells were cloned. IEC-6 cells transfected with vector only were used as control cells. These cells were treated with H2O2 (0-0.14mM) or indomethacin (0-2.5mM). The cell viability was determined by MTT-assay. Cell necrosis was evaluated by LDH-release assay. Further, apoptosis was evaluated by caspases-3/7 activity and TUNEL assay.nnnKEY FINDINGSnCell viability after H2O2 or indomethacin treatment was significantly higher in HSP60-overexpressing cells compared with that in control cells and HSP60-overexpressing cells. Apoptotic cells were also reduced in HSP60-overexpressing.nnnCONCLUSIONnThese results indicate that HSP60 plays an important role in protecting small intestinal mucosal cells from H2O2-induced or indomethacin-induced cell injury. HSP70-overexpressing cells did not show anti-apoptotic ability.nnnSIGNIFICANCEnThese findings possibly suggest that function of each HSP is different in the small intestine. Therefore, for the therapy of small intestinal mucosal lesion, HSP60-induction therapy could be a new therapeutic strategy.

The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90

We used an in situ proximity ligation assay to confirm whether AhR was translocated to the nucleus alone or together with HSP90. HSP90 was co‐localized with AhR after the nuclear translocation. It has been suggested that the ligand‐bound AhR was translocated to the nucleus with HSP90. Activated AhR acts as a transcription factor, as shown by the transcription induction of the gene CYP1A1 8 h after treatment with β‐NF.

Heat-Shock Protein 70-Overexpressing Gastric Epithelial Cells Are Resistant to Indomethacin-Induced Apoptosis

Background/Aims: Protecting intestinal mucosa from nonsteroidal anti-inflammatory drugs is still an unsolved problem. It has been revealed that apoptosis in epithelial cells as a result of mitochondrial injury is an important pathogenesis in indomethacin-induced gastric mucosal injury. In this study, we revealed the effect of overexpressed heat-shock protein 70 (HSP70) in indomethacin-induced apoptosis and oxidative stress. Methods: HSP70-overexpressing rat gastric mucosal cells (7018-RGM-1 cells) and control cells (pBK-CMV-12 cells) were used and treated with 0–500 μM of indomethacin for 24 h. Cell viability and cytotoxity were measured by a WST-8 assay and a lactate dehydrogenase release assay, respectively. Apoptosis was observed by fluorescence microscopy staining with Hoechst 33342 and propidium iodide. The expression of Bcl-2 family proteins, activation of caspase-3, and 4-hydroxy-2-nonenal (4-HNE)-modified proteins were assessed by Western blot analysis. Results: Indomethacin caused apoptosis of gastric epithelial cells. The 7018-RGM-1 cells survived significantly after indomethacin treatment compared to the control cells. The increase in pro-apoptotic Bad proteins, the decrease in anti-apoptotic Bcl-2 proteins, and caspase activation were all suppressed in the 7018-RGM-1 cells. A lower level of indomethacin-induced 4-HNE-modification was detected in the 7018-RGM-1 cells than in the control cells. Conclusion: Overexpressed HSP70 may potentiate resistance to apoptosis and oxidative stress in indomethacin-induced gastric epithelial cell injury.

Gentamicin inhibits HSP70-assisted protein folding by interfering with substrate recognition

MINT‐7384430: RNaseA (uniprotkb:P61823) binds (MI:0407) to HSP70 (uniprotkb:P34930) by surface plasmon resonance (MI:0107)

Cisplatin differently affects amino terminal and carboxyl terminal domains of HSP90

The 90‐kDa heat shock protein (HSP90) is a molecular chaperone that assists in the folding and assembly of proteins in the cytosol. We previously demonstrated that the antineoplastic reagent, cisplatin, inhibits the aggregation prevention activity of mammalian HSP90. We now show that cisplatin binds both the amino terminal and carboxyl terminal domains of the human HSP90 and differently affects these two domains. Cisplatin blocks the aggregation prevention activity of HSP90C, but not HSP90N. In contrast, cisplatin induces a conformational change in HSP90N, but not HSP90C. These results indicate that cisplatin modulates the HSP90 activities through two different mechanisms using the two distinct binding sites of the HSP90 molecule.

Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats.

BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A2A receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A2A receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats.MethodsGastric lesions were produced by oral gavage of indomethacin (30xa0mg/kg). ATL-313 (1–10xa0μg/kg) was given orally just before the indomethacin administration.ResultsThe ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A2A receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10xa0μg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected.ConclusionWe conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A2A agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Observational comparative trial of the efficacy of proton pump inhibitors versus histamine‐2 receptor antagonists for uninvestigated dyspepsia

Background and Aims:u2002 It is still controversial which drugs, proton pump inhibitors (PPI) or histamine‐2 receptor antagonists (H2RA), are more effective for dyspepsia in the Japanese population.

Effect of Alcohol Consumption on Leptin Level in Serum, Adipose Tissue, and Gastric Mucosa

It has been reported that the stomach is a source of leptin, which is the product of the obese (ob) gene. In the present study, the effect of alcohol on leptin level in serum, gastric mucosa, and adipose tissue was studied to understand the relationship between appetite and alcohol consumption. Male Sprague-Dawley rats were administered 1xa0ml of 25% ethanol perorally. Leptin levels in the serum, gastric mucosa, and adipose tissue were measured. The serum leptin level was significantly decreased 3 and 6xa0hr after ethanol administration, although the gastric leptin level was not affected. The leptin level in the adipose tissue was significantly increased 3xa0hr after administration. We conclude that the decreased serum leptin level after ethanol administration might be due to suppression of leptin secretion from adipose tissue to the systemic circulation. These findings might be important for understanding the relationship between alcohol consumption and appetite.