Jinko Oyake

New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline

Background : In functional gastrointestinal (GI) disorders including functional dyspepsia (FD) and irritable bowel syndrome (IBS), there might be no small extent of contributions of psychosomatic factors. As a therapy for IBS patients, the effectiveness of antidepressants has been reported.

Selective adenosine A2A receptor agonist, ATL‐146e, attenuates stress‐induced gastric lesions in rats

Background:  Activation of adenosine A2A receptors reduces the production of various pro‐inflammatory cytokines and suppresses neutrophil activation. Water‐immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress‐induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A2A receptors are known to be anti‐inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A2A receptor agonist, ATL‐146e, on water‐immersion stress‐induced gastric mucosal lesions was studied.

Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Backgroundd-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-α (TNF-α) plays a pivotal role. We examined the effects of a highly selective adenosine A2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure.MethodsMice were given an intraperitoneal dose of GalN (800 mg/g body weight)/LPS (100 ng/g body weight) with and without ATL-146e (0.01 µg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-α levels in the serum were determined.ResultsThe serum liver enzyme (ALT) level in vehicle-treated mice was 20 960 ± 2800 IU/ml and was reduced by 63% to 7800 ± 1670 IU/ml by treatment with 0.01 µg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF-α and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12 h from 65% to 13%.ConclusionThe present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-α secretion.

Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats

BackgroundCilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions.MethodsRats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production.ResultsCilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P < 0.001). The gastric contents of MPO, TNF-α, IL-1β, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol.ConclusionsIn this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats

Background and Aims:  Rolipram  is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro‐inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)‐induced liver injury in rats as a model.

Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates aspirin-induced gastric mucosal injury in rats.

Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCl (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-α and IL-1β after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.

MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism

Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay. Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting. We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2- dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells.

Enhancement of cytoprotective ability and cell restoration in 70-kDa heat shock protein gene-transfected rat gastric mucosal cells: HEAT SHOCK PROTEIN AND CELL SURVIVAL

Many recent studies have indicated the importance of heat shock proteins for cell survival under stress conditions. Some heat shock proteins are known to be involved in cytoprotection against environmental stresses, through their function as ‘molecular chaperones’.

Errors in measuring blood flow velocity behind hepatic mass lesions using color doppler sonography.

The authors designed microcomputer simulation models to investigate the combined effect of a distorted grayscale ultrasound image and an inaccurately measured Doppler angle on the accuracy of measurement of blood-flow velocity in vessels located behind mass lesions in the liver. Error decreased when flow was measured at the midpoint of the posttumoral segment of the vessel and increased with distance between the mass and the vessel, with inclination of the vessel, and with decrease in the diameter of the mass. Error was least with the sector probe, intermediate with the convex probe, and greatest with the linear probe. These findings suggest that the error can be minimized when measuring blood flow velocity in a vessel located behind a mass, if the Doppler images are acquired using a sector probe from the midpoint of the posttumoral segment of the vessel.

Improved Endoscopic Mucosal Resection (EMR) Using Endoscopic Submucosal Dissection (ESD) Method for Colorectal Laterally Spreading Tumors (LSTs)

Double Balloon Enteroscopy (DBE): New Information and Limitations Defined Bradford H. Jones, M.E. Harrison, David E. Fleischer, Nancy L. Maltby, Jonathan A. Leighton Purpose: DBE is a new enteroscope that has the capability to examine most, if not all of the small intestine to aid in the diagnosis and therapy of small intestinal disease. This enteroscope device, which includes an overtube and two balloons, is capable of advancing to the distal ileum by cycling the inflation and deflation of the two balloons with coordinated alternating pushing and retraction of the endoscope and the overtube. The aims of this study include (1) to determine at what point during the procedure it is reasonable to cease advancement of the enteroscope and begin withdrawal; (2) to assess the complications and adverse effects of DBE. Methods: 6 patients underwent DBE. Estimated distance advanced and time elapsed with each balloon cycle of the enteroscope were recorded. Each patient completed a symptom survey 7 days following the procedure. Procedural complications were also recorded. Results: The average distance advanced and time elapsed per balloon cycle are graphed below. The progression per cycle diminished after 12 cycles or approximately 50 minutes into the procedure. Five of 6 (83%) patients reported transient sore throat following DBE. Three of 6 (50%) patients reported abdominal discomfort. In all cases, these symptoms resolved within 72 hours. The only serious complication was a case of pulmonary aspiration. The patient experienced mild hypoxemia that quickly resolved, and she was discharged home after 48 hours of inpatient observation. Conclusions: Our data suggest that the rate of advancement of the DBE diminishes after approximately 12 cycles or 50 minutes, and thus this may be an appropriate time to initiate withdrawal of the scope. This conclusion will be tested as more data is collected regarding the distance advanced and time elapsed with each balloon cycle. The most commonly reported adverse effects of DBE include transient sore throat and abdominal discomfort. Abstracts