Koga Komatsu

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.

Systemic stress increases serum leptin level.

Background and Aim:  Leptin, the product of the obese (ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water‐immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior.

Cre- loxP -mediated bax gene activation reduces growth rate and increases sensitivity to chemotherapeutic agents in human gastric cancer cells

Dysregulation of apoptosis may be closely related to the development of cancer and its chemoresistance. Overexpression of Bax, an inducer of apoptosis, has led to increased cell death in a variety of cancer cell lines. In this study, we investigated the effect of Bax overexpression in two gastric cancer cell lines, MKN-28 and MKN-45, using a Cre-loxP-mediated inducible expression system. After induction of bax, both cell lines showed decreased proliferation, partially due to increased cell death. Furthermore, Bax-expressing MKN-28 cells were more sensitive to cisplatin. These results indicate that up-regulation of the bax gene may provide a novel strategy for the treatment of gastric cancer.

FR167653, a potent suppressant of interleukin-1 and tumor necrosis factor-alpha production, ameliorates colonic lesions in experimentally induced acute colitis.

Background: Interleukin‐1 (IL‐1) and tumor necrosis factor‐α (TNF‐α) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin‐1 and TNF‐α possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non‐immune cells. FR167653 (C24H18FN5O2.H2SO4.H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL‐1β and TNF‐α production. We hypothesized that the suppression of IL‐1 and TNF‐α induced by FR167653 could effectively attenuate experimentally induced colonic damage.

Gene expression profiling following constitutive activation of MEK1 and transformation of rat intestinal epithelial cells

BackgroundConstitutive activation of MEK1 (caMEK) can induce the oncogenic transformation of normal intestinal epithelial cells. To define the genetic changes that occur during this process, we used oligonucleotide microarrays to determine which genes are regulated following the constitutive activation of MEK in normal intestinal epithelial cells.ResultsMicroarray analysis was performed using Affymetrix GeneChip and total RNA from doxycycline inducible RIEtiCAMEK cells in the presence or absence of doxycycline. MEK-activation induced at least a three-fold difference in 115 gene transcripts (75 transcripts were up-regulated, and 40 transcripts were down-regulated). To verify whether these mRNAs are indeed regulated by the constitutive activation of MEK, RT-PCR analysis was performed using the samples from caMEK expressing RIE cells (RIEcCAMEK cells) as well as RIEtiCAMEK cells. The altered expression level of 69 gene transcripts was confirmed. Sixty-one of the differentially expressed genes have previously been implicated in cellular transformation or tumorogenesis. For the remaining 8 genes (or their human homolog), RT-PCR analysis was performed on RNA from human colon cancer cell lines and matched normal and tumor colon cancer tissues from human patients, revealing three novel targets (rat brain serine protease2, AMP deaminase 3, and cartilage link protein 1).ConclusionFollowing MEK-activation, many tumor-associated genes were found to have significantly altered expression levels. However, we identified three genes that were differentially expressed in caMEK cells and human colorectal cancers, which have not been previously linked to cellular transformation or tumorogenesis.

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.