Tamotsu Matsuhashi

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.

Induction of a 72-kDa heat-shock protein in cultured rat gastric mucosal cells and rat gastric mucosa by zinc L-carnosine.

An antiulcer drug, zinc l-carnosine (polaprezinc), provides gastric mucosal protection against various irritants. In this study, we evaluated the effects of zinc l-carnosine on expression of 72-kDa heat shock protein (HSP72, stress inducible HSP70), which is known as an endogenous cytoprotectant in a wide variety of cells, including rat gastric mucosa in vitro and in vivo. Expression of HSP72 after exposure to zinc l-carnosine, zinc sulfate, or l-carnosine (1–300 μM) in rat gastric mucosal cells (RGM1) and intragastric administration of zinc l-carnosine, zinc sulfate (30 or 100 mg/kg) and l-carnosine (76 mg/kg) was investigated by western blotting and densitometric analysis. Exposure to zinc l-carnosine and zinc sulfate increased the expression of HSP72 significantly in RGM1 cells. Intragastric administration of zinc l-carnosine and zinc sulfate showed significant increment in HSP72 in rat gastric mucosa also in vivo. The ability to induce HSP72 is significantly higher in zinc l-carnosine compared with zinc sulfate based on molecular concentration in vivo. However, l-carnosine did not increase the expression of HSP72 in vitro and in vivo. Zinc derivatives, especially zinc l-carnosine, could be a strong HSP72 (chaperon) inducer, which has been known to enhance mucosal protective ability.

Large Brunner’s Gland Hyperplasia Treated with Modified Endoscopic Submucosal Dissection

Brunner’s glands are mucosal and submucosal alkalinesecreting glands that are most commonly located in the duodenum, especially in the first part of the duodenum, although they are rarely found in the pylorus and jejunum. Hyperplasia of these glands is normally seen in 2% of upper gastrointestinal (GI) endoscopies [1]. Five percent to 10% of benign duodenal tumors are caused by lesions of Brunner’s gland [2]. They are usually asymptomatic and lesions are discovered incidentally but they can occasionally cause symptoms such as GI hemorrhage and obstruction when they reach sizes >2 cm [3, 4]. In this paper, we report a case of large hyperplasia of Brunner’s gland successfully treated by modified endoscopic submucosal dissection (ESD) technique.

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.

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.

Functional Roles of TGF-β1 in Intestinal Epithelial Cells Through Smad-Dependent and Non-Smad Pathways

Background and AimsTransforming growth factor-β1 (TGF-β1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-β1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells.MethodsWe used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-β1/Smad signaling molecules was examined. We evaluated the effect of TGF-β1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine.ResultsIEC-6 cells produced TGF-β1 and expressed functional TGF-β/Smad signaling molecules. The addition of TGF-β1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts.ConclusionsTGF-β1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways.

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.

Mechanical strain stress suppresses expression of HSP70 and wound restoration in gastric mucosal cells

The major heat shock protein, HSP70, is known to be involved in cytoprotection against environmental stresses mediated by their function as a “molecular chaperone.” However, the influence of HSP70 on gastric mucosal healing under physical stimulation or stress is not completely understood. Rat gastric mucosal cells (RGM-1) were stably transfected with pBK-CMV containing the human HSP70 gene (7018-RGM-1) or pBK-CMV alone (pBK-CMV-12). Artificial wounds were created. Mechanical stretch was applied to 7018-RGM-1 cells or pBK-CMV-12 cells. The effect of mechanical stretch on HSP70 expression was assessed by Western blot analysis. Expression of HSP70 was decreased by mechanical stretch in pBK-CMV-12 cells. However, expression of HSP70 was not decreased by mechanical stretch in 7018-RGM-1 cells. Furthermore, the wound restoration of pBK-CMV-12 cells was suppressed under mechanical stretch condition. On the other hand, the wound restoration of 7018-RGM-1 cells was not affected by mechanical stretch. These results suggest that HSP70 plays an important role in gastric wound healing under physical stress.