Masaru Odashima

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.

Association of 72-kDa heat shock protein expression with adaptation to aspirin in rat gastric mucosa

It is well documented that gastric mucosa canincrease its resistance to mucosal damage caused byaspirin during repeated long-term administration ofaspirin. However, the underlying mechanism of thisadaptation is not well established. In the present study,we investigated the effect of long-term (chronic)administration of aspirin on expression of heat shockproteins (HSPs), which are known as endogenouscytoprotectants, in rat gastric mucosa. Rats were administeredaspirin (100 mg/kg) daily for up to 20 days. Aftervarious periods of aspirin administration, a high doseof aspirin (250 mg/kg) was administered, and the mucosal damage was assessed. Expression of heat shockproteins (HSPs) in gastric mucosa was evaluated byWestern blot. Intracellular localization of each HSP wasstudied immunohistochemically. ProstaglandinE2 (PGE2) and leukotriene B4(LTB4) levels were also investigated.Long-term aspirin administration resulted in developmentof resistance to aspirin-induced mucosal damage, and theincrease of HSP72 expression correlated with mucosal resistance to aspirin.No significant increase was observed in HSP60 and HSP90levels. Immunohistochemical study showed an increase ofHSP72 in the cytoplasm of mucosal surface cells. The PGE2 level was suppressed and nochange in the level of LTB4 was observed. Itis possible that HSP72 could play important roles ingastric mucosal adaptation when the PGE2level is suppressed by NSAIDs.

Differential Induction of HSP60 and HSP72 by Different Stress Situations in Rats (Correlation with Cerulein-Induced Pancreatitis)

We previously reported that water-immersionstress specifically induced the synthesis of a 60-kDaheat-shock protein (HSP60, chaperonin homolog) inpancreatic cells and preinduction of HSP60 completely prevented development of cerulein-inducedpancreatitis in the rat in an HSP60 quantitativelydependent manner. In order to study the cytoprotectivefunction of a 72-kDa heat-shock protein (HSP72,stress-inducible hsp70), the effect of specific preinduction ofHSP72 by hyperthermia on cerulein-induced pancreatitiswas investigated and compared with the effect ofpreinduction of HSP60 in this study. Expression of HSP60 and HSP72 in the pancreas wasinvestigated by immunoblot before and after waterimmersion or hyperthermia. Following pretreatment withwater-immersion stress or hyperthermia, the rats wereinjected with cerulein (40 μg/kg, intraperitoneally).The pancreas wet weight and serum amylase concentrationwere measured before and after cerulein injection.Hyperthermia (42.5°C, 20 min) specifically induced HSP72 in the pancreas. The synthesis of HSP60was specifically induced by water-immersion stress inthe pancreas. Cerulein-induced pancreatitis was clearlyprevented by specific preinduction of HSP60 by water-immersion stress. However, preinductionof HSP72 by hyperthermia had no preventive effect oncerulein-induced pancreatitis. Our findings suggest thatHSP60 and HSP72 have distinct functions in the pancreas, and their induction mechanisms arealso different in vivo. These results could be importantfor understanding the mechanism of “adaptivecytoprotection” in the pancreas mediated byheat-shock proteins.

Disseminated intra-abdominal cystic lymphangiomatosis with severe intestinal bleeding. A case report.

We describe cystic lymphangiomatosis with intestinal bleeding developing multiple lymphangiomas in the small intestine, mesentery, mesocolon, omentum, retroperitoneum, and spleen. Small intestinal fluorography showed multiple polypoid lesions, mainly in the jejunum. Ultrasonography, computed tomography, and magnetic resonance imaging showed diffuse cystic tumors in the mesentery and spleen. Cystic lymphangiomatosis was proved by histologic findings of the biopsied specimen at laparotomy.

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats

BackgroundPortal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats.MethodsPHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6 N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups.ResultsPortal venous pressure was significantly higher in cirrhotic rats compared with control rats (P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress.ConclusionsThese findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.

Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

Background and Aims:  Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L‐carnosine, an anti‐ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG.

Induction of a 72-kDa heat shock protein and protection against lipopolysaccharide-induced liver injury in cirrhotic rats

Background and Aim:  A 70‐kDa heat shock protein (stress‐inducible HSP70, HSP72) has been reported to be a cytoprotectant in a variety of organs. It has been reported that HSP72 protected non‐cirrhotic rats against endotoxemia. However, its cytoprotective effect against endotoxemia in cirrhotic rats has not yet been studied. In this study, we investigated the cytoprotective effect of HSP72 on lipopolysaccharide (LPS)‐induced liver injury in carbon tetrachloride (CCl4)‐induced cirrhotic rats.

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

AIMS With 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. MAIN METHODS cDNA 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. KEY FINDINGS Cell 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. CONCLUSION These 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. SIGNIFICANCE These 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.

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.