Koji Takeuchi

Although the morbidity of ulcers is statistically higher in males than females, the mechanism of this difference remains unknown. Recent studies show that duodenal HCO3 - response to mucosal acidification is higher in females than males, and this may be a factor responsible for the sex difference in the mucosal protective mechanisms. In this article, we examined the duodenal HCO3 - responses to various stimuli in male and female rats, including estrogen, and reviewed the mechanisms responsible for the sex difference in the acid-induced HCO3 - secretion. Mucosal acidification was performed by exposing the duodenum to 10 mM HCl for 10 min. PGE2 was administered intravenously, while capsaicin was applied topically to the duodenum for 10 min. Tamoxifen was given s.c. 30 min before the acidification. Ovariectomy was performed 2 weeks before the experiments; half of the animals were given estrogen i.m. after the operation. Mucosal acidification increased duodenal HCO3 - secretion in male rats, and this response was inhibited by indomethacin and sensory deafferentation. Although no sex difference was found in HCO3 - responses to PGE2 and capsaicin, the response to acid was significantly greater in female than male rats. The different HCO3 - response to acid disappeared on ovariectomy, and this effect was totally reversed by the repeated administration of estrogen. The gene expression of ASIC3 in female rats was greater than in male rats and down-regulated by ovariectomy or tamoxifen treatment in an estradiol- dependent manner, while no sex difference was observed in TRPV1 and CFTR expressions. In conclusion, the acid-induced HCO3 - response is greater in female than male rats, and this phenomenon is not due to changes in PGE2 sensitivity or TRPV1/CFTR expressions but may be accounted for by increased expression of ASIC3 on sensory neurons, which is associated with the chronic influence of estrogen.

Objectives Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation that occurs when nonradioactive Boron-10 is irradiated with low-energy neutrons to produce high-energy α particles (10B [n, α] 7Li). Possible complications associated with extended surgical resection render high-grade meningioma (HGM) a challenging pathology and skull-base meningiomas (SBMs) even more challenging. Lately, we have been trying to control HGMs using BNCT. This study aims to elucidate whether the recurrence and outcome of HGMs and SBMs differ based on their location. Design Retrospective review. Setting Osaka Medical College Hospital and Kyoto University Research Reactor Institute. Participants Between 2005 and 2014, 31 patients with recurrent HGM (7 SBMs) were treated with BNCT. Main Outcome Measures Overall survival and the subgroup analysis by the anatomical tumor location. Results Positron emission tomography revealed that HGMs exhibited 3.8 times higher boron accumulation than the normal brain. Although tumors displayed transient increases in size in several cases, all lesions were found to decrease during observation. Furthermore, the median survival time of patients with SBMs post-BNCT and after being diagnosed as high-grade were 24.6 and 67.5 months, respectively (vs non-SBMs: 40.4 and 47.5 months). Conclusions BNCT could be a robust and beneficial therapeutic modality for patients with high-grade SBMs.

We examined the influence of adrenalectomy on NSAID-induced small intestinal damage in rats and investigated the possible involvement of adrenal glucocorticoids in the protective effects of urocortin I, a corticotropin-releasing factor (CRF) agonist. Male SD rats without fasting were administered indomethacin s.c. and killed 24 h later in order to examine the hemorrhagic lesions that developed in the small intestine. Urocortin I (20 µg/kg) was given i.v. 10 min before the administration of indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin (10 mg/kg) caused multiple hemorrhagic lesions in the small intestine, which were accompanied by a decrease in mucus secretion and increases in intestinal motility, enterobacterial invasion, and iNOS expression. Adrenalectomy markedly increased the ulcerogenic and motility responses caused by indomethacin, with further enhancements in bacterial invasion and iNOS expression; severe lesions occurred at 3 mg/kg, a dose that did not induce any damage in sham-operated rats. This worsening effect was also observed by the pretreatment with mifepristone (a glucocorticoid receptor antagonist). Urocortin I prevented indomethacin-induced enteropathy, and this effect was completely abrogated by the pretreatment with astressin 2B, a CRF2 receptor antagonist, but was not significantly affected by either adrenalectomy or the mifepristone pretreatment. These results suggested that adrenalectomy aggravated the intestinal ulcerogenic response to indomethacin, the intestinal hypermotility response may be a key element in the mechanism for this aggravation, and endogenous glucocorticoids played a role in intestinal mucosal defense against indomethacin-induced enteropathy, but did not account for the protective effects of urocortin I, which were mediated by the activation of peripheral CRF2 receptors.

We herein investigated, using a corticotropin-releasing factor (CRF) agonist and antagonists, whether CRF plays a role in the pathogenesis of ischemia/reperfusion-induced small intestinal lesions in rats. Under pentobarbital anesthesia, the superior mesenteric artery was clamped (ischemia) for 75 min, followed by reperfusion with removal of the clamp. After a 24-h reperfusion, the area of hemorrhagic lesions that developed in the small intestine was measured. Urocortin I (CRF receptor 1/2 agonist), astressin (CRF receptor 1/2 antagonist), NBI27914 (CRF receptor 1 antagonist), or astressin 2B (CRF receptor 2 antagonist) was administered i.v. twice: 5 min before ischemia and 6 hours after reperfusion. Ischemia/reperfusion caused hemorrhagic lesions in the small intestine in ampicillin- and aminoguanidine-inhibitable manners, accompanied by enterobacterial invasion and the up-regulation of inducible nitric oxide synthase expression and myeloperoxidase activity. The severity of ischemia/reperfusion-induced lesions was significantly reduced by astressin and astressin 2B, but not by NBI27914, with the suppression of bacterial invasion, myeloperoxidase activity, and inducible nitric oxide synthase expression. In contrast, urocortin I markedly aggravated these lesions, and this response was completely abrogated by the co-administration of astressin 2B, but not NBI27914. The gene expression of CRF, CRF receptor 1, and CRF receptor 2 was observed in the small intestine, and remained unchanged following ischemia/reperfusion. These results suggest that ischemia/reperfusion caused hemorrhagic lesions in the small intestine, the pathogenesis of which involved enterobacteria and inducible nitric oxide synthase/nitric oxide. These lesions were aggravated by urocortin I in an astressin 2B-inhibitable manner, but suppressed by astressin in a CRF receptor 2-dependent manner. Endogenous CRF may be involved in the pathogenesis of ischemia/reperfusion-induced enteritis, possibly via the activation of peripheral CRF receptor 2.

Background/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1~M5), and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. In the present study, we demonstrated, using M1~M5 KO mice, the importance of M4 receptors in carbachol (CCh) stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors. Methods: C57BL/6J mice of wild-type (WT) and M1-M5 KO were used. Under urethane anesthesia, acid secretion was measured in the stomach equipped with an acute fistula. CCh (30 µg/kg) was given s.c. to stimulate acid secretion. Atropine or octreotide (a somatostatin analogue) was given s.c. 20 min before the administration of CCh. CYN154806 (a somatostatin SST2 receptor antagonist) was given i.p. 20 min before the administration of octreotide or CCh. Results: CCh caused an increase of acid secretion in WT mice, and the effect was totally inhibited by prior administration of atropine. The effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KO mice. CYN154806, the SST2 receptor antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Octreotide, the somatostatin analogue, inhibited the secretion of acid under CCh-stimulated conditions in WT mice. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. Serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions, while those in WT mice were significantly decreased in response to CCh. Conclusions: These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors. It is assumed that the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect of somatostatin through SST2 receptors, resulting in enhancement of the acid response mediated by M3 receptors on parietal cells.

We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E₂, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wild-type mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin-sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE₂ produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases.

We investigated the roles of muscarinic (M) acetylcholine receptor subtype in the cholinergic stimulation of duodenal HCO3(-) secretion using knockout (KO) mice. Wild-type and M1-M5 KO C57BL/6J mice were used. The duodenal mucosa was mounted on an Ussing chamber, and HCO3(-) secretion was measured at pH 7.0 using a pH-stat method in vitro. Carbachol (CCh) or other agents were added to the serosal side. CCh dose-dependently stimulated HCO3(-) secretion in wild-type mice, and this effect was completely inhibited in the presence of atropine. The HCO3(-) response to CCh in wild-type mice was also inhibited by pirenzepine (M1 antagonist), 4DAMP (M3 antagonist), and tropicamide (M4 antagonist), but not by methoctramine (M2 antagonist). CCh stimulated HCO3(-) secretion in M2 and M5 KO animals as effectively as in WT mice; however, this stimulatory effect was significantly attenuated in M1, M3, and M4 KO mice. The decrease observed in the CCh-stimulated HCO3(-) response in M4 KO mice was reversed by the co-application of CYN154806, a somatostatin receptor type 2 (SST2) antagonist. Octreotide (a somatostatin analogue) decreased the basal and CCh-stimulated secretion of HCO3(-) in wild-type mice. The co-localized expression of somatostatin and M4 receptors was confirmed immunohistologically in the duodenum. We concluded that the duodenal HCO3(-) response to CCh was directly mediated by M1/M3 receptors and indirectly modified by M4 receptors. The activation of M4 receptors was assumed to inhibit the release of somatostatin from D cells and potentiate the HCO3(-) response by removing the negative influence of somatostatin via the activation of SST2 receptors.

Monosodium glutamate (MSG) is known to provide the umami taste in the food. We have recently reported that glutamate has the potential to protect the small intestine against non-steroidal anti-inflammatory drugs (NSAIDs)-induced lesions in rats. In this paper, we examined this protective effect using sodium loxoprofen, one of the NSAIDs frequently used in Asian countries, to determine whether MSG accelerates the healing of loxoprofen-induced small intestinal lesions in rats. Loxoprofen at 60 mg/kg caused hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. These lesions spontaneously healed within 7 days, but this healing process was delayed by repeated administration of loxoprofen at low doses (10, 30 mg/kg) for 5 d after lesion induction. The healing-impairment action of loxoprofen was accompanied by the down-regulation of vascular endothelium-derived growth factor (VEGF) expression and an angiogenic response. The impaired healing caused by loxoprofen was significantly restored by co-treatment with a diet containing 5% MSG for 5 d, accompanied by the enhancement of VEGF expression and angiogenesis. We suggest that daily intake of MSG not only protects the small intestine against NSAIDs-induced damage but also exerts healing-promoting effects on these lesions.

Background/Aims: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. Methods: Studies were performed in experimental animals. Results: Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE₂, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. Conclusion: These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs.