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April 1995 - March 2013
Publications
Publications (831)
We investigated the roles of prostaglandins (PGs), nitric oxide (NO) and enterobacteria in a model of ischemic enteritis. Under ether anesthesia, ischemic enteritis was induced in 18 h‐fasted rats by a stenosis in the superior mesenteric artery (SMA) that was produced by placing a needle (23 guage) on the vessel, ligating both the vessel and needle...
Background:
We introduced a rat model of ischemic enteritis and investigated the roles of enterobacteria, nitric oxide (NO), and prostaglandins (PGs) in its pathogenesis.
Methods:
Male rats were used after 18 h of fasting. Ischemic enteritis was induced by partial ligation of the superior mesenteric artery (SMA). Under ether anesthesia, SMA was...
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 inves...
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...
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...
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. Carbacho...
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 epit...
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...
Prostaglandin E2 not only prevents NSAID-generated small intestinal lesions, but also promotes their healing. The protective effects of prostaglandin E2 are mediated by the activation of EP4 receptors and functionally associated with the stimulation of mucus/fluid secretions and inhibition of intestinal hypermotility, resulting in the suppression o...
We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions.
Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restra...
We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats.
Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L A...
Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex...
Aims: The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats. Main methods: The stomach was perfused with acidified ASA at a...
Aims:
The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats.
Main methods:
The stomach was perfused with acidified ASA a...
We examined the effect of H2S on duodenal HCO3- secretion in rats and investigated the mechanism involved in this response. Animals were fasted overnight and anesthetized with urethane. A duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH stat-method. The loop was perfused at a rate of 0.2 mL/min with NaHS...
Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of ClC-2/CFTR chloride channels. We examined the effects of lubiprostone on indomethacin-indu...
We examined the effect of lubiprostone, a bicyclic fatty acid derived from PGE1 and a possible chloride channel type‐2 opener, on indomethacin (IM)‐induced small enteropathy and investigated the mechanisms involved, including the relationship to EP4 receptor. Methods: Male SD rats without fasting were given IM (10 mg/kg) s.c and killed 24 h later t...
Etodolac, a racemic (LR) nonsteroidal anti‐inflammatory drug (NSAID), has higher gastric safety compared to other conventional NSAIDs. However, it remains unknown whether the LR etodolac shows less adverse action in the small intestine. In the present study, we examined the effect of etodolac, both L/R and the enantiomers (S and R) on the gastric a...
We examined the effect of celecoxib, a selective COX‐2 inhibitor, on duodenal HCO3‐ and ulcerogenic responses caused by acid in rats, in comparison with indomethacin and loxoprofen (nonselective COX inhibitors) or SC‐560 (a selective COX‐1 inhibitor). Methods: Male SD rats were used after 18 h fasting. Under urethane anesthesia, the duodenal loop w...
Esophagitis was induced in rats within 3 h by ligating both the pylorus and transitional region between the forestomach and glandular portion under ether anesthesia. This esophageal injury was prevented by the administration of acid suppressants and antipepsin drug and aggravated by exogenous pepsin. Damage was also aggravated by pretreatment with...
Endogenous prostaglandins (PGs) play a role in modulating mucosal integrity and have various functions in the stomach, with E type PGs being the most effective. PGE2 provides gastric cytoprotection against damage induced in rats by HCl/ethanol, indomethacin, or acid back-diffusion after barrier disruption. These effects were mimicked by EP1 agonist...
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications worldwide, but cause damage in the small intestine as well as stomach. Probiotic preparations, especially containing live lactic acid bacteria, have been used for treatment of bowel disturbances such as diarrhea and constipation. In the present study,...
Antisecretory drugs such as histamine H2-receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by NSAIDs. However, it has recently been reported that these drugs exacerbate NSAID-induced small intestinal lesions in rats. Unfortunately, there are few effective agents for...
High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by s...
The extracellular calcium-sensing receptor (CaSR), a G protein-coupled cell receptor cloned from bovine parathyroid, has been demonstrated to play a regulatory role in various functions of the gastrointestinal tract. In the present study, we examined the effect of cinacalcet, a drug that acts as a calcimimetic through the allosteric activation of C...
We examined changes in the expression of a pro-angiogenic factor, vascular endothelial growth factor (VEGF), and an anti-angiogenic factor, endostatin, as well as matrix metalloproteinase (MMP)-2 and MMP-9 in the rat small intestine after administration of indomethacin and investigated the roles of these factors in the healing of indomethacin- indu...
We reviewed the prophylactic effect of monosodium glutamate (MSG), a substance known as the "umami", on NSAID-induced small intestinal damage in rats. Loxoprofen, one of NSAIDs frequently used in Asian countries, given orally at 60 mg/kg, caused hemorrhagic damage in the small intestine, mainly jejunum and ileum, concomitant with a down-regulation...
Background/aims:
The effects of feeding conditions (fasted or fed) and dietary fiber (DF) in the diet on gastrointestinal (GI) damage induced by aspirin (ASA) were examined in cats.
Methods:
Plain ASA (P-ASA, 20 mg/kg) or one enteric-coated ASA tablet (EC-ASA, containing 100 mg ASA) was administered p.o. once daily for 3 or 7 days just after mor...
We set up two models of gastric bleeding in rats using low-dose aspirin (ASA) and the antiplatelet drug clopidogrel, a P2Y12 receptor antagonist, and examined the effect of antiulcer drugs on gastric bleeding and ulcerogenic responses under such conditions. Under urethane anesthesia, two catheters were inserted into the rat stomach, one from the es...
In the present study, we investigated the mechanism responsible for the gender difference in the acid‐induced duodenal HCO3‐ secretion. Male and female SD rats were used after 18 h fasting. Under urethane anesthesia, a proximal duodenal loop was perfused with saline, and HCO3‐ secretion was measured. Mmucosal acidification was performed by exposing...
Nonsteroidal anti‐inflammatory drugs themselves are not only ulcerogenic in the gastrointestinal mucosa but also potentiate the gastric ulcerogenic responses to various stimuli including stress. In the present study, we investigated the roles of COX isozymes/PGs and their receptors in the mucosal defense against cold‐restraint stress‐induced gastri...
Non‐steroidal anti‐inflammatory drugs (NSAIDs) have been reported to be a common cause of small intestinal lesions in humans; however, there are few effective agents for the treatment of this complication. Antisecretory drugs such as histamine H2‐ receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastroint...
In the present study, we examined the effect of cinacalcet, a CaSR agonist, on basal and stimulated gastric acid secretion in mice. Male ddY mice were used after 18 h fasting. Under urethane anesthesia, the stomach was isolated, mounted between two halves of a lucite chamber, and acid secretion was measured at pH 5.0 with 2 mM NaOH using a pH‐stat...
Atrophic gastritis caused by infection with Helicobacter pylori is characterized by parietal cell loss, which is a main risk factor for gastric cancer. Parietal cells play a crucial role in the regulation of cell lineage maturation and proliferation in the gastric units. Among the classical cadherins, E-cadherin plays an important role not only in...
Enterobacteria play important roles in the pathophysiology of small intestinal injuries induced by nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the effects of rebamipide, a gastrointestinal mucoprotective drug, on indomethacin-induced small intestinal injuries, intestinal microbiota, and expression levels of α-defensin 5, which is...
We examined the effect of egualen, a stable azulene derivative, against gastric damage induced by ischemia/reperfusion (I/R), gastric bleeding induced by double antiplatelet therapy with aspirin (ASA) plus clopidogrel, and small intestinal damage generated by loxoprofen, and investigated the possible mechanisms involved in its protective action. Ma...
Background and purpose:
Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5-HT₃ receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of...
Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the...
We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E(2), contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activiti...
Though NSAIDs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the (1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, (2) effect of f...
Irsogladine, a mucosal protective drug, was developed in Japan for the treatment of peptic ulcer disease and acute gastritis. This drug is superior to gefarnate, the same therapeutic category drug, in a randomized, controlled and double-blind clinical study in 1987. The mechanisms of irsogladine's actions are apparently different from those of anti...
Antisecretory drugs such as histamine H(2)-receptor antagonists (H(2)-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects o...
Bisphosphonates (BPPs) were developed as antiresorptive drugs capable of treating diseases related to bone remodeling; however, they have untoward effects including ulceration in the upper gastrointestinal tract and worsen the healing-impairment action of nonsteroidal anti-inflammatory drugs, prescribed in patients with arthritis or osteoporosis. W...
In recent years, there have been significant advances both in understanding the mechanisms involved in gastrointestinal mucosal injury and protection, as well as in the development of successful strategies for prevention and treatment of gastrointestinal injury. Nevertheless, many people worldwide still suffer from gastrointestinal damage.This book...
Serotonin (5-HT) exerts multiple physiological functions not only in the central and peripheral nervous systems but also in the gastrointestinal tract, and these multiple functions are accounted for by a variety of 5-HT receptor subtypes. We investigated the role of 5-HT in the pathogenesis of indomethacin-induced intestinal lesions in mice, in rel...
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, decrease mucosal prostaglandin (PG) E 2 content by inhibiting cyclooxygenase (COX) activity and cause damage in the small intestine. The development of these lesions required the inhibition of both COX-1 and COX-2, because inhibition of COX-1 up-regulated COX-2 expression and PGs...
This article is the review of the recent reports in which a chronic gastric ulcer model, so-called acetic acid ulcer, was used during 2010-2012. Thirteen new papers were published to elucidate the mechanism of ulcer healing using rats and mice. In addition, 11 substances, mainly extracted from plants used for folk medicine and a proton pump inhibit...
In humans, nonsteroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage in the small intestine as well as in the stomach and duodenum. Gastric and duodenal lesions caused by NSAIDs can be effectively treated with antisecretory agents; however, there are few effective agents for the treatment of small intestinal lesions. Therefore, development...
Although antithrombotic therapy plays a central role in the treatment of cardiac disorders and peripheral arterial diseases, recent studies suggest that the risk of upper gastrointestinal bleeding is increased by the concomitant use of anti-platelet drugs with low-dose aspirin. We set up a screening model of gastric bleeding in rats using low-dose...
Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a commo...
Background/Aim: Helicobacter pylori (H. pylori), recognized as the major cause of gastritis and peptic ulcer diseases, has a high activity of urease, resulting in an abnormally high concentration of ammonia (NH 4+) in the stomach of infected patients. In the present study, we investigated whether HYAKUSOGAN, a gastroprotective drug which is a combi...
This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase...
Glutamate is known as the umami substance in the diet and umami taste has been traditionally preferred in East Asian countries. Recent our and others' studies showed that glutamate has potential to protect the gastrointestinal mucosa against noxious agents. In contrast, Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs...
Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouraci...
We reviewed the effect of monosodium glutamate (MSG) on the development and healing of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal lesions in rats. Loxoprofen (60 mg/kg, p.o.) induced lesions in the small intestine within 24 h, accompanied by a decrease of Muc2 expression and an increase in enterobacterial invasion and indu...
We set up a new model of gastric bleeding induced by the luminal perfusion of aspirin (ASA) in rats pretreated with clopidogrel under conditions where acid secretion is stimulated, and examined the effect of antiulcer drugs on the bleeding. Under urethane anesthesia, acid secretion was stimulated by i.v. infusion of histamine (8 mg/kg/h), and two c...
The secretion of HCO3(-) in the duodenum is increased by mucosal acidification, and this process is modulated by gas mediators such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), in addition to prostaglandins (PGs). The secretion is increased by NOR3 (NO donor), NaHS (H2S donor), and CORM-2 (CO donor). The HCO3(-) responses...
Recent advances in endoscopic techniques such as capsule endoscopy have revealed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) often cause mucosal lesions not only in the upper gastrointestinal tract, but also in the small intestine in humans. Gastric and duodenal lesions caused by NSAIDs can be treated with anti-secretory age...