bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of rebamipide on prostaglandin receptors‐mediated increase of inflammatory cytokine production by macrophages
Authors: Bamba H. , Ota S. , Kato A. , Miyatani H. , Kawamoto C. , Yoshida Y. , Fujiwara K. 
Published: August 2003

SummaryBackground : Rebamipide (Reb) is an anti‐ulcer drug, and has unique properties such as anti‐inflammatory action. We previously reported that prostaglandins (PGs) dramatically increased vascular endothelial growth factor (VEGF), a known angiogenic factor and a vascular permeable factor, by activated macrophages through specific PGE receptor and peroxisome proliferator‐activated receptor γ (PPARγ, a nuclear receptor of PG) mediated process. Effects of PGs on the production of other cytokines such as interleukin (IL)‐6 and IL‐8 have been controversial.Aim : To clarify the anti‐inflammatory roles of Reb, we examined the effect of Reb on PGE1‐ and 15‐deoxy‐Δ12, 14‐PGJ2 (a potent PPARγ ligand, 15d‐PGJ2) ‐induced increase of VEGF production by macrophages. Additionally, effects of these PGs on the production of IL‐6 and IL‐8, and modulation of these actions by Reb were studied.Methods : Phorbol 12‐myristate 13‐acetate‐differentiated U937 cells were used as a human macrophage model (H‐Mac). VEGF, IL‐6, IL‐8 and cAMP were measured by EIA.Results : Reb suppressed PGE1‐, but not 15d‐PGJ2‐, induced increase of VEGF production partially through decrease of cAMP formation. Reb suppressed PGE1 ‐, but not 15d‐PGJ2‐, induced increase of IL‐6 and IL‐8 production.Conclusion : Reb suppresses membrane, but not nuclear PG receptors mediated increase of inflammatory cytokine production, which may be involved in anti‐ulcer action of this drug.
Up‐regulation of TFF expression by PPARγ ligands in gastric epithelial cells
Authors: Shimada T. , Koitabashi A. , Kuniyoshi T. , Hashimoto T. , Yoshiura K. , Yoneda M. , Hiraishi H. , Terano A. 
Published: August 2003

SummaryBackground : Although trefoil factor family peptides (TFF peptides) are assumed to play important roles in gastric mucosal protection, the regulatory mechanism of gastric TFF expression has not been fully understood yet. Recent reports showed gastric expression of peroxisome proliferator‐activated receptor γ (PPARγ), a nuclear receptor known to be involved in the regulation of cell growth and differentiation in other cell types, such as adipocytes.Aim : To determine whether PPARγ affects the expression of TFF in gastric epithelial cells.Methods : MKN45 gastric cells were used as a model of gastric epithelial cells. DNA synthesis of the cells was determined by the measurement of BrdU incorporation. The effects of PPARγ ligands, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) and troglitazone (TGZ) on TFF expression were assessed by real‐time quantitative reverse transcription‐polymerase chain reaction (RT‐PCR).Results : MKN45 cells expressed a significant amount of PPARγ. Both 15d‐PGJ2 and TGZ suppressed DNA synthesis of the cells in a dose‐dependent manner. In the control condition, MKN45 cells most abundantly expressed TFF1 and the relative expression level of TFF1, TFF2, and TFF3 mRNA was 1700:32:1. TFF1 and TFF2 mRNA levels were significantly up‐regulated by the incubation of the cells with 15d‐PGJ2 (10 µm) or TGZ (30 µm), whereas TFF3 mRNA level was not affected.Conclusion : The results of the present study suggest a possible role of PPARγ in the regulation of TFF expression in gastric epithelial cells.
The protective effect of rebamipide on paracellular permeability of rat gastric epithelial cells
Authors: Joh T. , Takezono Y. , Oshima T. , Sasaki M. , Seno K. , Yokoyama Y. , Ohara H. , Nomura T. , Alexander J. S. , Itoh M. 
Published: August 2003

SummaryBackground : Barrier function in gastric epithelial cells is essential for the gastric defence mechanism against acid back‐diffusion into the mucosal layer. Our previous study indicated that trans‐epithelial resistance (TER) of rat gastric epithelial cells was rapidly increased when the cells were exposed to acid. This response to acid was diminished by indometacin.Aim : Evaluate the effects of a mucoprotective agent, rebamipide, on the nonsteroidal anti‐inflammatory drug (NSAID)‐induced increase of gastric epithelial permeability.Methods : Rat gastric epithelial cells were plated on tissue culture inserts. Cells were exposed to a NSAID (indometacin, 10−7 M). Trans‐epithelial permeability was measured by TER and diffusion rate of 14C‐mannitol. The effect of rebamipide was evaluated by measuring TER. Endogenous prostaglandin E2 (PGE2) production in culture medium was also measured.Results : Indometacin gradually and significantly decreased TER and increased 14C‐manitol permeability. Rebamipide reversed the indometacin‐induced changes in epithelial permeability and induced PGE2 synthesis. This induction was blocked by either indometacin or a Cyclooxygenase (COX)‐2 specific inhibitor.Conclusions : COX inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing PGE2. COX‐1 has an important role in the gastric defense mechanism. Rebamipide suppressed an indometacin‐induced increase in gastric epithelial permeability by increasing PGE2 levels in a COX‐2 dependent manner.
Effects of antioxidative agents on apoptosis induced by ischaemia‐reperfusion in rat intestinal mucosa
Authors: Kojima M. , Iwakiri R. , Wu B. , Fujise T. , Watanabe K. , Lin T. , Amemori S. , Sakata H. , Shimoda R. , Oguzu T. , Ootani A. , Tsunada S. , Fujimoto K. 
Published: August 2003

SummaryBackground & aim : We have previously demonstrated that ischaemia‐reperfusion induces apoptosis in the intestinal mucosa. To evaluate that reactive oxygen species enhanced intestinal apoptosis after ischaemia‐reperfusion, we examined whether antioxidants reduced apoptosis.Methods : Rats were infused through a duodenal tube with antioxidative agents, glutathione, rebamipide and dymethylsulfoxide during 2 h before an ischaemic insult. The superior mesenteric artery was occluded for 60 min, followed by 60 min reperfusion. Apoptosis was evaluated by percentage fragmented DNA (fragmented DNA/total DNA) and immunochemical staining.Results : Increase in apoptosis in the intestinal mucosa after ischaemia‐reperfusion was attenuated by intraduodenal infusion of antioxidative agents, but was not completely abolished.Conclusion : Scavenging effects of the antioxidative agents attenuated increases in intestinal apoptosis, indicating that oxidative stress after ischaemia‐reperfusion plays an important role in induction of apoptosis in the intestinal mucosa.
Review article: clinical significance of mucosal‐protective agents: acid, inflammation, carcinogenesis and rebamipide
Authors: Haruma K. , Ito M. 
Published: August 2003

SummaryWhile a great deal of clinical evidence has been found regarding anti‐acids for the treatment of gastric disorders including peptic ulcers, not all disorders can be explained only by the hyperfunction of acid secretion. Especially in the Asian region, glandular atrophy is more prominent than in Western countries, therefore low acid output is often observed in these patients. Improvement of mucosal protection is rational therapy for these patients; this is the reason for use of these agents in Asian countries. Rebamipide has many biological activities for gastric mucosa such as increasing the blood flow and biosynthesis prostaglandins and the decrease of oxygen radicals. These suggest the possible efficacy of rebamipide in the prevention of both Helicobacter pylori‐related and nonsteroidal anti‐inflammatory drug (NSAID)‐induced gastric injury, which has been proved by human studies. Rebamipide is the only mucosal‐protective drug which can improve the histological gastritis in vivo, whereas anti‐acids have a lesser effect in influencing gastritis. Improvement of gastritis is expressed not only in quantity but also in quality of gastritis, which is shown as the reduction of iNOS expression in the gastric mucosa. Clinically, it is suggested that rebamipide has the potential to prevent gastric carcinogenesis by improvement of histological gastritis.
Comparison of the effects of rebamipide with those of cimetidine on chronic gastritis associated with Helicobacter pylori in Mongolian gerbils
Authors: Higuchi K. , Tanigawa T. , Hamaguchi M. , Takashima T. , Sasaki E. , Shiba M. , Tominaga K. , Fujiwara Y. , Oshitani N. , Matsumoto T. , Watanabe T. , Arakawa T. 
Published: August 2003

SummaryBackground and Aims : The effects of rebamipide on chronic gastritis associated with Helicobacter pylori have not been well‐defined. We compared these effects of rebamipide with those of cimetidine in Mongolian gerbils infected with H. pylori.Methods : Mongolian gerbils with or without H. pylori were divided into 10 groups 6 weeks after inoculation and fed diets containing a drug (rebamipide or cimetidine) or control diet. All animals were sacrificed 4 weeks after grouping. Their stomachs were examined for histology, colonization by H. pylori, myeloperoxidase activity (myeloperoxidase), production of neutrophil chemokine (CINC/KC) and tumour necrosis factor‐α (TNF‐α), and serum gastrin levels.Results : H. pylori colonized all of the inoculated animals. Neither rebamipide nor cimetidine decreased myeloperoxidase activity, but each reduced wet stomach weight in H. pylori‐infected animals. The amount of increase in CINC/KC and TNF‐α in gastric tissue caused by H. pylori infection was decreased by treatment with rebamipide or cimetidine. H. pylori infection increased serum gastrin levels, and this increase was significantly enhanced by cimetidine but not rebamipide.Conclusions : Rebamipide may improve H. pylori‐infected chronic gastritis by preventing the production of inflammatory cytokines and chemokines, as does cimetidine, but may be preferable to cimetidine for long‐term administration for treatment of H. pylori‐infected chronic gastritis due to its effect on serum gastrin levels.
Gastric restitution is inhibited by dexamethasone, which is reversed by hepatocyte growth factor and rebamipide
Authors: Takahashi M. , Takada H. , Takagi K. , Kataoka S. , Soma R. , Kuwayama H. 
Published: August 2003

SummaryBackground : Glucocorticoids have been shown to induce peptic ulcers, especially when co‐administered with NSAIDs. Hepatocyte growth factor (HGF) plays a role in gastric ulcer repair, facilitating the restitution of gastric mucosal epithelial cells. HGF expression is induced by PGs in gastric fibroblasts. We hypothesized that dexamethasone (DEX) may inhibit PG production and HGF expression, thus inhibiting HGF‐induced gastric epithelial restitution.Aim : To investigate the effect of DEX on gastric restitution, using cultured gastric cells, the role of HGF in the restitution inhibited by DEX, and the effect of rebamipide on DEX‐ inhibited restitution.Methods : Human gastric fibroblasts were prepared from human stomach obtained at surgery; PGE2 and HGF is determined by ELISA; Restitution was assessed by the round wound restitution model, using coculture of gastric fibroblasts and epithelial cells; COX‐2 and HGF mRNA were quantified by TaqMan RT‐PCR system.Results : 1. DEX inhibited HGF mRNA and COX‐2 mRNA. Accordingly, it inhibited PGE2 and HGF release. 2. DEX inhibited the restitution of gastric cells. 3. The inhibition of restitution was reversed by HGF and rebamipide to the same extent. 4. Rebamipide induced PGE2 and HGF.Conclusion : DEX inhibits restitution via HGF depletion, and rebamipide reverses the inhibited restitution by HGF induction.
The effects of cure of Helicobacter pylori infection on the signal transduction of gastric epithelial cells
Authors: Azuma T. , Yamazaki S. , Yamakawa A. , Ito Y. , Ohtani M. , Dojo M. , Yamazaki Y. , Higashi H. , Hatakeyama M. 
Published: August 2003

SummaryBackground : The CagA protein of Helicobacter pylori is directly injected from the bacteria into cells via the bacterial type IV secretion system and undergoes tyrosine phosphorylation in the gastric epithelial cells. Translocated CagA forms a physical complex with the SRC homology 2 domain (SH2)‐containing tyrosine phosphatase SHP‐2, which plays an important role in mitogenic signal transduction in the host cells.Aim : We examined the effect of eradication therapy on the signal transduction pathway of gastric epithelial cells induced by the CagA protein of H. pylori.Methods : Gastric biopsy samples were obtained from 20 H. pylori‐positive atrophic gastritis patients before, and 3 months after, H. pylori infection eradication therapy, and subjected to immunoblot analysis to detect tyrosine phosphorylated CagA protein and CagA co‐immunoprecipitated endogenous SHP‐2.Results : Tyrosine phosphorylated CagA protein and CagA co‐immunoprecipitated endogenous SHP‐2 were detected in the gastric mucosa from H. pylori‐positive atrophic gastritis patients. All H. pylori strains from these patients were cagA‐positive type I strains. After curing H. pylori infection, the tyrosine phosphorylated CagA protein and CagA co‐immunoprecipitated endogenous SHP‐2 disappeared from the gastric mucosa.Conclusion : The cure of infection reduces the stimulated signal transduction of gastric epithelial cells by the translocated CagA protein of H. pylori, and may confer a beneficial effect on the reduction of cancer risk.
Effects of rebamipide, a gastro‐protective drug on the Helicobacter pylori status and inflammation in the gastric mucosa of patients with gastric ulcer: a randomized double‐blind placebo‐controlled multicentre trial
Authors: Fujioka T. , Arakawa T. , Shimoyama T. , Yoshikawa T. , Itoh M. , Asaka M. , Ishii H. , Kuwayama H. , Sato R. , Kawai S. , Takemoto T. , Kobayashi K. 
Published: August 2003

SummaryAims : To investigate the effects of rebamipide on the Helicobacter pylori eradication rate with amoxicillin and omeprazole. The trial also examined its histological effects on gastro‐mucosal inflammation after eradication.Methods : Two hundred and six H. pylori‐positive patients with active gastric ulcer underwent 8‐week based therapy (OA) consisting of 2‐week amoxicillin with omeprazole and subsequent 6‐week omeprazole. They randomly received either rebamipide (OA‐R) or placebo (OA‐P) for 16 weeks: combined with the OA based therapy, and subsequently for another 8 weeks. Besides eradication rate, inflammatory findings of gastric mucosa after eradication were evaluated histologically.Results : Per Protocol Set analysis showed no significant difference in eradication rate between OA‐R (64.6%; 95% confidence interval, 54.3–75.0%) and OA‐P (67.9%; 95% CI, 57.6–78.3%). Histological findings in the gastric mucosa of the ulcer region, however, indicated a significant improvement (P = 0.017) in inflammation scores in OA‐R (1.84 ± 0.41) compared with that in OA‐P (2.02 ± 0.39) after 16‐weeks of treatment. This suppressive effect on inflammation was observed even in the OA‐R patients unsuccessfully eradicated.Conclusion : Rebamipide demonstrated a suppressive effect on the persistent and possibly chronic inflammation in the gastric mucosa of the ulcer region after eradication, but the drug did not improve the eradication rate.
Review article: inflammation‐related promotion of gastrointestinal carcinogenesis – a perigenetic pathway
Authors: Tsuji S. , Kawai N. , Tsujii M. , Kawano S. , Hori M. 
Published: August 2003

SummaryChronic inflammation has been reported to accelerate neoplasmas in gastrointestinal tract. Certain bacteria including Helicobacter pylori directly interact with host cells, induce proinflammatory cytokines and stimulate production of free radicals. Free radicals cause mutations in target cells so that neoplastic clones are established. Accumulation of such genetic alterations may cause malignant transformation of some established clones. In addition, inflammatory alterations may promote growth, expansion and invasion of gastrointestinal epithelial cells. The latter changes caused by inflammation may occur even without further genetic mutations or epigenetic alterations, and therefore may be categorized as ‘perigenetic alterations’ of neoplastic cells. For an example, tumour necrosis factor α (TNF‐α) plays pivotal roles not only in the reduction but also in the growth, invasion and metastases of certain neoplasmas. Our studies show that TNF‐α increases intracellular radical production, degradates E‐cadherin / β‐catenin complex and promotes dispersion and migration in epithelial cells transformed with an activated src oncogene (v‐src). These data indicate that an inflammatory cytokine induces the malignant potential of src‐activated neoplastic cells. Interestingly, TNF‐α also induced these phenotypic changes in nonmutated cells whose c‐Src was activated by TGF‐α, suggesting that the invasive properties of the cell were not necessarily related to gene mutation. Furthermore, certain radical scavengers suppressed the invasive phenotype of the cells. These results indicate that perigenetic alterations are an important target of pharmacological intervention of carcinogenesis.
Effect of long‐term administration of rebamipide on Helicobacter pylori infection in mice
Authors: Hahm K. B. , Kim D. H. , Lee K. M. , Lee J. S. , Surh Y. J. , Kim Y. B. , Yoo B. M. , Kim J. H. , Joo H. J. , Cho Y. K. , Nam K. T. , Cho S. W. 
Published: August 2003

SummaryBackground : It has been suggested that chronic, persistent, uncontrolled inflammations in the stomach could provide the basic step for the beginning of carcinogenesis. One of the potential clinical applications of rebamipide is the inhibition of the immunoinflammatory response in gastric mucosa imposed by Helicobacter pylori.Aim : To determine the implications of long‐term rebamipide treatment in H. pylori infection, we studied the underlying moleculo‐pathological changes in gastric lesions in mice infected with H. pylori (SS1 strain), following this treatment.Methods : C57BL/6 mice were sacrificed 24 and 50 weeks after H. pylori infection, respectively. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels of IL‐1β, TNF‐α, IFN‐γ and IL‐10, mRNA transcripts of various mouse cytokines and chemokines, and NF‐κB binding activities, and finally the presence of gastric adenocarcinoma were compared between an H. pylori infected group (HP), and an H. pylori infected group administered with long‐term rebamipide‐containing pellet diets (HPR).Results : Serum levels of IL‐1β, IFN‐γ and TNF‐α, the gastric mucosal expression of ICAM‐1, HCAM and MMP, and transcriptional regulation of NF‐κB‐DNA binding were all significantly decreased in the HPR group compared with the HP group. An RNase protection assay showed, in the rebamipide administered group, significantly decreased mRNA levels of apoptosis‐related genes such as caspase‐8, FasL, Fas, TRAIL and various cytokines genes such as IFN‐γ, RANTES, TNF‐α, TNFR p75, IL‐1β. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not different in either group. However, long‐term administration of rebamipide showed the advantage of decreasing precancerous lesions like chronic atrophic gastritis and showed molecular evidence of attenuation of proliferation.Conclusion : The long‐term administration of rebamipide should be considered in the treatment of H. pylori since it demonstrated molecular and biological advantages like a lessening of gastric inflammation and a possible chemopreventive effect.
Long‐term evaluation of mice model infected with Helicobacter pylori: focus on gastric pathology including gastric cancer
Authors: Kim D. H. , Kim S. W. , Song Y. J. , Oh T. Y. , Han S. U. , Kim Y. B. , Joo H. J. , Cho Y. K. , Kim D. Y. , Cho S. W. , Kim M. W. , Kim J. H. , Hahm K. B. 
Published: August 2003

SummaryBackground : Long‐term evaluation of gastric pathology after H. pylori infection is very important in order to reveal its clinical implications, since debate still exists on the gastric carcinogenesis provoked by H. pylori infection in animal models.Aim : Either to evaluate the long‐term outcome of H. pylori infection or to determine how H. pylori could provoke gastric cancer in the mice model.Methods : Four‐week‐old specific pathogen free C57BL/6 mice (n = 115) were infected with SS1, the mouse‐adapted H. pylori strain. After 4, 8, 16, 24, 36, 50 and 80 weeks of bacterial infection, the H. pylori‐infected mice were sacrificed.Results : After 80 weeks of infection, almost all the H. pylori‐infected mice developed hyperplastic gastritis, but did not show any evidence of gastric adenoma, dysplasia or carcinoma. PCNA positive cells were most abundant after 50 weeks and tended to decrease thereafter up to 80 weeks, whereas apoptosis began to be noted 8 weeks after H. pylori infection, showing 7–8 apoptotic cells/high power field, and tending to increase as time passed. Normally observed neutral mucin decreased during the experiment, showing the most marked decrease 50 weeks after H. pylori infection. In contrast, acidic mucin was noted from 50 weeks after infection.Conclusion : The SS1‐infected mouse seems to be a suitable animal model for H. pylori‐related research, and H. pylori itself does not induce gastric cancer in normal wild‐type mouse model following long‐term exposure, which could be explained by the balance that exists between cell proliferation and apoptosis.
The effect of rebamipide on Helicobacter pylori extract‐mediated changes of gene expression in gastric epithelial cells
Authors: Yoshida N. , Ishikawa T. , Ichiishi E. , Yoshida Y. , Hanashiro K. , Kuchide M. , Uchiyama K. , Kokura S. , Ichikawa H. , Naito Y. , Yamamura Y. , Okanoue T. , Yoshikawa T. 
Published: August 2003

SummaryBackground : Recent studies have shown that Helicobacter pylori affects intracellular signal transduction in host cells, leading to the activation of transcriptional factors and the induction of pro‐inflammatory cytokines. On the other hand, rebamipide, an anti‐gastritis and anti‐ulcer agent, could scavenge reactive oxygen species and reduce interleukin‐8 (IL‐8) expression in gastric epithelial cells induced by H. pylori‐stimulation through the attenuated activation of nuclear factor‐κB (NF‐κB).Aims : In this study, we investigated the effects of rebamipide on gene expression in H. pylori‐stimulated epithelial cells using DNA chip.Methods : H. pylori water extract (HPE) was prepared from NCTC11637, the type strain of H. pylori. Total RNA was extracted from MKN45 cells, a human gastric cancer cell line, following HPE‐stimulation with and without rebamipide for 3 h, and differences in gene expression profiles were observed using GeneChip and Human 6800 probe array.Results : The GeneChip analysis demonstrated that 132 up‐regulated genes and 873 down‐regulated genes, such as growth factors, chemokines and transcription factors, were detected in MKN45 cells 3 h after stimulation of H. pylori. Among them, several genes, including bFGF, RANTES and MIP‐2β, were previously unknown to be expressed in H. pylori‐stimulated human gastric cells. Rebamipide reduced expression of 119 genes encoding cytokines, growth factors and their receptors and transcription factors.Conclusions : These findings suggest that rebamipide could inhibit inflammatory reactions and tumour progression by modifying H. pylori infection‐induced gene expression in gastric epithelial cells.