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Dive into the research topics where Hitoshi Tsugawa is active.

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Featured researches published by Hitoshi Tsugawa.


Oncogene | 2009

Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells.

Yoshimasa Saito; Hidekazu Suzuki; Hitoshi Tsugawa; I Nakagawa; Juntaro Matsuzaki; Yae Kanai; Taizo Hibi

Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2′-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer.


Journal of Clinical Biochemistry and Nutrition | 2011

Roles of oxidative stress in stomach disorders

Hidekazu Suzuki; Toshihiro Nishizawa; Hitoshi Tsugawa; Sachiko Mogami; Toshifumi Hibi

The stomach is a sensitive digestive organ that is susceptible and exposed to exogenous pathogens from the diet. In response to such pathogens, the stomach induces oxidative stress, which might be related to the development of gastric organic disorders such as gastritis, gastric ulcers, and gastric cancer, as well as functional disorders such as functional dyspepsia. In particular, the bacterium Helicobacter pylori plays a major role in eliciting and confronting oxidative stress in the stomach. The present paper summarizes the pathogenesis of oxidative stress in the stomach during the development of various stomach diseases.


PLOS ONE | 2012

Overexpression of miR-142-5p and miR-155 in Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Resistant to Helicobacter pylori Eradication

Yoshimasa Saito; Hidekazu Suzuki; Hitoshi Tsugawa; Hiroyuki Imaeda; Juntaro Matsuzaki; Kenro Hirata; Naoki Hosoe; Masahiko Nakamura; Makio Mukai; Hidetsugu Saito; Toshifumi Hibi

microRNAs (miRNAs) are small non-coding RNAs that can function as endogenous silencers of target genes and play critical roles in human malignancies. To investigate the molecular pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the miRNA expression profile was analyzed. miRNA microarray analysis with tissue specimens from gastric MALT lymphomas and surrounding non-tumor mucosae revealed that a hematopoietic-specific miRNA miR-142 and an oncogenic miRNA miR-155 were overexpressed in MALT lymphoma lesions. The expression levels of miR-142-5p and miR-155 were significantly increased in MALT lymphomas which do not respond to Helicobacter pylori (H. pylori) eradication. The expression levels of miR-142-5p and miR-155 were associated with the clinical courses of gastric MALT lymphoma cases. Overexpression of miR-142-5p and miR-155 was also observed in Helicobacter heilmannii-infected C57BL/6 mice, an animal model of gastric MALT lymphoma. In addition, miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their target. The results of this study indicate that overexpression of miR-142-5p and miR-155 plays a critical role in the pathogenesis of gastric MALT lymphoma. These miRNAs might have potential application as therapeutic targets and novel biomarkers for gastric MALT lymphoma.


Journal of Gastroenterology and Hepatology | 2010

Contribution of efflux pumps to clarithromycin resistance in Helicobacter pylori

Kenro Hirata; Hidekazu Suzuki; Toshihiro Nishizawa; Hitoshi Tsugawa; Hiroe Muraoka; Yoshimasa Saito; Juntaro Matsuzaki; Toshifumi Hibi

Background and Aims:  Although clarithromycin (CLR) is one of the most commonly recommended component drugs of Helicobacter pylori eradication regimens, the prevalence of CLR‐resistant H. pylori has been increasing. It is well known that CLR resistance is associated with point mutations in 23S rRNA, but an active multidrug efflux mechanism of H. pylori may also play a role in its drug resistance. At least four gene clusters have been identified as efflux pump systems in H. pylori and the present study was designed to investigate their role in the CLR resistance of clinical isolates of H. pylori.


British Journal of Cancer | 2013

CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence

Kenro Hirata; Hidekazu Suzuki; Hiroyuki Imaeda; Juntaro Matsuzaki; Hitoshi Tsugawa; Osamu Nagano; Keiko Asakura; Hideyuki Saya; Taizo Hibi

Background:Multiple early gastric cancers (EGCs) may develop in 6–14% of patients even after achieving curative endoscopic submucosal dissection (ESD); however, a useful biomarker for predicting recurrence is not available. The present study investigated whether the expression of CD44 variant 9 (CD44v9), a functional cancer stem cell marker, in the primary gastric cancer tissue represents an indicator of recurrence.Methods:Eighty-eight patients who underwent ESD for EGC from 2008 to 2010 were enrolled and monitored for recurrence for 3 years. The expression levels of CD44v9 in the tissue of initial EGCs were evaluated by immunohistochemistry, and the recurrence rate was compared between CD44v9-positive and CD44v9-negative groups. The mucin phenotype and expression of microRNA-21 (miR-21) and programmed cell death protein 4 (PDCD4) were also analysed.Results:The recurrence rate of EGC was significantly higher in the CD44v9-positive group than in the CD44v9-negative group (hazard ratio (HR), 21.8; 95% confidence interval (CI), 5.71–83.1). However, mucin phenotypes and the expression of miR-21 and PDCD4 did not predict recurrence after ESD. Meanwhile, grade of gastric atrophy was also identified as a significant marker of multiple recurrence (HR, 4.95; 95% CI, 1.30–18.8).Conclusion:CD44 variant 9 expression represents a potential predictive marker for recurrence in EGC.


International Journal of Cancer | 2013

The tumor suppressor microRNA-29c is downregulated and restored by celecoxib in human gastric cancer cells.

Yoshimasa Saito; Hidekazu Suzuki; Hiroyuki Imaeda; Juntaro Matsuzaki; Kenro Hirata; Hitoshi Tsugawa; Sana Hibino; Yae Kanai; Hidetsugu Saito; Toshifumi Hibi

MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous silencers of target genes and play critical roles during carcinogenesis. The selective cyclooxygenase‐2 (COX‐2) inhibitor celecoxib has been highlighted as a potential drug for treatment of gastrointestinal tumors. The aim of this study was to investigate the role of miRNAs in gastric carcinogenesis and the feasibility of a new therapeutic approach for gastric cancer. miRNA expression profiles were examined in 53 gastric tumors including gastric adenomas (atypical epithelia), early gastric cancers and advanced gastric cancers and in gastric cancer cells treated with celecoxib. miRNA microarray analysis revealed that miR‐29c was significantly downregulated in gastric cancer tissues relative to nontumor gastric mucosae. miR‐29c was significantly activated by celecoxib in gastric cancer cells. Downregulation of miR‐29c was associated with progression of gastric cancer and was more prominent in advanced gastric cancers than in gastric adenomas and early gastric cancer. In addition, expression of the oncogene Mcl‐1, a target of miR‐29c, was significantly increased in gastric cancer tissues relative to nontumor gastric mucosae. Activation of miR‐29c by celecoxib induced suppression of Mcl‐1 and apoptosis in gastric cancer cells. These results suggest that downregulation of the tumor suppressor miR‐29c plays critical roles in the progression of gastric cancer. Selective COX‐2 inhibitors may have clinical promise for the treatment of gastric cancer via restoration of miR‐29c.


Gastroenterology | 2011

Dysfunctional Gastric Emptying With Down-regulation of Muscle-Specific MicroRNAs in Helicobacter pylori-Infected Mice

Yoshimasa Saito; Hidekazu Suzuki; Hitoshi Tsugawa; Sachiko Suzuki; Juntaro Matsuzaki; Kenro Hirata; Toshifumi Hibi

BACKGROUND & AIMS Little is known about the pathogenic mechanisms of functional dyspepsia. We investigated the role of microRNAs (miRNAs) in gastric motility disorders associated with Helicobacter pylori infection. METHODS Male C57BL/6 mice were infected with H pylori. After long-term infection, gastric emptying was examined and compared with that of uninfected mice (controls). The miRNA expression profile was analyzed by miRNA microarray and quantitative reverse-transcriptase polymerase chain reaction. The results obtained from the animal study were confirmed by in vitro experiments. RESULTS Gastric emptying was significantly accelerated in mice after chronic infection with H pylori. Histologic examination showed that the muscular layers of the stomachs of H pylori-infected mice were significantly thickened. The miRNA expression profile revealed that the muscle-specific miRNAs miR-1 and miR-133 were significantly down-regulated in the stomachs after long-term infection with H pylori. However, expression of histone deacetylase 4 and serum response factor, which are reported target genes of miR-1 and miR-133, increased. Down-regulation of miR-1 and miR-133 and increased cell proliferation were observed in C2C12 mouse myoblast cells after coculture with H pylori. CONCLUSIONS Chronic infection with H pylori down-regulates expression of muscle-specific miRNAs and up-regulates expression of histone deacetylase 4 and serum response factor. These might cause hyperplasia in the muscular layer of the stomach and dysfunction in gastric emptying. These findings provide insight into the molecular pathogenesis of gastric motility disorders, including functional dyspepsia.


Antioxidants & Redox Signaling | 2011

Two Amino Acids Mutation of Ferric Uptake Regulator Determines Helicobacter pylori Resistance to Metronidazole

Hitoshi Tsugawa; Hidekazu Suzuki; Kazue Satoh; Kenro Hirata; Juntaro Matsuzaki; Yoshimasa Saito; Makoto Suematsu; Toshifumi Hibi

Metronidazole (Mtz) is a prodrug that is converted to its active form when its nitro group is reduced and superoxide radicals are generated. The superoxide radicals are directly toxic to the bacterium. On the other hand, the transcriptional regulator, ferric uptake regulator (Fur), of Helicobacter pylori is a direct suppressor of the iron-cofactored superoxide dismutase SodB, which is essential for protection against superoxide attack. Here, we demonstrate that in some Mtz-resistant strains, SodB activity is induced in a dose-dependent manner on exposure to Mtz. Further, under Mtz exposure, the generation of superoxide radicals in Mtz-resistant strains was significantly reduced as compared with that in the Mtz-susceptible strains. These Mtz-resistant strains were found to carry amino acids mutation of Fur (C78Y, P114S; mutant-type Fur). The binding affinity of the mutant-type Fur to an operator sequence on the sodB promoter (Fur-Box) was significantly reduced. Our approach demonstrated that SodB expression is derepressed by mutant-type Fur, which is associated with the development of Mtz resistance.


Neurogastroenterology and Motility | 2009

Delayed gastric emptying and disruption of the interstitial cells of Cajal network after gastric ischaemia and reperfusion.

Sachiko Suzuki; Hidekazu Suzuki; K. Horiguchi; Hitoshi Tsugawa; Juntaro Matsuzaki; Tomohisa Takagi; N. Shimojima; Toshifumi Hibi

Background  Gastrointestinal tract is one of the most susceptible organ systems to ischaemia. Not only mucosal injury but also alterations of the intestinal motility and loss of interstitial cells of Cajal (ICC) have been reported in response to ischaemia and reperfusion (I/R). However, there are few reports on the changes in the gastric motility after gastric I/R. The present study was designed to investigate the alterations in gastric emptying, the ICC and enteric nerves that regulate smooth muscle function in response to gastric I/R.


Antimicrobial Agents and Chemotherapy | 2012

Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failures of first- and second-line therapies

Juntaro Matsuzaki; Hidekazu Suzuki; Toshihiro Nishizawa; Kenro Hirata; Hitoshi Tsugawa; Yoshimasa Saito; Sawako Okada; Seiichiro Fukuhara; Toshifumi Hibi

ABSTRACT Sitafloxacin-based triple therapy achieved 83.6% (per-protocol) and 78.2% (intention-to-treat) success in eradicating Helicobacter pylori among 78 Japanese patients after clarithromycin-based first-line and metronidazole-based second-line triple therapies failed. Eradication succeeded in 32 out of 43 patients, even with gyrA mutation-positive Helicobacter pylori (per protocol). The position of the gyrA mutation (N87 or D91) was determined to be a better marker than MIC levels for predicting outcomes of sitafloxacin-based treatment.

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