Wataru Shibata

Yokohama City University, Yokohama, Kanagawa, Japan

Are you Wataru Shibata?

Claim your profile

Publications (65)581.92 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the possible existence of a correlation between the gastric transit time (GTT) measured by video capsule endoscopy (VCE) and the parameters of gastric emptying determined using 13C breath test (BreathID system). Eight healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to undergo VCE using the PillCam SB capsule endoscopy system or the 13C breath test for 4 hours after a test meal (400 kcal per 400 mL) containing 100 mg of 13C acetic acid administered after overnight fasting. The VCE images were analyzed and the GTT was determined using the proprietary RAPID software. The parameters, namely T lag, T 1/2 and GEC were calculated using the Oridion Research Software (β version). The GTT measured by VCE and the parameters of gastric emptying were compared statistically. No significant correlation was observed between the GTT and T lag (p = 0.5263), T 1/2 (p = 0.4100) or GEC (p = 0.2410), as determined by calculation of the Spearman’s rank correlation coefficient. GTT measured by VCE cannot serve as asubstitute for the gastric emptying time measured bythe 13C breath test.
    Hepato-gastroenterology 10/2014; 61(135):2159-62. DOI:10.5754/hge13358 · 0.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The natural immunomodulator lactoferrin is known to possess anti-inflammatory effects. However, there have been no studies examining the mode of action of lactoferrin in protecting the esophageal mucosa against damage. We investigated the effect of lactoferrin on gastric acid secretion and in protecting against acute acid reflux-induced esophagitis in rats. Male Wistar rats aged 8 weeks, weighing 210-240 g, were used for all the experiments. A gastric perfusion system was installed using the method of Ghosh et al. Lactoferrin was administered once via the caudate vein, starting 24 hours before an acute acid reflux (treatment mode), or saline (control). Statistical comparison of the parameters between the two test conditions was performed. No significant differences in basal or stimulated gastric acid secretion, or in the serum gastrin level were observed between the two test conditions. Esophageal damage was attenuated by lactoferrin in a dose-dependent manner, as reflected by the improvement in the esophageal tissue weight and macroscopic scores. Significant reductions in the histological scores, myeloperoxidase activity and the levels of proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β were also observed following lactoferrin administration. We concluded that lactoferrin exerts a protective effect against acute acid reflux-induced esophageal damage in rats.
  • Gastroenterology 05/2014; 146(5):S-872. DOI:10.1016/S0016-5085(14)63173-5 · 13.93 Impact Factor
  • Soichiro Sue, Wataru Shibata, Shin Maeda
    Gastroenterology 05/2014; 146(5):S-64. DOI:10.1016/S0016-5085(14)60227-4 · 13.93 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB284-AB285. DOI:10.1016/j.gie.2014.05.256 · 4.90 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-496. DOI:10.1016/S0016-5085(14)61787-X · 13.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the loss of E-cadherin is a real culprit or a bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here we demonstrate that liver-specific E-cadherin knockout mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial-mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial-mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.
    Proceedings of the National Academy of Sciences 01/2014; DOI:10.1073/pnas.1322731111 · 9.81 Impact Factor
  • Wataru Shibata, Shin Maeda
    Nippon rinsho. Japanese journal of clinical medicine 08/2013; 71(8):1346-51.
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. DESIGN: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. RESULTS: H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. CONCLUSIONS: Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.
    Gut 05/2013; 63(3). DOI:10.1136/gutjnl-2013-305092 · 13.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
    PLoS ONE 04/2013; 8(4):e60914. DOI:10.1371/journal.pone.0060914 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AIM: A rapid and non-invasive method of detecting fibrosis in patients with chronic liver diseases is of major clinical interest. The purpose of this study was to comparatively investigate the effectiveness of the Liver Fibrosis Index (LF Index) calculated using real-time tissue elastography (RTE) in patients with non-alcoholic fatty liver disease (NAFLD) and patients with chronic hepatitis C (CHC). METHODS: Twenty-seven patients with biopsy-proven NAFLD and 93 patients with biopsy-proven CHC were included. They underwent transient elastography (TE), serum liver fibrosis marker testing and RTE to calculate the LF Index. RESULTS: The LF Index showed a stepwise increase with increasing histological severity of fibrosis in CHC patients (P = 0.0102), whereas no significant correlation of the LF Index with the histological severity of liver fibrosis in NAFLD patients (P = 0.852). There was a significant correlation between the LF Index and liver stiffness measured by TE in CHC patients (r = 0.319, P = 0.0009). On the other hand, no such correlation was observed in NAFLD patients. While in CHC patients, the LF Index was correlated with the FIB-4 index, no such correlation was observed in NAFLD patients. CONCLUSION: The LF Index calculated by RTE is effective for assessment of liver fibrosis in patients with CHC. On the other hand, it is not useful in patients with NAFLD. This is the first study to compare the clinical usefulness of RTE as non-invasive assessment of liver fibrosis between CHC and NAFLD. Further investigations are required to refine statistical assessment of RTE.
    Hepatology Research 11/2012; 43(7). DOI:10.1111/hepr.12023 · 2.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AIM: Apelin-APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin-APJ signaling and Fas-mediated liver injury in mice. METHODS: APJ(-/-) mice and wild type (WT) mice were administered an intraperitoneal injection of an agonistic anti-Fas antibody (clone; Jo2), and sacrificed after 3 or 6 h to assess the liver histology. The expression levels of apelin and APJ, plasma levels of transaminases, activities of hepatic caspases and activations of stress-activated protein kinases were also analysed. RESULTS: Before the Jo2 injection, APJ was weakly expressed in the hepatocytes in spots; on the other hand, after the Jo2 injection, it had spread into whole hepatocytes. Moreover, the mRNA expression level of apelin and APJ in the liver increased after Jo2 injection. In the APJ(-/-) mice, the liver injuries and apoptotic changes were significantly inhibited as compared with those in the WT mice. Dramatic increase in JNK activation was observed in the WT mice after Jo2 injection, whereas such activation was completely absent in the APJ(-/-) mice. JNK inhibitor partially, but significantly suppressed Jo2-mediated liver injury in WT mice. CONCLUSION: Apelin-APJ signalling may promote Fas-induced liver injury at least partially via JNK activation, and may thus serve as a potential therapeutic target in cases of acute liver injury.
    Liver international: official journal of the International Association for the Study of the Liver 11/2012; 33(1). DOI:10.1111/liv.12006 · 4.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND & AIMS:: Interleukin (IL)8 has an important role in initiating inflammation in humans, attracting immune cells such as neutrophils through their receptors CXCR1 and CXCR2. IL8 has been proposed to contribute to chronic inflammation and cancer. However, mice do not have the IL8 gene, so human cancer cell lines and xenograft studies have been used to study the role of IL8 in colon and gastric carcinogenesis. We generated mice that carry a bacterial artificial chromosome that encompasses the entire human IL8 gene, including its regulatory elements (IL8Tg mice). METHODS:: We studied the effects of IL8 expression in APCmin+/- mice and IL8Tg mice given azoxymethane and dextran sodium sulfate (DSS). We also examined the effects of IL8 expression in gastric cancer in INS-GAS mice that overexpress gastrin and IL8Tg mice infected with Helicobacter felis. RESULTS:: In IL8Tg mice, expression of human IL8 was controlled by its own regulatory elements, with virtually no mRNA or protein detectable under basal conditions. IL8 was strongly upregulated upon systemic or local inflammatory stimulation, increasing mobilization of immature CD11b+Gr-1+ myeloid cells (IMC) with thioglycolate-induced peritonitis, DSS-induced colitis, and H felis-induced gastritis. IL8 was increased in colorectal tumors from patients and IL8Tg mice, compared with non-tumor tissues. IL8Tg mice developed more tumors than wild-type mice following administration of azoxymethane and DSS. Expression of IL8 increased tumorigenesis in APCmin+/- mice, compared with APCmin+/- mice that lack IL8; this was associated with increased numbers of IMCs and angiogenesis in the tumors. CONCLUSIONS:: IL8 contributes to gastrointestinal carcinogenesis by mobilizing IMCs, and might be a therapeutic target for gastrointestinal cancers.
    Gastroenterology 10/2012; 144(1). DOI:10.1053/j.gastro.2012.09.057 · 13.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.
    Cell metabolism 07/2012; 16(1):44-54. DOI:10.1016/j.cmet.2012.05.012 · 16.75 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):3301-3301. DOI:10.1158/1538-7445.AM2012-3301 · 9.28 Impact Factor
  • Wataru Shibata, Masahiko Inamori, Shin Maeda
    Nippon rinsho. Japanese journal of clinical medicine 04/2012; 70 Suppl 2:50-5.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Stromal cell-derived factor-1 (SDF-1/CXCL12), the main ligand for CXCR4, is overexpressed in human cancer. This study addressed the precise contribution of SDF-1 to gastric carcinogenesis. DESIGN: SDF-1 transgenic mice were created and a Helicobacter-induced gastric cancer model was used in combination with H/K-ATPase-IL-1β mice. Gastric tissue was analysed by histopathology and cells isolated from the stomach were analysed by molecular biological methods. RESULTS: Analysis of the H/K-ATPase/SDF-1 transgenic (SDF-Tg) mice showed that SDF-1 overexpression results in significant gastric epithelial hyperproliferation, mucous neck cell hyperplasia and spontaneous gastric dysplasia (wild-type mice 0/15 (0%) vs SDF-Tg mice 4/14 (28.6%), p=0.042, Fisher exact test) but has minimal effects on inflammation. SDF-Tg mice also showed a dramatic expansion of α-smooth muscle actin-positive myofibroblasts and CXCR4-expressing gastric epithelial cells in the progenitor zone, both of which preceded the development of significant gastritis or dysplasia. Gremlin 1-expressing mesenchymal stem cells, the putative precursors of myofibroblasts, were also increased within the dysplastic stomachs of SDF-Tg mice and showed chemotaxis in response to SDF-1 stimulation. SDF-1 overexpression alone resulted in minimal recruitment of haematopoietic cells to the gastric mucosa, although macrophages were increased late in the disease. When SDF-Tg mice were crossed with H/K-ATPase-IL-1β mice or infected with Helicobacter felis, however, there were dramatic synergistic effects on recruitment of bone marrow-derived cells and progression to preneoplasia. CONCLUSION: Activation of the SDF-1/CXCR4 axis can contribute to early stages of carcinogenesis primarily through recruitment of stromal cells and modulation of the progenitor niche.
    Gut 02/2012; 62(2). DOI:10.1136/gutjnl-2011-301824 · 13.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues. We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers. We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.
    Gastroenterology 01/2012; 142(4):824-833.e7. DOI:10.1053/j.gastro.2011.12.058 · 13.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to reduce inflammation and attenuate fibrosis in the liver. In this study, we investigated the effects of PPARγ on the liver injury induced by 20 mg/kg Concanavalin A (Con A). The mice were administered one of the three types of PPARγ ligands (pioglitazone, ciglitazone, and troglitazone) for 1 week, and the serum alanine aminotransferase (ALT) levels at 20 h after Con A injection were significantly elevated in the PPARγ ligand-treated mice. Furthermore, the serum ALT levels after Con A injection in the PPARγ hetero-knock-out mice (PPARγ(+/-) mice) were lower than those in the wild-type mice (WT mice). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed extensive liver damage induced by Con A in the pioglitazone-treated mice. Electrophoresis mobility shift assay (EMSA) revealed that activation of translocation of nuclear factor- (NF-) κB, which is a suppressor of apoptosis, in the nucleus of the hepatocytes was suppressed in the pioglitazone-treated mice after Con A injection. In this study, we showed that PPARγ exacerbated Con A-induced liver injury via suppressing the translocation of NF-κB into the nucleus, thereby inhibiting the suppression of liver cell apoptosis.
    PPAR Research 01/2012; 2012:940384. DOI:10.1155/2012/940384 · 1.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to characterize the pancreatic cystic lesions in von Hippel-Lindau (VHL) disease and to document the changes that occur in the pancreas. We retrospectively analyzed the medical records and the computed tomography (CT) and magnetic resonance imaging (MRI) findings of 20 VHL patients who were diagnosed between 1996 and 2010 at our hospital. The clinical findings, family history and type of tumors and/or cysts were reviewed for each patient. We also analyzed the imaging findings for the pancreas in detail. Pancreatic involvement was noted in 16 of the 20 patients (80%). Eleven patients had multiple cysts diffusely distributed in the pancreas, and one patient had a single cyst in the pancreas head. Two patients had serous cystic neoplasms (SCNs) with multiple cysts, and another two patients had neuroendocrine tumors (NETs) which were conventional radiological findings. The largest cysts of four patients (26.7%) increased in size and that of three patients (20%) decreased in size during the follow-up period. We performed surgical resections for the pancreatic tumors (one NET and one SCN) and also performed endoscopic treatment for a pancreatic cyst in one VHL patient with obstructive jaundice. None of the patients died as a result of pancreatic disease. The most common type of pancreatic lesions was multiple cysts. SCNs were present in only 10% of the VHL patients. Pancreatic cysts showed positive and/or negative growth according to the CT and MRI findings. The pancreatic cystic lesions did not influence the outcome of the VHL patients.
    Internal Medicine 01/2012; 51(11):1301-7. DOI:10.2169/internalmedicine.51.7194 · 0.97 Impact Factor

Publication Stats

1k Citations
581.92 Total Impact Points


  • 2012–2014
    • Yokohama City University
      • Department of Gastroenterology
      Yokohama, Kanagawa, Japan
  • 2009–2012
    • Columbia University
      • Division of Digestive and Liver Disease
      New York City, New York, United States
  • 2006–2009
    • The University of Tokyo
      • Department of Gastroenterology
      Tōkyō, Japan
  • 2004
    • Chigasaki Municipal Hospital
      Chigaraki, Kanagawa, Japan