Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease

Miyoshi Jun, Hisamatsu Tadakazu, Matsuoka Katsuyoshi, Naganuma Makoto, Maruyama Yuriko, Yoneno Kazuaki, Mori Kiyoto, Kiyohara Hiroki, Nanki Kosaku, Okamoto Susumu, Yajima Tomoharu, Iwao Yasushi, Ogata Haruhiko, Hibi Toshifumi, Kanai Takanori

Digestion 90 ( 2 ) 130 - 136 2014.11

ISSN 0012-2823

Background: We evaluated the clinical efficacy of adalimumab (ADA) for Crohn's disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. Methods: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of ≤ 4. Results: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of ≤ 3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. Conclusions: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients.

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Propofol versus traditional sedative agents for endoscopic submucosal dissection

Nishizawa Toshihiro, Suzuki Hidekazu, Matsuzaki Juntaro, Kanai Takanori, Yahagi Naohisa

Digestive Endoscopy 26 ( 6 ) 701 - 706 2014.11

ISSN 0915-5635

Methods PubMed, the Cochrane library, and the Igaku-Chuo-Zasshi database were searched in order to identify randomized trials eligible for inclusion in the systematic review. Data from the eligible studies were combined to calculate pooled odds ratios (OR) of developing restlessness, full awakening at 1 h post-ESD, hypoxia, and hypotension.Background and Aim Propofol has been suggested to be superior to benzodiazepines when used as a sedative agent for endoscopic examination. The aim of the present study was to systematically evaluate the safety and efficacy of propofol sedation for endoscopic submucosal dissection (ESD).Results We identified three randomized trials (298 patients) from the database search. Compared with traditional sedative agents, the pooled OR of restlessness and full awakening at 1 h post-ESD with propofol sedation were 0.41 (95% confidence interval [CI]: 0.21-0.81) and 8.59 (95% CI: 4.29-17.2), respectively, without significant heterogeneity. Compared with traditional sedative agents, the pooled OR of hypoxia and hypotension with propofol sedation were 1.13 (95% CI: 0.58-2.21) and 0.92 (95% CI: 0.25-3.41), respectively, indicating no significant differences between the groups.Conclusion Propofol sedation during ESD is more effective as compared with traditional sedative agent. The risk of complications is similar.

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Obscure gastrointestinal bleeding

Hirata Kenro, Hosoe Naoki, Imaeda Hiroyuki, Naganuma Makoto, Murata Hiroko, Ueno Mari, Suzuki Hidekazu, Ogata Haruhiko, Kanai Takanori

Clinical Journal of Gastroenterology 7 ( 5 ) 397 - 401 2014.10

ISSN 1865-7257

Pyogenic granulomas usually occur on the skin or oral mucosa; however, they rarely develop in the gastrointestinal tract, particularly in the ileum. We report the case of an 82-year-old female who experienced occasional bloody stools. Initially, no significant bleeding source could be identified via conventional endoscopy; however, repeat capsule endoscopy identified a bleeding polyp (8 mm) in the ileum. Therefore, we resected the polyp via double-balloon enteroscopy. Histopathological findings showed increased, lobulated, and enlarged capillaries and desquamated epithelium indicative of epithelial erosion. In addition, neutrophil-predominant inflammatory cell infiltrate and interstitial edema were observed in the intercapillary stroma. Immunohistochemical analysis showed positive staining for vascular endothelial cell markers. Previous reports have mentioned that pyogenic granulomas in the oral cavity were associated with the female hormonal receptor, vascular endothelial growth factor, and proliferative immune markers; however, no significant staining was observed in our patient. This is the first report discussing an association between pyogenic granulomas and these markers. Pyogenic granulomas in the ileum are rare and may cause fatal anemia. Pyogenic granulomas should be considered in the differential diagnosis of obscure gastrointestinal bleeding.

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Classical Th1 cells obtain colitogenicity by co-existence of RORγt-expressing T cells in experimental colitis

Saigusa Keiichiro, Hisamatsu Tadakazu, Handa Tango, Sujino Tomohisa, Mikami Yohei, Hayashi Atsushi, Mizuno Shinta, Takeshita Kozue, Sato Toshiro, Matsuoka Katsuyoshi, Kanai Takanori

Inflammatory Bowel Diseases 20 ( 10 ) 1820 - 1827 2014.10

ISSN 1078-0998

Background: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (RORγt)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without RORγt expression in the pathogenesis of colitis remains poorly understood. Methods: We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4+CD45RBhigh T cells obtained from wild-type, RORγtgfp/gfp, or RORγtgfp/+ mice into RAG-2-/- mice. Results: RAG-2-/- mice receiving transfer of in vitro-manipulated RORγtgfp/gfp Th1 cells developed colitis. RAG-2-/- mice co-transferred with splenic CD4+CD45RBhigh T cells obtained from wild-type mice and RORγtgfp/gfp mice developed colitis with a significant increase in RORγtgfp/gfp cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4+CD45RBhigh T cells obtained from RORγtgfp/gfp mice. Furthermore, RAG-2-/- mice transferred with in vivo-manipulated RORγtgfp/gfp cTh1 cells developed colitis with a significant increase in RORγtgfp/gfp cTh1 cell numbers. Conclusions: These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of RORγt-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.

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Modified bowel preparation regimen for use in second-generation colon capsule endoscopy in patients with ulcerative colitis

Usui Shingo, Hosoe Naoki, Matsuoka Katsuyoshi, Kobayashi Taku, Nakano Masaru, Naganuma Makoto, Ishibashi Yuka, Kimura Kayoko, Yoneno Kazuaki, Kashiwagi Kazuhiro, Hisamatsu Tadakazu, Inoue Nagamu, Serizawa Hiroshi, Hibi Toshifumi, Ogata Haruhiko, Kanai Takanori

Digestive Endoscopy 26 ( 5 ) 665 - 672 2014.09

ISSN 0915-5635

Background and Aim We have reported that second-generation colon capsule endoscopy (CCE-2) might be feasible for assessing the severity of mucosal inflammation in ulcerative colitis (UC). However, because of the low rate (69%) of complete evaluation of the colon and owing to inadequate cleansing. We believe that the method of bowel preparation could be improved by reducing volume. In the present study, we attempted to improve the colon-cleansing regimen in order to optimize the usefulness of CCE-2 in the management of UC patients.Methods: Twenty patients with histologically confirmed UC were enrolled. Patients took a maximum 2.2 L lavage solution (polyethylene glycol solution and magnesium citrate) in two or three divided doses. To assess the effectiveness of the modified bowel preparation regimen, we evaluated the rate of total colonobservation, the effectiveness of bowel cleansing, andinterobserver agreement in assessing UC disease activity. We used a four-point grading scale (poor, fair, good, and excellent) for evaluating the quality of bowel cleansing. Matts' endoscopic score was used to evaluate disease activity.Results: The rate of total colon observation was 85%, and 15 patients (75%) excreted the CCE-2 within 8 h. The proportion of excellent plus good cleansing was approximately 60%. There was a substantial interobserver agreement (κ = 0.777) in assessment of overall cleansing, which was still substantial at the fair cleansing level (κ = 0.700).Conclusion: Using CCE-2, the modified bowel preparation regimen, with reduced volume has the potential to succeed in the evaluation of mucosal severity in UC.

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Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease.

Mizuno S, Mikami Y, Kamada N, Handa T, Hayashi A, Sato T, Matsuoka K, Matano M, Ohta Y, Sugita A, Koganei K, Sahara R, Takazoe M, Hisamatsu T, Kanai T.

Inflamm Bowel Dis 20 ( 8 ) 1426 - 34 2014.08

Joint Work, Accepted

BACKGROUND:

Interleukin (IL)-22-producing RORγt innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORγt ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD.

METHODS:

CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated.

RESULTS:

CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORγt and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1α and Claudin-1 in human intestinal epithelial organoids.

CONCLUSIONS:

RORγt ILCs might enhance mucosal barrier function through the upregulation of Reg1α through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORγt ILCs.

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Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells.

Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Usui S, Furuhashi H, Kimura A, Nishiyama K, Maejima T, Okada Y, Kurihara C, Shimamura K, Ebinuma H, Saito H, Yokoyama H, Watanabe C, Komoto S, Nagao S, Sugiyama K, Aosasa S, Hatsuse K, Yamamoto J, Hibi T, Miura S, Hokari R, Kanai T.

J Hepatol 61 ( 1 ) 98 - 106 2014.07

Joint Work, Accepted

BACKGROUND & AIMS:

Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis.

METHODS:

ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4)(-/-)ACAT1(+/+) and TLR4(-/-)ACAT1(-/-) mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis.

RESULTS:

ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling.

CONCLUSIONS:

ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Acyl-coenzyme A:cholesterol acyltransferase; Bone morphogenetic protein and activin membrane-bound inhibitor; Free cholesterol; Hepatic stellate cell; Toll-like receptor 4; Transforming growth factor-β

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Risk factors for decreased bone mineral density in inflammatory bowel disease

Wada Yasuyo, Hisamatsu Tadakazu, Naganuma Makoto, Matsuoka Katsuyoshi, Okamoto Susumu, Inoue Nagamu, Yajima Tomoharu, Kouyama Keisuke, Iwao Yasushi, Ogata Haruhiko, Hibi Toshifumi, Abe Takayuki, Kanai Takanori

Clinical Nutrition 2014.06

ISSN 0261-5614

Background & aim: Although inflammatory bowel disease (IBD) patients are at risk for metabolic bone disease, studies analyzing this correlation have identified various risk factors, including disease phenotype, age, sex and steroid therapy. Furthermore, few studies have assessed risk factors for bone loss in Japanese IBD patients. This study analyzed risk factors for metabolic bone disease in Japanese IBD patients. Methods: This cross-sectional study assessed 388 patients with IBD aged 20-50 years, including 232 with ulcerative colitis (UC) and 156 with Crohn's disease (CD). Bone mineral density of the femoral neck, total femur and lumbar spine was quantified by dual-energy X-ray absorptiometry. The blood concentrations of bone metabolism markers were measured. History of smoking and bone fracture, and nutritional intake were assessed using questionnaires. Results: Of the 388 patients with IBD, 78 (20.1%; UC, 17.2%; CD, 24.4%) had osteopenia and 17 (4.4%; UC, 3.4%; CD, 5.8%) had osteoporosis, as assessed by T-score. Bone mineral density of the lumbar vertebrae was lower in males than in females. Multivariate regression analysis showed that risk factors for bone loss in UC patients were male sex, low body mass index (BMI), high steroid dose and disease location. Risk factors for bone loss in CD patients were male sex and low BMI. Conclusion: Among Japanese patients with IBD, male sex and low BMI were associated with increased risk for metabolic bone disease. In addition, Steroid therapy shouldn't be indiscriminate in UC patients. These findings may help identify patients at particularly high risk of metabolic bone disease and may help implement appropriate therapies in a timely manner and improve long-term quality of life.

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Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus

Sugiyama Kazuo, Ebinuma Hirotoshi, Nakamoto Nobuhiro, Sakasegawa Noriko, Murakami Yuko, Chu Po Sung, Usui Shingo, Ishibashi Yuka, Wakayama Yuko, Taniki Nobuhito, Murata Hiroko, Saito Yoshimasa, Fukasawa Masayoshi, Saito Kyoko, Yamagishi Yoshiyuki, Wakita Takaji, Takaku Hiroshi, Hibi Toshifumi, Saito Hidetsugu, Kanai Takanori

PLoS ONE 9 ( 4 ) 2014.04

Most of experiments for HCV infection have been done using lytic infection systems, in which HCV-infected cells inevitably die. Here, to elucidate metabolic alteration in HCV-infected cells in a more stable condition, we established an HCV-persistently- infected cell line, designated as HPI cells. This cell line has displayed prominent steatosis and supported HCV infection for more than 2 years, which is the longest ever reported. It enabled us to analyze metabolism in the HCV-infected cells integrally combining metabolomics and expression arrays. It revealed that rate-limiting enzymes for biosynthesis of cholesterol and fatty acids were up-regulated with actual increase in cholesterol, desmosterol (cholesterol precursor) and pool of fatty acids. Notably, the pentose phosphate pathway was facilitated with marked up-regulation of glucose-6- phosphate dehydrogenase, a rete-limiting enzyme, with actual increase in NADPH. In its downstream, enzymes for purine synthesis were also up-regulated resulting in increase of purine. Contrary to common cancers, the TCA cycle was preferentially facilitated comparing to glycolysis pathway with a marked increase of most of amino acids. Interestingly, some genes controlled by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of antioxidation and metabolism, were constitutively up-regulated in HPI cells. Knockdown of Nrf2 markedly reduced steatosis and HCV infection, indicating that Nrf2 and its target genes play important roles in metabolic alteration and HCV infection. In conclusion, HPI cell is a bona fide HCV-persistently-infected cell line supporting HCV infection for years. This cell line sustained prominent steatosis in a hypermetabolic status producing various metabolites. Therefore, HPI cell is a potent research tool not only for persistent HCV infection but also for liver metabolism, overcoming drawbacks of the lytic infection systems. © 2014 Sugiyama et al.

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Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation

Mikami Yohei, Mizuno Shinta, Nakamoto Nobuhiro, Hayashi Atsushi, Sujino Tomohisa, Sato Toshiro, Kamada Nobuhiko, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Ebinuma Hirotoshi, Hibi Toshifumi, Yoshimura Akihiko, Kanai Takanori

PLoS ONE 9 ( 1 ) 2014.01

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2^-/- mice adoptively transferred with CD4⁺CD45RB^high T cells; and IL-10 ^-/- mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b^-CD11c^lowPDCA-1⁺ plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4⁺CD45RB^high T cell-transferred RAG-2^-/- mice and IL-10^-/- mice in parallel with the emergence of macrophages (Mφs) and conventional DCs (cDCs). Furthermore, liver Mφ/cDCs emerging during intestinal inflammation not only promote the proliferation of naïve CD4⁺ T cells, but also instruct them to differentiate into IFN-γ-producing Th1 cells in vitro. The emergence of pathological Mφ/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mφ/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation. © 2014 Mikami et al.

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Magnetic resonance enterography of Crohn's disease

Naganuma Makoto, Hisamatsu Tadakazu, Kanai Takanori, Ogata Haruhiko

Expert Review of Gastroenterology and Hepatology 9 ( 1 ) 37 - 45 2014.01

ISSN 1747-4124

Magnetic resonance enterography (MRE) has been reported to be a useful modality for the evaluation of luminal inflammation and extraintestinal complications in Crohn's disease (CD). A recent study indicated that the diagnostic ability of MRE was comparable to the diagnostic ability of other devices, such as ileocolonoscopy. MRE can be performed repeatedly because there is no radiation exposure. Therefore, MRE is useful as a method of follow-up for younger patients with established CD. It is useful for evaluating the efficacy of medical treatments, such as biologics. MRE can detect small intestinal lesions even if the endoscope does not pass through the stenosis. The concerns of availability of expertise and the costs associated with MRE should be addressed so MRE can be widely used for CD patients in the near future.

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Free cholesterol accumulation in hepatic stellate cells

Tomita Kengo, Teratani Toshiaki, Suzuki Takahiro, Shimizu Motonori, Sato Hirokazu, Narimatsu Kazuyuki, Okada Yoshikiyo, Kurihara Chie, Irie Rie, Yokoyama Hirokazu, Shimamura Katsuyoshi, Usui Shingo, Ebinuma Hirotoshi, Saito Hidetsugu, Watanabe Chikako, Komoto Shunsuke, Kawaguchi Atsushi, Nagao Shigeaki, Sugiyama Kazuo, Hokari Ryota, Kanai Takanori, Miura Soichiro, Hibi Toshifumi

Hepatology 59 ( 1 ) 154 - 169 2014.01

ISSN 0270-9139

Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion: These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

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Continuous low-dose irradiation by I-125 seeds induces apoptosis of gastric cancer cells regardless of histological origin

Takabayashi Kaoru, Kashiwagi Kazuhiro, Kawata Tetsuya, Sato Toshiro, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Takaishi Hiromasa, Hibi Toshifumi, Ogata Haruhiko, Yahagi Naohisa, Kitagawa Yuko, Shigematsu Naoyuki, Kanai Takanori

Cancer Biology and Therapy 15 ( 1 ) 81 - 88 2014.01

ISSN 1538-4047

The efficacy of conventional radiation therapy for gastric cancer is controversial. In this study, we evaluated the in vitro and in vivo effects of continuous low-dose-rate irradiation by I-125 seeds on different histological types of gastric cancer cell lines. Three human gastric cancer cell lines (MKN74, MKN45, and NUGC4) were treated with or without continuous low-dose irradiation by I-125 seeds in vitro and in vivo. Cell viability, apoptosis, caspase-3 assay, and cell-cycle distribution were examined in vitro. Body weight and tumor volumes of BALB/c nude mice bearing MKN74, MKN45, and NUGC4 gastric cancer xenografts were measured, and in vivo cell proliferation and apoptosis assays were performed by Ki67 and TUNEL staining, respectively. Continuous low-dose-rate irradiation by I-125 seeds reduced cell viability and induced cell apoptosis through the activation of caspase-3, and led to the accumulation of cells in the G2/M phase in vitro. It also suppressed the growth of gastric cancer xenografts in nude mice, while inhibiting cell proliferation and inducing apoptosis as demonstrated by Ki67 and TUNEL staining. Therefore, our data suggest that continuous low-dose-rate irradiation by I-125 seeds could be a promising new option for gastric cancer treatment, regardless of histological origin. © 2014 Landes Bioscience.

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Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice.

Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Okada Y, Kurihara C, Irie R, Yokoyama H, Shimamura K, Usui S, Ebinuma H, Saito H, Watanabe C, Komoto S, Kawaguchi A, Nagao S, Sugiyama K, Hokari R, Kanai T, Miura S, Hibi T.

Hepatology 59 ( 1 ) 154 - 69 2014.01

Joint Work, Accepted

Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH.

CONCLUSION:

These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

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Diet, microbiota, and inflammatory bowel disease

Kanai Takanori, Matsuoka Katsuyoshi, Naganuma Makoto, Hayashi Atsushi, Hisamatsu Tadakazu

Korean Journal of Internal Medicine 29 ( 4 ) 409 - 415 2014

ISSN 1226-3303

The incidence and prevalence of inflammatory bowel diseases (IBDs) including ulcerative colitis and Crohn disease are rapidly increasing in Western countries and in developed Asian countries. Although biologic agents targeting the immune system have been effective in patients with IBD, cessation of treatment leads to relapse in the majority of patients, suggesting that intrinsic immune dysregulation is an effect, not a cause, of IBD. Dramatic changes in the environment, resulting in the dysregulated composition of intestinal microbiota or dysbiosis, may be associated with the fundamental causes of IBD. Japan now has upgraded water supply and sewerage systems, as well as dietary habits and antibiotic overuse that are similar to such features found in developed Western countries. The purpose of this review article was to describe the association of diet, particularly Japanese food and microbiota, with IBD. © 2014 The Korean Association of Internal Medicine.

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Diagnosis and management of intestinal Behçet's diseas

Hisamatsu Tadakazu, Naganuma Makoto, Matsuoka Katsuyoshi, Kanai Takanori

Clinical Journal of Gastroenterology 7 ( 3 ) 205 - 212 2014

ISSN 1865-7257

Behçets disease (BD) is a chronic relapsing disease with multiple organ system involvement characterized clinically by oral and genital aphthae, cutaneous lesions, and ophthalmological, neurological, and/or gastrointestinal manifestations. Little clinical evidence is available regarding the management of patients with intestinal BD, despite recognition that the presence of intestinal lesions is a poor prognostic factor, causing perforation and massive bleeding. Many recent case reports have suggested that anti-tumor necrosis factor alpha (TNF)α monoclonal antibodies (mAbs) are effective in patients with intestinal BD. Adalimumab, a fully human anti-TNFα mAb, has been approved in Japan for the treatment of intestinal BD. Here, we review the pathogenesis, diagnosis and management of intestinal BD, including evidence of the efficacy of anti-TNFα mAbs. © 2014 Springer Japan.

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Acyl-CoA

Tomita Kengo, Teratani Toshiaki, Suzuki Takahiro, Shimizu Motonori, Sato Hirokazu, Narimatsu Kazuyuki, Usui Shingo, Furuhashi Hirotaka, Kimura Akifumi, Nishiyama Kiyoshi, Maejima Tadashi, Okada Yoshikiyo, Kurihara Chie, Shimamura Katsuyoshi, Ebinuma Hirotoshi, Saito Hidetsugu, Yokoyama Hirokazu, Watanabe Chikako, Komoto Shunsuke, Nagao Shigeaki, Sugiyama Kazuo, Aosasa Suefumi, Hatsuse Kazuo, Yamamoto Junji, Hibi Toshifumi, Miura Soichiro, Hokari Ryota, Kanai Takanori

Journal of Hepatology 61 ( 1 ) 98 - 106 2014

ISSN 0168-8278

Background & Aims Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis. Methods ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4) ^-/-ACAT1^+/+ and TLR4^-/-ACAT1^-/- mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl₄) for 4 weeks to induce liver fibrosis. Results ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling. Conclusions ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Cross-talk between ROR_γt ⁺ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production In Crohn's disease

Mizuno Shinta, Mikami Yohei, Kamada Nobuhiko, Handa Tango, Hayashi Atsushi, Sato Toshiro, Matsuoka Katsuyoshi, Matano Mami, Ohta Yuki, Sugita Akira, Koganei Kazutaka, Sahara Rikisaburo, Takazoe Masakazu, Hisamatsu Tadakazu, Kanai Takanori

Inflammatory Bowel Diseases 20 ( 8 ) 1426 - 1434 2014

ISSN 1078-0998

Background: Interleukin (IL)-22-producing ROR_γt ⁺ innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of ROR _γt
⁺ ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD. Methods: CD45+ lineage marker-ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14+ macrophages, and IL-22 production was evaluated. Results: CD127⁺CD56^- and CD127 ⁺CD56⁺ ILC, but not CD127^-CD56⁺ or CD127^-CD56^- ILC, subsets expressed ROR_γt and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1_α and Claudin-1 in human intestinal epithelial organoids. Conclusions: ROR_γt
⁺ ILCs might enhance mucosal barrier function through the upregulation of Reg1 _α through production of IL-22. Although CD14⁺ macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by ROR_γt
⁺ ILCs. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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Endoscopic and pathologic changes of the upper gastrointestinal tract in Crohn's disease

Sakuraba Atsushi, Iwao Yasushi, Matsuoka Katsuyoshi, Naganuma Makoto, Ogata Haruhiko, Kanai Takanori, Hibi Toshifumi

BioMed Research International 2014 2014

ISSN 2314-6133

Background. Crohn's disease (CD) may involve any part of the gastrointestinal tract. We assessed the prevalence and features of upper gastrointestinal (UGI) lesions in CD. Methods. This was a retrospective study that included 138 CD patients that underwent esophagogastroduodenoscopy (EGD). The rate of Crohn's specific endoscopic lesions in the esophagus, stomach, and duodenum was assessed, and immunohistochemical analysis was performed. Changes in the UGI lesions were assessed in those who had two or more EGD. Results. Of 138 patients, 51.3% had Crohn's specific UGI lesions. The rates of Crohn's specific lesion in the esophagus, upper-to-middle stomach, lower stomach, duodenal bulb, and 2nd portion of the duodenum were 6.5%, 47.8%, 24.6%, 31.9%, and 18.1%, respectively. Granulomas were detected in 6.1%, 25.0%, and 11.4% in the upper-to-middle stomach, lower stomach, and duodenal bulb, respectively, but none in the esophagus and 2nd portion of the duodenum. Thirty-seven were analyzed for Helicobacter pylori and 4 were positive (10.8%). Improvements of UGI lesions were seen in 14 out of 49 (28.5%) and were unchanged in 59.2% and worsened in 12.2%. Conclusions. The prevalence of Crohn's specific UGI lesions was common in our case series, and immunohistochemical studies suggested that the majority was unrelated to Helicobacter pylori infection. Worsening of UGI lesions over the course was rare. © 2014 Atsushi Sakuraba et al.

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Effectiveness and clinical results of endoscopic management of sigmoid volvulus using unsedated water-immersion colonoscopy

Sugimoto Shinya, Hosoe Naoki, Mizukami Takeshi, Tsunoda Yuya, Ito Tsuyoshi, Imamura Satoshi, Tamura Toshihide, Nagakubo Shuichi, Morohoshi Yuichi, Koike Yuji, Fujita Yuriko, Komatsu Hirokazu, Ogata Haruhiko, Kanai Takanori

Digestive Endoscopy 26 ( 4 ) 564 - 568 2014

ISSN 0915-5635

Background and Aim Although intestinal obstruction as a result of sigmoid volvulus (SV) may be successfully resolved using endoscopic detorsion, surgical treatment remains the main therapeutic strategy. We evaluated the endoscopic detorsion procedure using unsedated water-immersion colonoscopy for the treatment of SV. Methods A retrospective chart review was conducted on the clinical background and prognosis of 21 SV patients who underwent 71 endoscopic detorsion procedures using unsedated, water-immersion colonoscopy. Results In all, 14 (67%) male and seven (33%) female patients, with a mean age of 73 years (range, 54-95 years) were enrolled; 86% were >70 years of age. Among these patients, 90% had a background of key predisposing factors. In the 21 patients, endoscopic detorsion was successfully done using unsedated water-immersion colonoscopy. SV recurred in 10 patients at a median of 180 days. Endoscopic detorsion for recurrent SV was successfully achieved in all cases, and none of the secondary cases became severe. Only male patients were observed to experience three or more recurrent episodes of SV. Conclusions SV occurred most commonly in elderly patients with a surgical risk. Our experience suggests that conservative endoscopic treatment using unsedated water-immersion colonoscopy is a safe, reasonable, conservative endoscopic approach for elderly patients in the absence of necrotic findings. We currently use this procedure in most of our cases. © 2014 The Authors. Digestive Endoscopy © 2014 Japan Gastroenterological Endoscopy Society.

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