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Induction of CD69 expression by cag PAI-positive Helicobacter pylori infection

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World Journal of Gastroenterology 2011年第32期17卷 3691-3699页

作者： naoki Mori Chie Ishikawa Masachika Senba Department of Microbiology and Oncology Graduate School of Medicine University of the Ryukyus Nishihara Okinawa 903-0215 Japan Department of Internal Medicine Omoromachi Medical Center 1-3-1 Uenoya Naha Okinawa 900-0011 Japan Transdisciplinary Research Organization for Subtropics and Island Studies University of the Ryukyus Nishihara Okinawa 903-0213 Japan Department of Pathology Institute of Tropical Medicine Nagasaki University Nagasaki 852-8523 Japan

AIM: To investigate and elucidate the molecular mechanism that regulates inducible expression of CD69 by Helicobacter pylori (H. pylori ) infection. METHODS: The expression levels of CD69 in a T-cell line, Jurkat, primary human peripheral blood mononuclear cells (PBMCs), and CD4 + T cells, were assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry. Activation of CD69 promoter was detected by reporter gene. Nuclear factor (NF)-κB activation in Jurkat cells infected with H. pylori was evaluated by electrophoretic mobility shift assay. The role of NF-κB signaling in H. pylori-induced CD69 expression was analyzed using inhibitors of NF-κB and dominant-negative mutants. The isogenic mutants with disrupted cag pathogenicity island (cag PAI) and virD4 were used to elucidate the role of cag PAI-encoding type Ⅳ secretion system and CagA in CD69 ***: CD69 staining was detected in mucosal lymphocytes and macrophages in specimens of pa- tients with H. pylori-positive gastritis. Although cag PAI- positive H. pylori and an isogenic mutant of virD4 induced CD69 expression, an isogenic mutant of cag-PAI failed to induce this in Jurkat cells. H. pylori also induced CD69 expression in PBMCs and CD4 + T cells. The activation of the CD69 promoter by H. pylori was mediated through NF-κB. Transfection of dominant-negative mutants of IκBs, IκB kinases, and NF-κB-inducing kinase inhibited H. pylori-induced CD69 activation. Inhibitors of NF-κB suppressed H. pylori-induced CD69 mRNA expression. CONCLUSION: The results suggest that H. pylori induces CD69 expression through the activation of NF-κB. cagPAI might be relevant in the induction of CD69 expression in T cells. CD69 in T cells may play a role in H. pylori-induced gastritis.

关键词： CD69 T cells Helicobacter pylori cag pathogenicity island Nuclear factor-κB

Impact of glucocorticoid on neurogenesis

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Neural Regeneration Research 2017年第7期12卷 1028-1035页

作者： Haruki Odaka naoki Adachi Tadahiro Numakawa Department of Life Science and Medical Bioscience School of Advanced Science and EngineeringWaseda University Department of Cell Modulation Institute of Molecular Embryology and GeneticsKumamoto University Department of Biomedical Chemistry School of Science and TechnologyKwansei Gakuin University Department of Mental Disorder Research National Institute of NeuroscienceNational Center of Neurology and Psychiatry (NCNP)

Neurogenesis is currently an area of great interest in *** is closely linked to brain diseases,including mental disorders and neurodevelopmental *** embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of ***,proliferation/differentiation of the neural stem/progenitor cells（NSPCs）is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase（PI3K）/Akt,hedgehog,and *** review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms;this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

关键词： neural progenitor cells glucocorticoids neurogenesis in tracellular signaling pathways

Apoptosis and non-alcoholic fatty liver diseases

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World Journal of Gastroenterology 2018年第25期24卷 2661-2672页

作者： Tatsuo kanda Shunichi Matsuoka Motomi Yamazaki Toshikatsu Shibata Kazushige Nirei Hiroshi Takahashi Tomohiro Kaneko Mariko Fujisawa Teruhisa Higuchi Hitomi Nakamura naoki Matsumoto Hiroaki Yamagami Masahiro Ogawa Hiroo Imazu Kazumichi Kuroda Mitsuhiko Moriyama Division of Gastroenterology and Hepatology Department of Medicine Nihon University School of Medicine

The number of patients with nonalcoholic fatty liver diseases(NAFLD) including nonalcoholic steatohepatitis(NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma(HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.

关键词： Apoptosis Autophagy c-Jun N-terminal kinase Nonalcoholic fatty liver diseases Nonalcoholic steatohepatitis

Ligand density-dependent influence of arginine-glycine- aspartate functionalized gold nanoparticles on osteogenic and adipogenic differentiation of mesenchymal stem cells

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Nano Research 2018年第3期11卷 1247-1261页

作者： Jingchao Li Ying Chen naoki Kawazoe Guoping Chen Intemational Center for Materials Nanoarchitectonics National lnstitute for Materials Science 1-1 Namiki Tsukuba Ibaraki 305-0044Japan Department of Materials Science and Engineering Graduate School of Pure and Applied Sciences University of Tsukuba 1-1-1 Tennodai Tsukuba Ibaraki 305-8577 Japan Research Center for Functional Materials National Institute for Materials Science 1- 1 Namiki Tsukuba Ibaraki 305-0044 Japan

Extracellular matrix （ECM） plays a very important role in regulating cell function and fate. It is highly desirable to fabricate biomimetic models to investigate the role of ECM in stem cell differentiation. In this study, arginine- glycine--aspartate （RGD）-modified gold nanoparticles （Au NPs） with tunable surface ligand density were prepared to mimic the ECM microenvironment. Their effect on osteogenic and adipogenic differentiation of human mesenchymal stem cells （MSCs） was investigated. The biomimetic Au NPs were taken up by MSCs in a ligand density-dependent manner. The biomimetic NPs with a high RGD density had an inhibitive effect on the alkaline phosphatase （ALP） activity, calcium deposition, and osteogenic marker gene expression of MSCs. Their effect on oil droplet formation and adipogenic marker gene expression was negative when RGD density was low, while their effect was promotive when RGD density was high. The biomimetic Au NPs regulated the osteogenic and adipogenic differentiation of MSCs mainly through affecting the focal adhesion and cytoskeleton. This study highlights the roles of biomimetic NPs on stem cell differentiation that could provide a meaningful strategy in fabricating functional biomaterials for tissue engineering and biomedical applications.

关键词： arginine-glycine--aspartate(RGD) density biomimetic goldnanopartides (Au NPs) osteogenic differentiation adipogenic differentiation mesenchymal stem cells

Clinical utility of the platelet-lymphocyte ratio as a predictor of postoperative complications after radical gastrectomy for clinical T2-4 gastric cancer

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World Journal of Gastroenterology 2017年第14期23卷 2519-2526页

作者： Kenichi Inaoka Mitsuro kanda Hiroaki Uda Yuri Tanaka Chie Tanaka Daisuke Kobayashi Hideki Takami naoki Iwata Masamichi Hayashi Yukiko Niwa Suguru Yamada Tsutomu Fujii Hiroyuki Sugimoto Kenta Murotani Michitaka Fujiwara Yasuhiro Kodera Department of Gastroenterological Surgery (Surgery II) Nagoya University Graduate School of Medicine Division of Biostatistics Clinical Research Center Aichi Medical University Hospital

AIMTo identify simple and sensitive markers for postoperative complications after gastrectomy, the predictive values were compared among candidate preoperative ***-hundred and twelve patients with previously untreated clinical T2-4 gastric cancer who underwent a D2 standard gastrectomy (distal gastrectomy or total gastrectomy) were included in the analysis. Correlations between 21 parameters that can be determined by preoperative routine blood tests and clinically relevant postoperative complications (grade II or higher according to the Clavien-Dindo classification) were evaluated. The optimal cutoff values and clinical significance of the selected markers were further evaluated by subgroup analyses according to age, body mass index, operative procedure and clinical disease ***-six patients (21.1%) experienced grade II or higher postoperative complications. The platelet-lymphocyte ratio (PLR, total lymphocyte count/platelet count × 100) exhibited the highest area under the curve value (0.639) for predicting postoperative complications among the 21 parameters, and the optimal cutoff value was determined to be 0.71 (sensitivity = 70%, specificity = 56%). In the univariate analysis, the odds ratio of a low PLR for the occurrence of postoperative complications was 2.94 (95%CI: 1.66-5.35, P < 0.001), and a multivariate binomial logistic analysis involving other potential risk factors identified a low PLR as an independent risk factor for postoperative complications (OR = 3.32, 95%CI: 1.82-6.25, P < 0.001). In subgroups classified according to age, body mass index, operative procedure and clinical disease stage, the low PLR group exhibited an increased incidence of postoperative *** preoperative PLR is a simple and useful predictor of complications after curative gastrectomy in patients with clinical T2-4 gastric cancer.

关键词： Gastric cancer Gastrectomy Platelet-lymphocyte ratio Postoperative complication Prediction

Gastrointestinal stromal tumor of the stomach with axillary lymph node metastasis: A case report

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World Journal of Gastroenterology 2017年第9期23卷 1720-1724页

作者： naoki Kubo Nobumichi Takeuchi Department of Surgery Ina central HospitalInashiNagano 396-8555Japan

Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesenchymal tumors, although metastasis to the perigastric lymph nodes is relatively rare, compared with liver or peritoneal metastasis. In this report, we describe a case of stomach GIST with a solitary simultaneous metastasis in the left axillary lymph node. A 68-year-old man was diagnosed with a large upper-stomach GIST, and computed tomography and positron emission tomography revealed masses in the left axilla and right mediastinum. We did not detect evidence of metastases to the liver, or other sites including the perigastric lymph nodes, although findings from the surgically resected axillary lymph nodes were compatible with GIST metastasis. Treatment using imatinib markedly reduced the gastric and mediastinal lesions, and this response persisted for 3 years. The patient subsequently experienced rapid growth of the gastric lesion without mediastinal or axilla recurrence, which required palliative surgery. Despite continuing medical treatment(sunitinib and regorafenib), the patient died of liver metastases 23 mo after the surgery. Based on our findings, it appears that the axillary lymph nodes can be a potential metastatic site for GIST metastasis.

关键词： Gastrointestinal stromal tumor Axillary Lymph node Metastasis Imatinib

Hepatitis C virus NS5A inhibitors and drug resistance mutations

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World Journal of Gastroenterology 2014年第11期20卷 2902-2912页

作者： Shingo Nakamoto Tatsuo kanda Shuang Wu Hiroshi Shirasawa Osamu Yokosuka Department of Molecular Virology Graduate School of MedicineChiba UniversityChiba 260-8677Japan Department of Gastroenterology and Nephrology Graduate School of MedicineChiba UniversityChiba 260-8677Japan

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HCV-infected patients. “First generation” HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

关键词： ACH-3102 Direct-acting antiviral agents Daclatasvir Hepatitis C virus Ledipasvir

Selective extraction of In(Ⅲ),Ga(Ⅲ) and Zn(Ⅱ) using a novel extractant with phenylphosphinic acid

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Chinese Journal of Chemical Engineering 2016年第2期24卷 232-236页

作者： Yuji Sasaki naoki Matsuo Tatsuya Oshima Yoshinari Baba Department of Applied Chemistry Faculty of EngineeringUniversity of Miyazaki

A new extractant, [N,N-di（2-ethylhexyl）aminolmethylphenylphosphinic acid （DEAPP）, was synthesized to de- velop the mutual separation techniques of In（Ⅲ）, Ga（Ⅲ） and Zn（Ⅱ）. The extraction selectivity for In（Ⅲ）, Ga（Ⅲ） and Zn（Ⅱ） with DEAPP was higher than that of the commercial phosphorus acid extractants such as D2EHPA and PC-88A. The extraction selectivity for metal ions in 1 mob L 1 aqueous ammonium nitrate solution with DEAPP was in the following order： In（Ⅲ）〉 Ga（Ⅲ）〉 Zn（Ⅱ）. These selective extraction behaviors indicate that the amino moiety of DEAPP plays an important role in the mutual separation of ln（Ⅲ）, Ga（Ⅲ） and Zn（ll）. The extraction equilibria of In（Ⅲ）, Ga（Ⅲ） and Zn（Ⅱ） with DEAPP （ = HR） were expressed by the following reactions： In3＋＋ 2（HR）2 InR3（HR）＋ 3H＋, Ga3＋＋ 1.5（HR）2 ＋ N- = GaR2（HR）（NO3）＋ 2H＋, and Zn2＋ 4- 2（HR）2 ZnR2 （HR） 2 determined 4- 2H＋. The extraction equilibrium constants of In（Ⅲ）, Ga（Ⅲ） and Zn（Ⅱ） with DEAPP were to be Kex, M = 1.7 × 104 [*** 1], 4.17 [（***-1）s], and 1.55 × 10 2 [-], respectively.

关键词： Liquid-liquid extraction Phosphinic acid Indium(Ⅲ) Gallium(Ⅲ) Zinc(Ⅱ) Mutual separation Extraction equilibrium

Gastrojejunostomy followed by induction chemotherapy for incurable gastric cancer with outlet obstruction

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World Journal of Gastroenterology 2010年第34期16卷 4367-4370页

作者： Yasuhiro Okumura Manabu Ohashi Souya Nunobe Tomohiro Iwanaga Tatsuo kanda Yoshiaki Iwasaki Department of Surgery Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Department of Gastrointestinal Surgery Tokyo University Hospital Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences

A 72-year-old male gastric cancer patient with outlet obstruction underwent laparoscopic exploration. The examination disclosed intraperitoneal free cancer cells with no overt peritoneal, lymphatic, or hepatic metastasis. The patient underwent laparoscopy-assisted gastroje-junostomy (LAGJ) and started chemotherapy with S-1 plus cisplatin on postoperative day 13. Three course of the chemotherapy shrank the tumor markedly. Then, the patient underwent gastrectomy with a curative intent. Laparotomy revealed no intraperitoneal free cancer cells, and microscopically complete resection was achieved. The patient received S-1 chemotherapy as postoperative adjuvant treatment for 1 year, and is still alive with no evidence of peritoneal recurrence. LAGJ followed by S-1 plus cisplatin is one of the optional treatments that should be considered for patients with outlet obstruction as it may widen opportunities for potentially curative resection.

关键词： Gastric cancer Outlet obstruction CY1 Laparoscopy-assisted gastrojejunostomy S-1 plus cisplatin