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Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1

World Journal of Gastroenterology 2013年第33期19卷 5500-5507页

作者： Atsushi Iraha Hiroshi Chinen Akira Hokama Takumi Yonashiro Tetsu Kinjo Kazuto Kishimoto manabu nakamoto Tetsuo Hirata Nagisa Kinjo Futoshi Higa Masao Tateyama Fukunori Kinjo Jiro Fujita Department of Infectious Respiratoryand Digestive MedicineFaculty of MedicineUniversity of the Ryukyus Department of Endoscopy University of the Ryukyus Hospital Uruma Bio Co Ltd

AIM:To evaluate the protective effects of fucoidan on oxidative stress-induced barrier disruption in human intestinal epithelial ***:In Caco-2 cell monolayer models,the disruption of barrier function by oxidative stress is mediated by *** integrity of polarized Caco-2 cell monolayers was determined by measuring the transepithelial resistance(TER)and permeability was estimated by measuring the paracellular transport of FITC-labeled4-kDa dextran(FD4).The protective effects of fucoidan on epithelial barrier functions on polarized Caco-2 cell monolayers were evaluated by TER and FD4 *** expression of tight junction(TJ)proteins was assessed using reverse-transcription polymerase chain reaction(RT-PCR)and immunofluorescence ***:Without H2O2treatment,fucoidan significantly increased the TER compared to control(P<0.05),indicating a direct enhancement of intestinal epithelial barrier ***,H2O2disrupted the epithelial barrier function in a time-dependent *** prevented the H2O2-induced destruction in a dosedependent *** significantly decreased H2O2-induced FD4 flux(P<0.01),indicating the prevention of disruption in paracellular *** showed that Caco-2 cells endogenously expressed claudin-1 and-2,and occludin and that H2O2reduced the mRNA expression of these TJ *** with fucoidan attenuated the reduction in the expressions of claudin-1 and claudin-2 but not *** staining revealed that the expression of claudin-1 was intact and high on the cell surface.H2O2disrupted the integrity of *** with fucoidan dramatically attenuated the expression of ***:Fucoidan enhanced intestinal epithelial barrier function by upregulating the expression of ***,fucoidan may be an appropriate therapy for the treatment of inflammatory bowel diseases.

关键词： Fucoidan Tight junction Intestinal epithelial cells Oxidative stress Inflammatory bowel diseases

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Endoscopic and histopathological study on the duodenum of Strongyloides stercoralis hyperinfection

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World Journal of Gastroenterology 2008年第11期14卷 1768-1773页

作者： Kazuto Kishimoto Akira Hokama Tetsuo Hirata Yasushi Ihama manabu nakamoto Nagisa Kinjo Fukunori Kinjo Jiro Fujita Department of Endoscopy Ryukyu University HospitalOkinawa 903-0215Japan Department of Medicine and Therapeutics(First Department of Internal Medicine) Control and Prevention of Infectious DiseaseFaculty of Medicine University of the RyukyusOkinawa 903-0215Japan

AIM:To investigate endoscopic and histopathological findings in the duodenum of patients with Strongyloides stercoralis(***)hyperinfection. METHODS:Over a period of 23 years(1984-2006),we investigated 25 patients *** hyperinfection who had had an esophagogastroduodenoscopy before undergoing treatment for *** clinical and endoscopic findings were analyzed retrospectively. RESULTS:Twenty-four(96%)of the patients investigated were under immunocompromised condition which was mainly due to a human T lymphotropic virus type 1(HTLV-1)*** abnormal endoscopic findings,mainly edematous mucosa,white villi and erythematous mucosa,were observed in 23(92%) *** degree of duodenitis including villous atrophy/destruction and inflammatory cell infiltration corresponded to the severity of the endoscopic findings. The histopathologic yield for identifying larvae was 71.4% by duodenal *** endoscopic findings of duodenitis were more severe in patients whose biopsies were positive for larvae than those whose biopsies were negative(Endoscopic severity score:4.86±2.47vs 2.71 ±1.38,P<0.05). CONCLUSION:Our study clearly demonstrates that,in addition to stool analysis,endoscopic observation and biopsies are very *** also emphasize that *** and HTLV-1 infections should be ruled out before immunosuppressive therapy is administered in endemic regions.

关键词： Strongyloides stercoralis Strongyloidiasis Hyperinfection Endoscopy Histopathology Duodenum

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Diagnosis of intestinal tuberculosis using a monoclonal antibody to Mycobacterium tuberculosis

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World Journal of Gastroenterology 2012年第47期18卷 6974-6980页

作者： Yasushi Ihama Akira Hokama Kenji Hibiya Kazuto Kishimoto manabu nakamoto Tetsuo Hirata Nagisa Kinjo Haley L Cash Futoshi Higa Masao Tateyama Fukunori Kinjo Jiro Fujita Department of Infectious Respiratoryand Digestive MedicineFaculty of MedicineUniversity of the RyukyusOkinawa 903-0215Japan Department of Endoscopy Ryukyu University HospitalOkinawa 903-0215Japan

AIM:To investigate the utility of immunohistochemical(IHC) staining with an antibody to Mycobacterium tuberculosis(***) for the diagnosis of intestinal tuberculosis(TB).METHODS:We retrospectively identified 10 patients(4 males and 6 females;mean age = 65.1 ± 13.6 years) with intestinal *** characteristics,including age,gender,underlying disease,and symptoms were *** radiograph and laboratory tests,including sputum Ziehl-Neelsen(ZN) staining,*** culture,and sputum polymerase chain reaction(PCR) for tubercle bacilli DNA,as well as Tuberculin skin test(TST) and QuantiFERON-TB gold test(QFT),were *** records recorded on the basis of Sato's classification were also reviewed,in addition to data from intestinal biopsies examined for histopathological findings,including hematoxylin and eosin staining,and ZN staining,as well as *** culture,and PCR for tubercle bacilli *** the present study,archived formalin-fixed paraffin-embedded(FFPE) intestinal tissue samples were immunohistochemically stained using a commercially available species-specific monoclonal antibody to the 38-kDa antigen of the *** *** sections were also stained with the pan-macrophage marker CD68 ***:From the clinical data,we found that no patients were immunocompromised,and that the main symptoms were diarrhea and weight *** patients displayed active pulmonary TB,six patients(60%) had a positive TST,and 4 patients(40%) had a positive *** findings revealed that all patients had type 1 findings(linear ulcers in a circumferential arrangement or linear ulcers arranged circumferentially with mucosa showing multiple nodules),all of which were located in the right hemicolon and/or terminal *** patients(70%) had concomitant healed lesions in the ileocecal *** acid-fast bacilli were detected with ZN staining of the intestinal tissue samples,and both *** culture and PCR

关键词： Colonoscopy Intestinal tuberculosis Immunohistochemistry Monoclonal antibody Mycobacterium tuberculosis

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Endoscopic and histopathological features of gastrointestinal amyloidosis

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World Journal of Gastrointestinal Endoscopy 2011年第8期3卷 157-161页

作者： Akira Hokama Kazuto Kishimoto manabu nakamoto Chiharu Kobashigawa Tetsuo Hirata Nagisa Kinjo Fukunori Kinjo Seiya Kato Jiro Fujita Department of Infectious Respiratory and Digestive Medicine Faculty of Medicine University of the Ryukyus Okinawa 903-0125 Japan Department of Endoscopy University Hospital of the Ryukyus Okinawa 903-0125 Japan Department of Pathology and Cell Biology Faculty of Medicine University of the Ryukyus Okinawa 903-0125 Japan

Amyloidosis is a rare disorder, characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloidosis can be acquired or hereditary, and systemic or localized to a single organ, such as the gastrointestinal (GI) tract. Clinical manifestations may vary from asymptomatic to fatal forms. Primary amyloidosis (monoclonal immunoglobulin light chains, AL) is the most common form of amyloidosis. AL amyloidosis has been associated with plasma cell dyscrasias, such as, mul- tiple myeloma. Secondary amyloidosis is caused by the deposition of fragments of the circulating acute-phase reactant, serum amyloid A protein (SAA). Common causes of AA amyloidosis are chronic inflammatory dis-orders. Although GI symptoms are usually nonspecific, histopathological patterns of amyloid deposition are associated with clinical and endoscopic features. Amyloid deposition in the muscularis mucosae, submucosa, and muscularis propria has been dominant in AL amyloidosis, leading to polypoid protrusions and thickening of the valvulae conniventes, whereas granular amyloid deposition mainly in the propria mucosae has been related to AA amyloidosis, resulting in the fine granular appearance, mucosal friability, and erosions. As a result, AL amyloidosis usually presents with constipation, mechanical obstruction, or chronic intestinal pseudoobstruction while AA amyloidosis presents with diarrhea and malabsorption Amyloidotic GI symptoms are mostly refractory and have a negative impact on quality of life and survival. Diagnosing GI amyloidosis requires high suspicion of evaluating endoscopists. Because of the absence of specific treatments for reducing the abundance of the amyloidogenic precursor protein, we should be aware of certain associations between patterns of amyloid deposition and clinical and endoscopic features.

关键词： Amyloidosis Amyloid Congo red Endoscopy Gastrointestinal tract Histopathology

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Detection of active bleeding from gastric antral vascular ectasia by capsule endoscopy

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World Journal of Gastrointestinal Endoscopy 2013年第3期5卷 138-140页

作者： Tetsuya Ohira Akira Hokama Nagisa Kinjo manabu nakamoto Chiharu Kobashigawa Yuya Kise Satoshi Yamashiro Fukunori Kinjo Yukio Kuniyoshi Jiro Fujita Department of Endoscopy University Hospital of the RyukyusOkinawa 903-0125Japan Department of Infectious Respiratory and Digestive MedicineGraduate School of MedicineUniversity of the RyukyusOkinawa 903-0125Japan Division of Thoracic and Cardiovascular Surgery Graduate School of MedicineUniversity of the RyukyusOkinawa 903-0125Japan

Gastric antral vascular ectasia(GAVE) has been recognized as one of the important causes of occult and obscure gastrointestinal *** diagnosis is typically made based on the characteristic endoscopic features,including longitudinal row of flat,reddish stripes radiating from the pylorus into the antrum that resemble the stripes on a *** appearances,however,can easily be misinterpreted as moderate to severe *** it is believed that capsule endoscopy(CE) is not helpful for the study of the stomach with its large lumen,GAVE can be more likely to be detected at CE rather than conventional *** can be regarded as "physiologic" endoscopy,without the need for gastric inflation and subsequent compression of the *** blood flow of the ecstatic vessels may be diminished in an inflated ***,GAVE may be prominent in *** herein describe a case of active bleeding from GAVE detected by CE and would like to emphasize a possibility that CE can improve diagnostic yields for GAVE.

关键词： Gastrointestinal bleeding Gastrointestinal endoscopy Capsule endoscopy Gastric antral vascular ectasia Argon plasma coagulation

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Esophagitis dissecans superficialis and autoimmune bullous dermatoses: A review

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World Journal of Gastrointestinal Endoscopy 2010年第7期2卷 252-256页

作者： Akira Hokama Yu-ichi Yamamoto Kiyohito Taira Mitsuteru Nakamura Chiharu Kobashigawa manabu nakamoto Tetsuo Hirata Nagisa Kinjo Fukunori Kinjo Kenzo Takahashi Jiro Fujita Department of Infectious Respiratory and Digestive MedicineFaculty of Medicine University of the RyukyusOkinawa 903-0125Japan Department of Dermatology Faculty of MedicineUniversity of the RyukyusOkinawa 903-0125Japan Department of Endoscopy University Hospital of the RyukyusOkinawa 903-0125Japan

Esophagitis dissecans superficialis(EDS)is a rare and severe endoscopic finding characterized by sloughing of large fragments of esophageal mucosal *** EDS has been reported in association with serious illnesses and certain medications,the pathophysiological association of autoimmune bullous dermatoses with EDS has gained remarkable *** these dermatoses,pemphigus vulgaris and pemphigoid frequently present with various types of esophageal involvement including *** review the pathophysiology and clinical features of this involvement with the presentation of our *** importance of endoscopic evaluation of this entity is discussed.

关键词： Esophagitis dissecans superficialis Endoscopy Autoimmune bullous dermatoses Pemphigus vulgaris Mucous membrane pemphigoid Bullous pemphigoid Desmoglein

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Endoscopic and radiographic features of gastrointestinal involvement in vasculitis

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World Journal of Gastrointestinal Endoscopy 2012年第3期4卷 50-56页

作者： Akira Hokama Kazuto Kishimoto Yasushi Ihama Chiharu Kobashigawa manabu nakamoto Tetsuo Hirata Nagisa Kinjo Futoshi Higa Masao Tateyama Fukunori Kinjo Kunitoshi Iseki Seiya Kato Jiro Fujita Department of Infectious Respiratory and Digestive MedicineFaculty of MedicineUniversity of the Ryukyus Endoscopy Unit University Hospital of the Ryukyus Dialysis Unit University Hospital of the Ryukyus Department of Pathology and Cell Biology Faculty of MedicineUniversity of the Ryukyus

Vasculitis is an inflammation of vessel walls,followed by alteration of the blood flow and damage to the dependent *** can cause local or diffuse pathologic changes in the gastrointestinal (GI) *** variety of GI lesions includes ulcer,submucosal edema,hemorrhage,paralytic ileus,mesenteric ischemia,bowel obstruction,and life-threatening *** endoscopic and radiographic features of GI involvement in vasculitisare reviewed with the emphasis on small-vessel vasculitis by presenting our typicalcases,including Churg-Strauss syndrome,HenochSch nlein purpura,systemic lupus erythematosus,and Beh et's *** endoscopic features are ischemic enterocolitis and *** computed tomographic findings include bowel wall thickening with the target sign and engorgement of mesenteric vessels with comb *** of endoscopic and radiographic GI manifestations can help make an early diagnosis and establish treatment strategy.

关键词： Behcet’s disease Churg-Strauss syndrome Computed tomography Endoscopy Gastrointestinal tract Henoch-Schonlein purpura Histopathology Lupus mesenteric vasculitis Systemic lupus erythematosus Vasculitis

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Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

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World Journal of Gastroenterology 2018年第17期24卷 1839-1858页

作者： Naofumi Mukaida Yasunari nakamoto Division of Molecular Bioregulation Cancer Research Institute Kanazawa University Second Department of Internal Medicine Faculty of Medical Sciences University of Fukui

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

关键词： natural killer T cell natural killer cell chimeric antigen receptor T cell T cell receptor cytokine-induced killer cell program death-1 cytotoxic lymphocyte antigen-4 regulatory T cell dendritic cell myeloid-derived suppressor cell PD-ligand 1 peptide vaccine tumor-associated antigen tumor infiltrating lymphocyte

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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

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Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review

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World Journal of Gastroenterology 2013年第47期19卷 8940-8948页

作者： Shuang Wu Tatsuo Kanda Shingo nakamoto Fumio Imazeki Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba UniversityGraduate School of MedicineChiba 260-8677Japan Postdoctoral Fellow Foreign Researcher of the Japan Society for Promotion of Science (JSPS)Tokyo 102-0083Japan Department of Molecular Virology Chiba UniversityGraduate School of MedicineChiba 260-8677Japan Safety and Health Organization Chiba UniversityChiba 263-8522Japan

Direct-acting antiviral agents(DAAs)for hepatitis C virus(HCV)infection are one of the major advances in its medical *** HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States,Europe,and *** combined with peginterferon plus ribavirin,these agents increase sustained virologic response rates to70%-80%in treatment-na?ve patients and previoustreatment relapsers with chronic HCV genotype 1 *** peginterferon plus ribavirin,DAA monotherapies increased DAA-resistance *** new DAAs for HCV are now in clinical development and are likely to be approved in the near ***,it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain ***,these mutations exhibit cross-resistance to multiple *** prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown,and it is as yet uncertain whether such variants are sensitive to *** performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease ***,we reviewed the literature on resistance variants of HCV protease inhibitors in treatment na?ve patients with chronic HCV genotype 1,as well as our experience.

关键词： Direct-acting antiviral agent Hepatitis C virus Protease inhibitor Resistance mutation Sequence analysis

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