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Constitutive androstane receptor agonist, TCPOBOP,attenuates steatohepatitis in the methionine choline-deficientdiet-fed mouse

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World Journal of Gastroenterology 2007年第42期13卷 5635-5641页

作者： Edwina S Baskin-Bey Akira Anan hajime isomoto Steven F Bronk Gregory J Gores Department of Medicine Division of Gastroenterology and Hepatology Miles and Shirely Fitterman Center for Digestive Diseases Mayo Clinic College of Medicine Rochester MN 55905 United States

AIM： To ascertain whether constitutive androstane receptor （CAR） activation by 1,4-bis-[2-（3,5,- dichloropyridyloxy）] benzene （TCPOBOP） modulates steatohepatitis in the methionine choline-deficient （MCD） diet-fed ***： C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, ***： Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis （44.6 ＋ 5.4% vs 30.4 ＋ 4.5%, P 〈 0.05） and serum triglyceride levels （48 ＋ 8 vs 20 ＋ 1 mg/dL, P 〈 0.05） in MCD diet- fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal co-oxidation and peroxisomal p-oxidation, namely CYP4A10, LPBE, and 3-ketoacyI-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above ***： CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

关键词： Apoptosis CYP4A Fatty acid oxidation,Inflammation

Programmed cell death-1 inhibitor-related sclerosing cholangitis:A systematic review

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World Journal of Gastroenterology 2020年第3期26卷 353-365页

作者： Takumi Onoyama Yohei Takeda Taro Yamashita Wataru Hamamoto Yuri Sakamoto Hiroki Koda Soichiro Kawata Kazuya Matsumoto hajime isomoto Division of Medicine and Clinical Science Department of Multidisciplinary Internal MedicineFaculty of MedicineTottori UniversityTottori prefecture 683-8504Japan Internal Medicine Irisawa Medical ClinicShimane prefecture 690-0025Japan

BACKGROUND Programmed cell death-1(PD-1)inhibitor has been indicated for many types of ***,these inhibitors also cause immune-related adverse *** disorder is a phenotype of immune-related adverse event affecting 0%–4.5%of patients treated with PD-1 *** studies have reported PD-1 inhibitor-related sclerosing cholangitis(SC);however,the associated clinical and pathological features are *** To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the *** The review,conducted using electronic databases in PubMed,was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in *** scanned the references of the selected literature to identify any further relevant *** cases previously studied by us,including three that have not yet been published,were included in this *** Thirty-one PD-1 inhibitor-related SC cases were *** age of patients was 67 years(range,43–89),with a male to female ratio of 21:*** main disease requiring PD-1 inhibitor treatment was non-small cell lung *** that caused PD-1 inhibitor-related SC were nivolumab(19 cases),pembrolizumab(10 cases),avelumab(1 case),and durvalumab(1 case).The median number of cycles until PD-1 inhibitor-related SC onset was 5.5(range,1–27).Abdominal pain or discomfort(35.5%,11/31)was the most frequent *** serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes,and a normal level of serum immunoglobulin *** dilation without obstruction(76.9%,20/26),diffuse hypertrophy of the extrahepatic biliary tract(90.5%,19/21),and multiple strictures of the intrahepatic biliary tract(30.4%,7/23)were *** 11/23(47.8%)cases,pathological examination indicated that CD8+T cells were the dominant inflammatory cells i

关键词： Nivolumab Pembrolizumab Avelumab Durvalumab Atezolizumab Programmed cell death-1 inhibitor Immune-related adverse events Cholangitis

Plasma leptin and ghrelin concentrations in patients with Crohn's disease

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World Journal of Gastroenterology 2005年第46期11卷 7314-7317页

作者： Yoshito Nishi hajime isomoto Hiroaki Ueno Ken Ohnita Chun Yang Wen Fuminao Takeshima Ryosuke Mishima Masamitsu Nakazato Shigeru Kohno Second Department of Internal Medicine Nagasaki University School of Medicine Sakamoto 1-7-1 Nagasaki Japan Department of Endoscopy Nagasaki University School of Medicine Sakamoto 1-7-1Nagasaki Japan Department of Molecular Pathology Atomic Bomb Disease Institute Nagasaki University School of MedicineSakamoto 12-4 Nagasaki Japan Third Departmentof Internal Medicine Miyazaki Medical College KiyotakeMiyazaki Japan

AIM: To determine the concentrations of leptin and ghrelin, which have opposite effects on appetite,energy expenditure, and weight control, in the plasma of patients with Crohn's disease (CD), which is often associated with weight loss and ***: Plasma leptin and ghrelin concentrations were determined in 28 outpatients with CD by radioimmunoassay. Age- and sex-matched controls with and without Helicobacter pylori(H pylori) infection (28for each) were enrolled in the study. Circulating levels of these hormones were assessed with respect to CD activity, disease localization and medical ***: There were no significant differences in ghrelin levels between CD patients and H pylorinegative controls. However, circulating ghrelin levels were significantly lower in H pylori-infected subjects than in CD patients and uninfected controls. Plasma leptin levels were comparable among the groups. Localization and medication profile had no significant impact on circulating ghrelin and leptin ***: Apart from H pyloriinfection, CD itself has no significant influence on circulating ghrelin and leptin levels in the outpatients who were mostly in inactive state.

关键词： Crohn's disease Ghrelin Leptin Helicobacter pylori

Endoscopic identification of Peyer's patches of the terminal ileum in a patient with Crohn's disease

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World Journal of Gastroenterology 2004年第18期10卷 2767-2768页

作者： Hiroshi Ishimoto hajime isomoto Saburo Shikuwa Chun Yang Wen Takashi Suematu Masahiro Ito Ikuo Murata Hiromi Ishibashi Shigeru Kohno DepartmentofInternalMedicine NationalNagasakiMediealCenter2-1001KubaraOmuraNagasaki856-8562Japan GastrointestinalUnit.MassachusettsGenerulHospital DepartmentofMedicineHarvardMedicalSchoolJackson70655FruitStreetBostonMa02114USA DepartmentofMolecularPalhology AtomicBombDiseaseInstituteNagasakiUniversitySchoolofMedicine1-7-1SakarnotoNagasnki852-8501Japan ContralElectroscopeLaboratory NagasakiUniversitySchoolofMedicineNagasaki852-8501Japan DepartmentofPathology NationalNagasakiMedicalCenterj2-1001KubaraOmuraNagasaki856-8562Japan

We presented a 20-year-old patient with Crohn's disease (CD).Colonoscopy revealed longitudinal ulceration in the terminal ileum and rectal aphtoid *** treatment with mesalamine and total parenteral nutrition,repeat colonoscopy revealed a granular elevated area in the terminal ileum,which appeared as an irregular dome-like elevation with irregularly arranged villi on magnifying *** specimens taken from the region showed microgranulomas and lymphoid hyperplasia,Scanning electron microscopy revealed the presence of M cells,confirming that the area corresponded to Peyer's ***'s patches by magnifying endoscopy and electron microscopy may provide insights into the pathogenesis of CD.

关键词： Adult Biopsy Crohn Disease Endoscopes, Gastrointestinal Humans Ileum Intestinal Mucosa Male Microscopy, Electron, Scanning Peyer's Patches

Endoscopic ultrasound-guided fine-needle aspiration biopsy-Recent topics and technical tips

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World Journal of Clinical Cases 2019年第14期7卷 1775-1783页

作者： Kazuya Matsumoto Yohei Takeda Takumi Onoyama Soichiro Kawata Hiroki Kurumi Hiroki Koda Taro Yamashita hajime isomoto Division of Internal Medicine Irisawa Medical ClinicMatsue 690-0025Japan Department of Multidisciplinary Internal Medicine Tottori UniversityYonago 683-8504Japan

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is a useful procedure that enables reliable pathological diagnoses of pancreatobiliary diseases, subepithelial lesions, and swollen lymph nodes. In recent years, a pathological diagnosis based on EUS-FNA has made it possible to provide accurate treatment methods not only in these fields, but also in respiratory organs and otorhinolaryngology. This review discusses the latest topics pertaining to EUS-FNA as well as procedural tips.

关键词： Endoscopic ultrasound-guided fine-needle aspiration biopsy Cytology Pathology Pancreatobiliary diseases Subepithelial lesions Lymph nodes

High concentrations of human β-defensin 2 in gastric juice of patients with Helicobacter pylori infection

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World Journal of Gastroenterology 2005年第31期11卷 4782-4787页

作者： hajime isomoto Hiroshi Mukae Hiroshi Ishimoto Yoshito Nishi Chun-Yang Wen Akihiro Wad Ken Ohnita Toshiya Hirayama Masamitsu Nakazato Shigeru Kohno Second Department of Internal Medicine Nagasaki University School of Medicine Sakamoto 1-7-1Nagasaki Japan Department of Molecular Pathology Atomic Bomb Disease Institute Nagasaki University School of MedicineSakamoto 12-4 Nagasaki Japan Department of Bacteriology Institute of Tropical Medicine Nagasaki University School of Medicine Sakamoto 12-4 Nagasaki Japan Third Department of Internal Medicine Miyazaki Medical College Kiyotake Miyazaki Japan

MIA： Human β-defensin （HBD）-1 and HBD-2 are endogenous antimicrobial peptides. Unlike HBD-1, the HBD-2 expression is augmented by Helicobacter pylori （H pylon）. We sought to determine HBD-1 and HBD-2 concentrations in gastric juice during Hpylori infection. METHODS： HBD-1 and HBD-2 concentrations were measured by radioimmunoassay in plasma and gastric juice of 49 Hpylori-infected and 33 uninfected subjects and before and after anti-H pyloritreatment in,13 patients with Hpylori-associated gastritis. Interleukin （IL）-1β and IL-8 concentrations in gastric juice were measured by enzyme-linked immunosorbent assay （ELISA）. Histological grades of gastritis were determined using two biopsy specimens taken from the antrum and corpus. Reverse phase high performance liquid chromatography （RP-HPLC） was used to identify HBD-2. RESULTS： HBD-2 concentrations in gastric juice, but not in plasma, were significantly higher in Hpylori-positive than -negative subjects, albeit the post-treatment levels were unchanged. Immunoreactivity for HBD-2 was exclusively identified in Hpylori-infected mucosa by RPHPLC. HBD-2 concentrations in gastric juice correlated with histological degree of neutrophil and mononuclear cell infiltration in the corpus. IL-1β levels correlated with those of IL-8, but not HBD-2. Plasma and gastric juice HBD-1 concentrations were similar in H pylori-infected and uninfected subjects. CONCLUSION： Our results place the β-defensins, especiallyHBD-2, in the front line of innate immune defence. Moreover, HBD-2 may be involved in the pathogenesis of Hpylori-associated gastritis, possibly through its function as immune and inflammatory mediator.

关键词： β-defensin 1 β-defensin 2 Helicobacterpylori

Role of the preoperative usefulness of the pathological diagnosis of pancreatic diseases

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World Journal of Gastrointestinal Oncology 2016年第9期8卷 656-662页

作者： Kazuya Matsumoto Yohei Takeda Takumi Onoyama Soichiro Kawata Hiroki Kurumi Masaru Ueki Norimasa Miura hajime isomoto Department of Gastroenterology Tottori University Hospital Department of Next Generation Advanced Medical Promotion Center Tottori University Hospital Division of Pharmacotherapeutics Department of Pathophysiological and Therapeutic ScienceFaculty of MedicineTottori University

Pancreatic cancer is the fifth leading cause of cancer death and has the lowest survival rate of any solid *** ultrasound-guided fine-needle aspiration biopsy(EUS-FNA) is currently capable of providing a cytopathological diagnosis of pancreatic malignancies with a higher diagnostic power,with a sensitivity and specificity of 85%-89% and 98%-99%,compared to pancreatic juice cytology(PJC),whose sensitivity and specificity are only 33.3%-93% and 83.3%-100%.However,EUS-FNA is not effective in the cases of carcinoma in situ and minimally invasive carcinoma because both are undetectable by endoscopic ultrasonography,although PJC is able to detect *** for the frequency of complications such as post endoscopic retrograde cholangiopancreatography pancreatitis,EUS-FNA is safer than *** diagnose pancreatic cancer appropriately,it is necessary for us to master both procedures so that we can select the best methods of sampling tissues while considering the patient's safety and condition.

关键词： Endoscopic ultrasound-guided fine-needle aspiration biopsy Cytology Pathology Pancreatic juice cytology Pancreatic cancer

Association of polymorphic alleles of CTLA4 with inflammatory bowel disease in the Japanese

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World Journal of Gastroenterology 2005年第27期11卷 4188-4193页

作者： Haruhisa Machida Kazuhiro Tsukamoto Chun-Yang Wen Yukiko Narumi Saburou Shikuwa hajime isomoto Fuminao Takeshima Yohei Mizuta Norio Niikawa Ikuo Murata Shigeru Kohno Second Department of Internal Medicine Nagasaki University School of Medicine 1-7-1 SakamotoNagasaki 852-8501 Japan Department of Pharmacotherapeutics Nagasaki University Graduate School of Biomedical Sciences 1-14 Bunkyo-machi Nagasaki 852-8521Japan Department of Molecular Pathology Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences 1-12-4 Sakamoto Nagasaki 852-8523Japan Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences 1-12-4 Sakamoto Nagasaki 852-8523 Japan

AIM： To examine an association between the cytotoxic Tlymphocyte antigen 4 （CTLA4） gene that plays a role in downregulation of T-cell activation and inflammatory bowel disease consisting of ulcerative colitis （UC） and Crohn＇s disease （CD） in the ***： We studied 108 patients with UC, 79 patients with CD, and 200 sex-matched healthy controls, with respect to three single nucleotide polymorphisms （SNPs） in CTLA4, such as C-318T in the promoter region, A＋49 Gin exon 1 and G＋6230A in the 3＇ untranslated region （3＇-UTR） by a PCR-restriction fragment length polymorphism method, and to an （AT）, repeat polymorphism in 3＇-UTR by fragment analysis with fluorescence-labeling on denaturing sequence gels. Frequency of alleles and genotypes and their distribution were compared statistically between patients and controls and among subgroups of patients, using X^2 and Fisher exact ***： The frequency of ＂A/A＂ genotype at the G＋6230A SNP site was statistically lower in UC patients than in controls （3.7% vs 11.0%, P = 0.047, odds ratio （OR） = 0.311）. Moreover, the frequency of ＂G/G＂ genotype at the A＋49G SNP site was significantly higher in CD patients with fistula （48.6%） than those without it （26.2%）（P = 0.0388, OR=2.67）.CONCLUSION： The results suggest that CTLA4 located at 2q33 is a determinant of UC and responsible for fistula formation in CD in the Japanese.

关键词： Ulcerative colitis CTLA4 gene Diseasesusceptible gene Crohn's disease Fistula formation

NAT2＊6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

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World Journal of Gastroenterology 2007年第45期13卷 6003-6008页

作者： Norihide Higuchi Naoko Tahara Katsunori Yanagihara Kiyoyasu Fukushima Naofumi Suyama Yuichi Inoue Yoshitsugu Miyazaki Tsutomu Kobayashi Koh-ichiro Yoshiura Norio Niikawa, Chun-Yang Wen, hajime isomoto,Saburou Shikuwa, Katsuhisa Omagari, Yohei Mizuta, Shigeru Kohno, Kazuhiro Tsukamoto Norio Niikawa Chun-Yang Wen hajime isomoto Saburou Shikuwa Katsuhisa Omagari Yohei Mizuta Shigeru Kohno Kazuhiro Tsukamoto Department of Pharmacotherapeutics Nagasaki University Graduate School of Biomedical Sciences 1-14 Bunkyo-machi Nagasaki 852-8521 Japan Department of Internal Medicine Nagasaki University Graduate School of Biomedical Sciences Sakamoto 1-7-1 Nagasaki 852-8501 Japan Division of Internal Medicine Japanese Red Cross Nagasaki Genbaku Isahaya Hospital Isahaya 859-0497 Japan Department of Internal Medicine Nagasaki Municipal Medical Center Nagasaki 852-8012 Japan Y Department of Internal Medicine Isahaya Health Insurance General Hospital Isahaya 854-8501 Japan Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences Sakamoto 1-12-4 Nagasaki 852-8523 Japan SORST JST Kawaguchi Japan Department of Digestive Disease Center Beihua University Jilin 132013 Jilin Province China

AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression ***: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.

关键词： Tuberculosis Anti-tuberculosis drugs Drug-induced hepatotoxicity NAT2-haplotype DNA-baseddiagnosis