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Vaccine therapy for dysbiosis-related diseases

World Journal of Gastroenterology 2020年第21期26卷 2758-2767页

作者： kosuke fujimoto Satoshi Uematsu Department of Immunology and Genomics Osaka City University Graduate School of MedicineOsaka 545-8585Japan Division of Innate Immune Regulation International Research and Development Center for Mucosal VaccinesThe Institute of Medical ScienceThe University of TokyoTokyo 113-8654Japan Division of Metagenome Medicine Human Genome CenterThe Institute of Medical ScienceThe University of TokyoTokyo 113-8654Japan Collaborative Research Institute for Innovative Microbiology The University of TokyoTokyo 113-8654Japan

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases,such as obesity,diabetes,rheumatoid arthritis,and inflammatory bowel diseases represented by Crohn’s disease and ulcerative colitis.Dysregulated gut microbiome contributes to the pathogenesis of such disorders;however,there are few effective treatments for controlling only disease-mediating bacteria.Here,we review current knowledge about the intestinal microbiome in health and disease,and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides,which we have recently developed.Unlike other conventional injectable immunizations,our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity.This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection,and control metabolic symptoms mediated by intestinal bacteria(e.g.Clostridium ramosum)by induction of high titers of antigen-specific IgA at target mucosal sites.In the future,our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.

关键词： Dysbiosis IgA Microbiome Mucosal immunity Pathobiont Vaccine

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A COMPREHENSIVE SOFTWARE SUITE FOR THE ANALYSIS OF CDNAS

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Genomics, Proteomics & Bioinformatics 2005年第3期3卷 179-188页

作者： KAZUHARU ARAKAWA HARUO SUZUKI kosuke FUJISHIMA KENJI fujimoto SHO UEDA MOTOMU MATSUI MASARU TOMITA INSTITUTE FOR ADVANCED BIOSCIENCES KEIO UNIVERSITY FUJISAWA 252-8520 JAPAN BIOINFORMATICS PROGRAM OF THE GRADUATE SCHOOL OF MEDIA AND GOV- ERNANCE KEIO UNIVERSITY FUJISAWA 252-8520 JAPAN INSTITUTE FOR ADVANCED BIOSCIENCES KEIO UNIVERSITYFUJISAWA 252-8520 JAPAN

We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detection of translation initia- tion and termination signals, statistical analysis of codon usage, comparative study of amino acid composition, comparative modeling of the structures of product proteins, prediction of alternative splice forms, and metabolic pathway reconstruction. The software package is freely available under the GNU General Public License at http： / /***/ data/cdna/.

关键词： cDNA bioinformatics, software

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Dual therapy with zinc acetate and rifaximin prevents from ethanolinduced liver fibrosis by maintaining intestinal barrier integrity

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World Journal of Gastroenterology 2021年第48期27卷 8323-8342页

作者： Yuki fujimoto kosuke Kaji Norihisa Nishimura Masahide Enomoto Koji Murata Soichi Takeda Hiroaki Takaya Hideto Kawaratani Kei Moriya Tadashi Namisaki Takemi Akahane Hitoshi Yoshiji Department of Gastroenterology Nara Medical UniversityKashihara 6348521NaraJapan

BACKGROUND Hepatic overload of gut-derived lipopolysaccharide dictates the progression of alcoholic liver disease(ALD)by inducing oxidative stress and activating Kupffer cells and hepatic stellate cells through toll-like receptor 4 signaling.Therefore,targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of ALD.Zinc acetate and rifaximin,which is a nonabsorbable antibiotic,had been clinically used for patients with cirrhosis,particularly those with hepatic encephalopathy,and had been known to improve intestinal barrier dysfunction.However,only few studies focused on their efficacies in preventing the ALD-related fibrosis development.AIM To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD model.METHODS To induce ALD-related liver fibrosis,female C57BL/6J mice were fed a 2.5%(v/v)ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbon tetrachloride(CCl4)injection twice weekly(1 mL/kg)for 8 wk.Zinc acetate(100 mg/L)and/or rifaximin(100 mg/L)were orally administered during experimental period.Hepatic steatosis,inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular analyses.Moreover,the direct effects of both agents on Caco-2 barrier function were assessed by in vitro assays.RESULTSIn the ethanol plus CCl4-treated mice,combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4.This combination significantly inhibited the Kupffer cells expansion and the proinflammatory response with blunted hepatic exposure of lipopolysaccharide and the toll-like receptor 4/nuclear factor kB pathway.Consequently,liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2,-9,-13,and Timp1.Both agents improved the atrophic changes and permeability in the ileum,with restoration of tight junction proteins(TJPs)by decreasing the expressions of tumor necrosis

关键词： Liver fibrosis Intestinal permeability Alcoholic liver disease Lipopolysaccharide Toll-like receptor Tight junction protein

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Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites

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Portal Hypertension & Cirrhosis 2023年第3期2卷 109-114页

作者： Fumimasa Tomooka Kei Moriya Takahiro Kubo Akihiko Shibamoto Jyunya Suzuki Satoshi Iwai Soichi Takeda Yuki fujimoto Masahide Enomoto Koji Murata Yuki Tsuji Yukihisa Fujinaga Koh Kitagawa Norihisa Nishimura Hiroaki Takaya kosuke Kaji Hideto Kawaratani Tadashi Namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji Department of Gastroenterology and Hepatology Nara Medical UniversityKashiharaJapan Department of Gastroenterology Nara Prefectural General Medical CenterShichijo-NishimachiJapan

Aims:No solid evidence-based opinion was raised regarding predictors of the degree of ascites reduction with tolvaptan.This retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of this.Methods:The study population consisted of 80 patients with liver cirrhosis treated with tolvaptan for hepatic ascites effusions at Nara Medical University Hospital from May 2014 to December 2018.Forty-three patients who lost>1.5 kg of body weight in the first week after starting tolvaptan were classified as good responders and the remaining 37 as poor responders.Various laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its efficacy.Results:In the univariate analysis,no significant differences with respect to age(67.6 vs.69.8 years,p>0.05),sex,body mass index(24.8 vs.23.7 kg/m^(2),p>0.05),Child-Pugh score(9.4 vs.9.7,p>0.05),and Model for End-stage Liver Disease score(11 vs.12,p>0.05)were found between the two groups.Conversely,aspartate transferase and alanine transaminase(ALT)levels were significantly lower in the good response group(52.9±56.3 vs.68.8±50.7 U/L,p<0.05;26.2±30.6 vs.40.5±33.5 U/L,p<0.01),whereas serum copeptin and serum sodium concentrations were significantly higher(57.1±15.0 vs.45.8±16.0 pg/mL,p<0.01;136.3±3.4 vs.133.8±5.8 mEq/L,p<0.05).In the multivariate analysis,serum copeptin concentration and ALT were statistically significant factors(p<0.01,p<0.05).Regression analysis of the association between the tolvaptan efficacy for refractory ascites and pretreatment serum copeptin concentration showed that a copeptin concentration cutoff of 45.9 pg/mL could predict treatment efficacy with a sensitivity,specificity,and area under the curve of 76.7%,59.5%,and 0.71%,respectively.Conclusion:Serum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis.

关键词： ascites copeptin decompensated liver cirrhosis diuretics tolvaptan

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Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis

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World Journal of Gastroenterology 2009年第41期15卷 5193-5199页

作者： Mitsuteru Kitade Hitoshi Yoshiji Ryuichi Noguchi Yasuhide Ikenaka kosuke Kaji Yusaku Shirai Masaharu Yamazaki Masahito Uemura Junichi Yamao Masao fujimoto Akira Mitoro Masahisa Toyohara Masayoshi Sawai Motoyuki Yoshida Chie Morioka Tatsuhiro Tsujimoto Hideto Kawaratani Hiroshi Fukui Third Department of Internal Medicine Nara Medical University

AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18expression and HOMA-R were signifi cantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.

关键词：胰岛素抵抗血管生成细胞角蛋白脂肪肝酒精性串扰肝炎佛罗里达州

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Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

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World Journal of Gastroenterology 2006年第42期12卷 6786-6791页

作者： Hitoshi Yoshiji Ryuichi Noguchi Hideyuki Kojima Yasuhide Ikenaka Mitsuteru Kitade kosuke Kaji Masahito Uemura Junichi Yamao Masao fujimoto Masaharu Yamazaki Masahisa Toyohara Akira Mitoro Hiroshi Fukui Third Department of Internal Medicine Nara Medical University Nara Japan

AIM: To evaluate the effect of combination treatment with the interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-Ⅰ) on several fibrotic indices in patients with refractory chronic hepatitis C (CHC). METHODS: Perindopril (an ACE-Ⅰ; 4 mg/d) and/or natural IFN (3 MU/L; 3 times a week) were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed. RESULTS: ACE-Ⅰdecreased the serum fibrosis markers, whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-Ⅰ, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-b was significantly attenuated almost in parallel with suppression of the serum fibrosis markers. CONCLUSION: The combination therapy of an ACE- Ⅰand IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

关键词：抗纤维化血管紧张素丙型病毒肝炎病毒感染

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Combined treatment of vitamin K_2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis

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World Journal of Gastroenterology 2007年第23期13卷 3259-3261页

作者： Hitoshi Yoshiji Ryuichi Noguchi Masaharu Yamazaki Yasuhide Ikenaka Masayoshi Sawai Masatoshi Ishikawa Hideto Kawaratani Tsuyoshi Mashitani Mitsuteru Kitade kosuke Kaji Masahito Uemura Junichi Yamao Masao fujimoto Akira Mitoro Masahisa Toyohara Motoyuki Yoshida Hiroshi Fukui Third Department of Internal Medicine Nara Medical University

Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor (ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodule in the liver detected by enhanced computed tomography along with elevation of the tumor markers, namely, alpha-fetoprotein (AFP) and lectin-reactive demarcation (AFP-L3), suggesting the presence of latent HCC. After oral administration of VK and ACE-I, the serum levels of both AFP and AFP-L3 gradually decreased without any marked alteration of the serum aminotransferase activity. After one-year treatment, not only the serum levels of AFP and AFP-L3 returned to the normal ranges, but also the dysplastic nodule disappeared. Since both VK and ACE-I are widely used without serious side effects, this combined regimen may become a new strategy for chemoprevention against HCC.

关键词：维生素K2 ACE抑制剂肝细胞癌 VEGF

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Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report

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World Journal of Gastroenterology 2007年第27期13卷 3760-3762页

作者： kosuke Kaji Hitoshi Yoshiji Masahide Yoshikawa Masaharu Yamazaki Yasuhide Ikenaka Ryuichi Noguchi Masayoshi Sawai Masatoshi Ishikawa Tsuyoshi Mashitani Mitsuteru Kitade Hideto Kawaratani Masahito Uemura Junichi Yamao Masao fujimoto Akira Mitoro Masahisa Toyohara Motoyuki Yoshida Hiroshi Fukui Third Department of Internal Medicine Nara Medical University Nara Japan Department of Parasitology Nara Medical University Nara Japan

Although the etiology of eosinophilic cholecystitis is still obscure, the postulated causes include allergies, parasites, hypereosinophilic syndrome, and eosinophilic gastroenteritis. It is sometimes accompanied by several complications, but a simultaneous onset with pericarditis is very rares. A 28-year-old woman complained of acute right hypocondrial pain and dyspnea associated with systemic eruption. Several imaging modalities revealed acute cholecystitis and pericarditis with massive pericardial effusion. A marked peripheral blood eosinophilia was observed, and the eruption was diagnosed as urticaria. Her serum had a high titer of antibody against Ascaris lumbricoides . Treatment with albendazole drastically improved all clinical manifestations along with normalization of the imaging features and eosinophilia. We report herein a rare case of simultaneous onset of acute cholecystitis and pericarditis associated with a marked eosinophilia caused by parasitic infection.

关键词：胆囊炎蛔虫寄生物嗜曙红细胞过多心包炎

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Eosinophilic cholecystitis as a rare manifestation of visceral larva migrans

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World Journal of Gastroenterology 2007年第45期13卷 6119-6119页

作者： Hitoshi Yoshiji Masahide Yoshikawa kosuke Kaji Hiroshi Fukui Department of Internal Medicine Nara Medical University Nara Japan Department of Parasitology Nara Medical University Nara Japan

Eosinophilic cholecystitis is an infrequent form of cholecystitis. The etiology of eosinophilic cholecystitis is still obscure, and it is sometimes accompanied with several complications, but a simultaneous onset with pericarditis is very rare. We would like to make an alternative interpretation of our recent report "Kaji K, Yoshiji H, Yoshikawa M, Yamazaki M, Ikenaka Y, Noguchi R, Sawai M, Ishikawa M, Mashitani T, Kitade M, Kawaratani H, Uemura M, Yamao J, fujimoto M, Mitoro A, Toyohara M, Yoshida M, Fukui H. Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report. World J Gastroenterol 2007; 13: 3760-3762."

关键词：胆囊炎内脏幼虫蛔虫

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A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2012年第5期4卷 115-118页

作者： Yosuke Aihara Hitoshi Yoshiji Masaharu Yamazaki Yasuhide Ikenaka Ryuichi Noguchi Chie Morioka kosuke Kaji Haruki Tastumi Keisuke Nakanishi Maiko Nakamura Junichi Yamao Masahisa Toyohara Akira Mitoro Masayoshi Sawai Motoyuki Yoshida Masao fujimoto Masahito Uemura Hiroshi Fukui Third Department of Internal Medicine Nara Medical UniversityNara 634-8522Japan

Sorafenib,a multikinase inhibitor,is the first and only drug,which improves significantly the overall survival in patients with advanced hepatocellular carcinoma(HCC).However,many patients experience diverse side effects,some of them severe and unexpected.To date,acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib.Here,we report the case of a 43-yearold woman with hepatitis C virus-related advanced HCC.She received sorafenib,and later complained ofa sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense.Laboratory examination showed mild elevation of transaminases,biliary enzymes,bilirubin,inflammation markers,and a marked peripheral eosinophilia.Abdominal computed tomography(CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris.Consequently,sorafenib treatment was stopped immediately,and steroid-pulse therapy was performed.Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings,eosinophilia,and liver functions.In summary,we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.

关键词： Hepatocelluar carcinoma Sorafenib Acalculous cholecystitis

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