研究者詳細 - 横田　憲治

Seventeen-year effects of eradicating Helicobacter pylori on the prevention of gastric cancer in patients with peptic ulcer; a prospective cohort study 査読

Susumu Take, Motowo Mizuno, Kuniharu Ishiki, Fumihiro Hamada, Tomowo Yoshida, Kenji Yokota, Hiroyuki Okada, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 50 ( 6 ) 638 - 644 2015年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

We previously reported that eradication of Helicobacter pylori in our cohort of patients with peptic ulcer disease reduced their risk of developing gastric cancer to approximately one-third after a mean follow-up period of 3.4 years (up to 8.6 years). We have now followed these patients for a longer period.
A total of 1,222 consecutive patients with peptic ulcer diseases who completed more than 1-year follow-up after receiving H. pylori eradication therapy were followed with annual endoscopic surveillance for a mean of 9.9 years (as long as 17.4 years).
H. pylori infection was judged cured in 1,030 patients (eradication-success group) but persisted in 192 (eradication-failure group) after initial eradication therapy. In the eradication-failure group, 114 patients received re-treatment at a mean of 4.4 years after the start of follow-up, and 105 of these were cured of infection. Gastric cancer developed in 21 of the 1,030 patients in the eradication-success group and in nine of the 192 in the failure group (p = 0.04). The risk of developing gastric cancer in the eradication-success group (0.21 %/year) was significantly lower than that in the failure group (0.45 %, p = 0.049). The longest interval between the initial H. pylori eradication and the occurrence of gastric cancer was 14.5 years in the eradication-success group and 13.7 years in the eradication-failure group.
A prophylactic effect for gastric cancer persists for more than 10 years after H. pylori eradication therapy, but we should be aware that cancer can develop even after that interval.

DOI： 10.1007/s00535-014-1004-5

[A Study to Determine the Optimum Antigens for the Serodiagnosis of Helicobacter Pylori Infection in Japanese Patients and the Association with IgG Subclass and Gastric Cancer]. 査読

Kita M, Take S, Okada H, Matsushita O, Yokota K

Rinsho byori. The Japanese journal of clinical pathology 63 ( 2 ) 180 - 186 2015年2月

細菌必須遺伝子を標的とする阻害リード化合物の口腔細菌に対する効果

苔口進, 狩山玲子, 横田憲治, 渡辺朱理

日本環境感染学会誌 30 ( Suppl. ) 438 - 438 2015年1月

環境汚染菌の消毒剤含浸ワイプによる拭き取り効果の検討

横田憲治, 渡邉都貴子, 林俊治, 渡辺朱理, 苔口進, 平井義一

日本環境感染学会誌 30 ( Suppl. ) 206 - 206 2015年1月

Antibacterial activity of a novel synthetic progesterone species carrying a linoleic acid molecule against Helicobacter pylori and the hormonal effect of its steroid on a murine macrophage-like cell line 査読

Avarzed Amgalanbaatar, Hirofumi Shimomura, Kouichi Hosoda, Shunji Hayashi, Kenji Yokota, Yoshikazu Hirai

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 140 17 - 25 2014年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Helicobacter pylori, a pathogen responsible for gastric and duodenal diseases, absorbs various steroid compounds into the cell membrane even though some are toxic to this bacterium. An earlier study by our group has demonstrated that progesterone is bactericidal to H. pylori. In this study, we newly synthesized a steroid compound, 17 alpha-hydroxyprogesterone linoleic acid ester (17hPL), to examine antibacterial activity against H. pylori. As expected, 17hPL acted as a bactericidal agent to H. pylori and had no effect on the survival of other common bacterial species. This steroidal substance interacted with phosphatidylethanolamine (PE) on the outer membrane of H. pylori to induce the release of PE from the bacterial cell membrane and to ultimately lyse the bacterial cells. One of the hormonal effects of progesterone is the inhibition of nitric oxide (NO) production from mouse macrophages activated by lipopolysaccharide (LPS). We therefore examined the inhibition effect of 17hPL on the NO production of RAW 264.7 cells, a murine macrophage-like cell line, stimulated with LPS and demonstrated that 17hPL is relatively weaker in its capability to inhibit NO production in LPS-activated cells than progesterone. These results suggest the possibility that 17hPL could be an oral medicine for selectively treating patients infected with H. pylori. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2013.10.023

病院内の環境細菌調査

横田憲治, 渡邉都貴子, 苔口進, 林俊治, 平井義一

日本環境感染学会誌 29 ( Suppl. ) 287 - 287 2014年1月

[New Helicobacters other than H. pylori]. 査読

Yokota K, Kita M, Okada H, Matsushita O, Oguma K

Nihon rinsho. Japanese journal of clinical medicine 71 ( 8 ) 1374 - 1379 2013年8月

The Genetic Diversity of Helicobacter pylori Virulence Genes Is Not Associated with Gastric Atrophy Progression 査読

Masahide Kita, Kenji Yokota, Hiroyuki Okada, Susumu Take, Ryuta Takenaka, Yoshiro Kawahara, Keiji Oguma, Osamu Matsushita, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 67 ( 2 ) 93 - 98 2013年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at -80 degrees C prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was slc/ml (93%). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.

DOI： 10.18926/AMO/49667

Detoxification of 7-Dehydrocholesterol Fatal to Helicobacter pylori Is a Novel Role of Cholesterol Glucosylation 査読

Hirofumi Shimomura, Kouichi Hosoda, David J. Mcgee, Shunji Hayashi, Kenji Yokota, Yoshikazu Hirai

JOURNAL OF BACTERIOLOGY 195 ( 2 ) 359 - 367 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

The glucosylation of free cholesterol (FC) by Helicobacter pylori cells has various biological significances for the survival of this bacterium. H. pylori cells with glucosylated FC are capable of evading host immune systems, such as phagocytosis by macrophages and activation of antigen-specific T cells, and surviving in the gastric mucosal tissues for long periods. An additional role of cholesterol glucosylation in the survival of H. pylori which is distinct from the role of escaping the host immune system, however, has yet to be identified. This study demonstrated that 7-dehydrocholesterol (7dFC), an FC precursor, is a toxic compound fatal to H. pylori cells, but the cell membrane of H. pylori is capable of absorbing this toxic sterol via glucosylation. In contrast to the case with 7dFC, no toxicity to H. pylori cells was detected from the glucosylated 7dFC. In addition, cgt gene mutant H. pylori cells that cannot glucosylate cholesterols had higher susceptibility to the toxic action of 7dFC than wild-type H. pylori cells. These results indicate that the cgt gene product of H. pylori serves to detoxify the sterol fatal to this bacterium and to permit this toxic sterol as a cell membrane lipid component. In summary, this study defined a novel role of cholesterol glucosylation in H. pylori.

DOI： 10.1128/JB.01495-12

Reinfection rate of Helicobacter pylori after eradication treatment: a long-term prospective study in Japan 査読

Susumu Take, Motowo Mizuno, Kuniharu Ishiki, Takayuki Imada, Tetsuji Okuno, Tomowo Yoshida, Kenji Yokota, Keiji Oguma, Masahide Kita, Hiroyuki Okada, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 47 ( 6 ) 641 - 646 2012年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

We previously reported that the reinfection rate with Helicobacter pylori in Japan was low despite a high prevalence of infection. In the present study, we extended our previous work to more accurately determine the reinfection rate.
We enrolled 1625 patients (219 women and 1406 men, mean age 50.8 years) who had received H. pylori eradication therapy. After documentation of eradication, bacterial culture and urea breath test were carried out yearly. H. pylori strains were analyzed by using random amplification of polymorphic DNA fingerprinting.
A total of 1609 patients were followed for up to 12.5 years (mean 4.7 years); H. pylori became re-positive in 26 patients. In 13 of the 26 patients, H. pylori became positive at the first-year follow up. Stored H. pylori isolates were available for analysis from ten of the 13 patients; four of the isolates were genetically different from the initial strain, but the other six were identical to the initial strain. In the other 13 patients, H. pylori became positive at later follow up (mean 4.8 years; range 1.8-8.0 years). In all of the four of these patients whose isolates could be analyzed, the H. pylori strains were different from the initial strain. Assuming that reinfection occurred in the four patients positive for different strains of H. pylori at the first-year follow up and in the 13 positive at later follow up, the reinfection rate was 0.22% per year.
When probable recrudescence (H. pylori positivity with identical strains) was excluded, the reinfection rate of H. pylori in this Japanese population was very low, but we note that reinfection can occur over many years.

DOI： 10.1007/s00535-012-0536-9

Clostridium botulinum Type E Toxins Bind to Caco-2 Cells by a Different Mechanism from That of Type A Toxins 査読

Kai Zhang, Yumiko Yamamoto, Tomonori Suzuki, Kenji Yokota, Shaobo Ma, Ni Nengah Dwi Fatmawati, Keiji Oguma

ACTA MEDICA OKAYAMA 66 ( 3 ) 253 - 261 2012年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Cultured Clostridium botulinum strains produce progenitor toxins designated as 12S, 16S, and 19S toxins. The 12S toxin consists of a neurotoxin (NTX, 7S) and a non-toxic non-hemagglutinin (NTNH). The 16S and 19S toxins are formed by conjugation of the 12S toxin with hemagglutinin (HA), and the 19S toxin is a dimer of the 16S toxin. Type A cultures produce all 3 of these progenitor toxins, while type E produces only the 12S toxin. The 7S toxin is cleaved into heavy (H) and light (L) chains by a protease(s) in some strains, and the H chain has 2 domains, the N-terminus (Hn) and C-terminus (Hc). It has been reported that type A toxins bind to the intestinal cells or cultured cells via either HA or Hc. In this study, we investigated the binding of type A and E toxins to Caco-2 cells using Western blot analysis. Both the type E 7S and 12S toxins bound to the cells, with the 7S toxin binding more strongly, whereas, in the type A strain, only the 16S/19S toxins showed obvious binding. Pre-incubation of the type E 7S toxin with IgG against recombinant type E Hc significantly inhibited the 7S toxin binding, indicating that He might be a main binding domain of the type E toxin.

Phosphatidylethanolamine of Helicobacter pylori functions as a steroid-binding lipid in the assimilation of free cholesterol and 3β-hydroxl steroids into the bacterial cell membrane. 査読

Shimomura H, Hosoda K, Hayashi S, Yokota K, Hirai Y

Journal of bacteriology 194 ( 10 ) 2658 - 2667 2012年5月

Role of heat shock protein derived from Streptococcus sanguinis in Behcet’s disease 査読

Kaneko F, Togashi A, Nomura E, Isogai E, Yokota K, Oguma K

J Med Micorobiol Diagnosis 2012年

Steroid hormones as bactericidal agents to Helicobacter pylori 査読

Kouichi Hosoda, Hirofumi Shimomura, Shunji Hayashi, Kenji Yokota, Yoshikazu Hirai

FEMS MICROBIOLOGY LETTERS 318 ( 1 ) 68 - 75 2011年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Helicobacter pylori is a unique bacterial species that assimilates various steroids as membrane lipid components. Our group has recently found, however, that certain steroids may impair the viability of H. pylori. In this study, we go on to reveal that estradiol, androstenedione, and progesterone (PS) all have the potential to inhibit the growth of H. pylori. Of these three steroid hormones, progesterone demonstrated the most effective anti-H. pylori action. 17 alpha-hydroxyprogesterone caproate (17 alpha PSCE), a synthetic progesterone derivative, had a much stronger anti-H. pylori action than progesterone, whereas 17 alpha-hydroxyprogesterone, a natural progesterone derivative, completely failed to inhibit the growth of the organism. Progesterone and 17 alpha PSCE were both found to kill H. pylori through their bacteriolytic action. Among five bacterial species investigated, H. pylori was the only species susceptible to the bactericidal action of progesterone and 17 alpha PSCE. The other four species, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epiderimidis, all resisted this action. Progesterone and free-cholesterol (FC) obstructed each other's effects against the H. pylori cell. Taken in sum, these results suggest that progesterone and FC may bind to the identical region on the H. pylori cell surface. We expect these findings to contribute to the development of a novel anti-H. pylori steroidal agent.

DOI： 10.1111/j.1574-6968.2011.02239.x

The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori 査読

Susumu Take, Motowo Mizuno, Kuniharu Ishiki, Tomowo Yoshida, Nobuya Ohara, Kenji Yokota, Keiji Oguma, Hiroyuki Okada, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 46 ( 3 ) 318 - 324 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

We previously reported that eradication of Helicobacter pylori reduced the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up our patient group to investigate the occurrence and clinical features of gastric cancers that developed after cure of the infection.
Prospective post-eradication evaluations were conducted on 1674 consecutive patients who had received successful H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosal atrophy, and H. pylori infection. After confirmation of cure of the infection, follow-up endoscopy was performed yearly.
The patients were followed for up to 14.1 years (a mean of 5.6 years). During the follow-up, gastric cancer developed in 28 of the 1674 patients as long as 13.7 years after the cure of H. pylori infection. The risk of developing gastric cancer was 0.30% per year. Histologically, 16 of the gastric cancers were the intestinal type and 12 were the diffuse type; the risk of each cancer type was 0.17 and 0.13% per year, respectively. There was no significant inflammatory cell infiltration in the background gastric mucosa at the time the cancers were recognized.
There is a risk of developing gastric cancer of both the intestinal and diffuse types even after the cure of H. pylori infection and extinction of gastric inflammation. It is important to inform patients about the risk of gastric cancer after eradication therapy and offer them surveillance endoscopy.

DOI： 10.1007/s00535-010-0347-9

Behçet's disease (Adamantiades-Behçet's disease). 査読

Kaneko F, Togashi A, Saito S, Sakuma H, Oyama N, Nakamura K, Yokota K, Oguma K

Clinical & developmental immunology 2011 681956 2011年

Passive Oral Immunization by Egg Yolk Immunoglobulin (IgY) to Vibrio cholerae Effectively Prevents Cholera 査読

Kazuyuki Hirai, Hideyuki Arimitsu, Koji Umeda, Kenji Yokota, Lianhua Shen, Kiyoshi Ayada, Yoshikatsu Kodama, Takao Tsuji, Yoshikazu Hirai, Keiji Oguma

ACTA MEDICA OKAYAMA 64 ( 3 ) 163 - 170 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

In an attempt to prepare egg yolk immunoglobulin (IgY) to treat and prevent cholera, hens were immunized by a mixture of heat- or formalin-killed Vibrio cholerae O1 and O139 organisms, or by the recombinant cholera toxin B subunit (CTB). The IgYs were partially purified from egg yolk and orally administered to suckling mice before or after challenge with live O1 or O139 cells. The anti-O1 and O139 IgYs and the mixture of either IgY with anti-CTB IgY significantly protected the occurrence of cholera caused by both O1 and O139 infection. Since large amounts of IgY can be prepared very easily and at low cost, this seems to be a useful procedure for preventing and treating cholera.

コレラ菌およびコレラ毒素Bサブユニットに対するニワトリ抗体(IgY)の有用性

平井一行, 衛藤友美, 大野佑子, 田村臣哉, 山本由弥子, 難波ひかる, 阪口義彦, 横田憲治, 小熊惠二

日本薬学会年会要旨集 130年会 ( 3 ) 84 - 84 2010年3月

Steroids mediate resistance to the bactericidal effect of phosphatidylcholines against Helicobacter pylori 査読

Hirofumi Shimomura, Kouichi Hosoda, Shunji Hayashi, Kenji Yokota, Keiji Oguma, Yoshikazu Hirai

FEMS MICROBIOLOGY LETTERS 301 ( 1 ) 84 - 94 2009年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Helicobacter pylori assimilates various steroids as membrane lipid components, but it can also survive in the absence of steroids. It thus remains to be clarified as to why the organism relies on steroid physiologically. In this study, we have found that phosphatidylcholine carrying a linoleic acid molecule or arachidonic acid molecule has the potential to kill steroid-free H. pylori. The bactericidal action of phosphatidylcholines against H. pylori was due to the lytic activity of the phosphatidylcholines themselves and not due to the lytic activity of the unsaturated fatty acids or lyso-phosphatidylcholine resulting from the hydrolysis of the phosphatidylcholines. In contrast to the steroid-free H. pylori, the organism that absorbed and glucosylated free cholesterol was unaffected by the bactericidal action of the phosphatidylcholines. Similarly, H. pylori that absorbed estrone without glucosylating it also resisted the bactericidal action of the phosphatidylcholines. The steroids absorbed by H. pylori existed in both the outer and inner membranes, while the glucosyl-steroids produced via the steroid absorption were localized in the outer membrane rather than in the inner membrane. These results indicate that H. pylori absorbs the steroids to reinforce the membrane lipid barrier and thereby expresses resistance to the bacteriolytic action of hydrophobic compounds such as phosphatidylcholine.

DOI： 10.1111/j.1574-6968.2009.01807.x