研究者詳細 - 中山　真彰

論文 - 中山　真彰

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Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma. 国際誌

Htoo Shwe Eain, Hotaka Kawai, Masaaki Nakayama, May Wathone Oo, Toshiaki Ohara, Yoko Fukuhara, Kiyofumi Takabatake, Quisheng Shan, Yamin Soe, Kisho Ono, Keisuke Nakano, Nobuyoshi Mizukawa, Seiji Iida, Hitoshi Nagatsuka

JCI insight 9 ( 10 ) 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.

DOI： 10.1172/jci.insight.174618

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans. 国際誌

Yuki Shinoda-Ito, Kazuhiro Omori, Takashi Ito, Masaaki Nakayama, Atsushi Ikeda, Masahiro Ito, Toshiaki Ohara, Shogo Takashiba

Antibiotics (Basel, Switzerland) 12 ( 11 ) 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

DOI： 10.3390/antibiotics12111562

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans. 国際誌

Yuki Shinoda-Ito, Kazuhiro Omori, Takashi Ito, Masaaki Nakayama, Atsushi Ikeda, Masahiro Ito, Toshiaki Ohara, Shogo Takashiba

Antibiotics (Basel, Switzerland) 12 ( 11 ) 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

DOI： 10.3390/antibiotics12111562

Association of illness perception and alexithymia with fatigue in hemodialysis recipients: a single-center, cross-sectional study. 国際誌

Yoko Tanemoto, Ui Yamada, Masaaki Nakayama, Takeaki Takeuchi, Fumiaki Tanemoto, Yugo Ito, Daiki Kobayashi, Daisuke Ohta, Masahiro Hashizume

Scientific reports 13 ( 1 ) 16592 - 16592 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Fatigue in hemodialysis recipients interferes with daily activities and renal rehabilitation, and its underlying causes and treatment remain unclear. Psychological factors, like illness perceptions and alexithymia, cause fatigue in other diseases; however, their contribution to hemodialysis-related fatigue is unknown. This cross-sectional study included 53 hemodialysis recipients. To assess participants' fatigue, we used a self-administered patient-reported outcome questionnaire whose items have shown correlation with those of established scales, such as the Profile of Mood States and Visual Analogue Scales. The associations among the scores of the revised Illness Perceptions Questionnaire (IPQ-R), Toronto Alexithymia Scale (TAS-20), and Hospital Anxiety and Depression Scale and fatigue were analyzed using bivariable and multivariable analyses. Patients with fatigue had significantly higher median scores for the IPQ-R subscales "Identity" and "Negative emotional representation about illness" than those without fatigue, suggesting the association of specific illness perception with fatigue. Median scores for the TAS-20 subscale "Difficulty identifying feelings" were also significantly higher among fatigued patients, suggesting the association of alexithymia with fatigue. Depression was not associated with fatigue. Multivariable logistic regression revealed the association of a high "Identity" score with the risk of fatigue (adjusted odds ratio, 1.32; 95% confidence interval, 1.00-1.73; P = 0.04), while there were no significant association between a high "Difficulty identifying feelings" score and the risk of fatigue (adjusted odds ratio, 1.09; 95% confidence interval, 0.95-1.24). Specific illness perception and alexithymia were slightly associated with hemodialysis-related fatigue. Cognitive-behavioral therapy for these conditions could reduce fatigue and promote renal rehabilitation.

DOI： 10.1038/s41598-023-43935-9

Pathophysiology of encapsulating peritoneal sclerosis: lessons from findings of the past three decades in Japan.

Masaaki Nakayama, Masanobu Miyazaki, Chieko Hamada, Yasuhiko Ito, Kazuho Honda

Clinical and experimental nephrology 27 ( 9 ) 717 - 727 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD). In Japan, EPS became a central issue in the clinical setting during the mid-90s and the beginning of this century. However, following the introduction of biocompatible neutral PD solutions containing lower levels of glucose degradation products, the incidence and clinical severity of EPS has been greatly lessened. During the past three decades, the etiology of EPS has been elucidated by findings obtained by peritoneal biopsy, laparoscopy, and surgical intervention. Accumulating findings suggest the need for a paradigm change on the nature of EPS pathophysiology; notably, EPS appears not to reflect peritoneal sclerosis per se, but rather the formation of a neo-membrane as a biological reaction to peritoneal injury. This narrative review looks back on the history of EPS in Japan, and discusses EPS pathophysiology, the impact of neutral PD solution on peritoneal protection, and a future novel diagnostic approach, ultra-fine endoscope, for the identification of patients at high risk of EPS.

DOI： 10.1007/s10157-023-02360-y

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

The Fungal Metabolite (+)-Terrein Abrogates Inflammatory Bone Resorption via the Suppression of TNF-α Production in a Ligature-Induced Periodontitis Mouse Model

Hidefumi Sako, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Hidetaka Ideguchi, Saki Yoshimura-Nakagawa, Kyosuke Sakaida, Chiaki Nagata-Kamei, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

Journal of Fungi 9 ( 3 ) 314 - 314 2023年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

DOI： 10.3390/jof9030314

The Fungal Metabolite (+)-Terrein Abrogates Inflammatory Bone Resorption via the Suppression of TNF-α Production in a Ligature-Induced Periodontitis Mouse Model. 国際誌

Hidefumi Sako, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Hidetaka Ideguchi, Saki Yoshimura-Nakagawa, Kyosuke Sakaida, Chiaki Nagata-Kamei, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

Journal of fungi (Basel, Switzerland) 9 ( 3 ) 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

DOI： 10.3390/jof9030314

侵襲性歯周炎の血液診断マーカー候補となる細胞外小胞由来マイクロRNAとその炎症誘導機構の探索

森彩乃, 山本直史, 井手口英隆, 河村麻理, 河本美奈, 伊東昌洋, 小野喜章, 中山真彰, 江口傑徳, 大野充昭, 大森一弘, 高柴正悟

日本歯周病学会会誌 64 ( 春季特別 ) 114 - 114 2022年5月

Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E2 Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades. 査読国際誌

Masaaki Nakayama, Mariko Naito, Kazuhiro Omori, Shintaro Ono, Koji Nakayama, Naoya Ohara

Journal of immunology (Baltimore, Md. : 1950) 208 ( 5 ) 1146 - 1154 2022年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.

DOI： 10.4049/jimmunol.2100866

Attempt of thyX gene silencing and construction of a thyX deleted clone in a Mycobacterium bovis BCG 査読

Yuki Arimura, Yusuke Minato, Takayuki Wada, Masaaki Nakayama, Ayako Ryumon, Nao Hirata, Chie Nakajima, Yasuhiko Suzuki, Manabu Ato, Kazuo Kobayashi, Naoko Ohara, Seiji Iida, Naoya Ohara

Microbiology and Immunology 66 ( 1 ) 10 - 14 2022年1月

Attempt of thyX gene silencing and construction of a thyX deleted clone in a Mycobacterium bovis BCG. 国際誌

Yuki Arimura, Yusuke Minato, Takayuki Wada, Masaaki Nakayama, Ayako Ryumon, Nao Hirata, Chie Nakajima, Yasuhiko Suzuki, Manabu Ato, Kazuo Kobayashi, Naoko Ohara, Seiji Iida, Naoya Ohara

Microbiology and immunology 66 ( 1 ) 10 - 14 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mycobacterium tuberculosis, the causative agent of tuberculosis, possess flavin-dependent thymidylate synthase, ThyX. Since thyX is absent in humans and was shown to be essential for M. tuberculosis normal growth, ThyX is thought to be an attractive novel TB drug target. This study assessed thyX essentiality in Mycobacterium bovis BCG strains using CRISPR interference based gene silencing and found that thyX is not essential in an M. bovis BCG Tokyo derivative strain. A thyX deletion mutant strain was successfully constructed from that strain, which reinforces the non-essentiality of thyX under a certain genetic background.

DOI： 10.1111/1348-0421.12944

GRIM-19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation. 国際誌

Tomomi Kurane, Tetsuro Matsunaga, Tomoaki Ida, Kazuko Sawada, Akira Nishimura, Masayuki Fukui, Masayuki Umemura, Masaaki Nakayama, Naoya Ohara, Sohkichi Matsumoto, Takaaki Akaike, Goro Matsuzaki, Giichi Takaesu

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 ( 1 ) e22096 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tuberculosis is a communicable disease caused by Mycobacterium tuberculosis which primarily infects macrophages and establishes intracellular parasitism. A mycobacterial virulence factor Zn2+ metalloprotease 1 (Zmp1) is known to suppress interleukin (IL)-1β production by inhibiting caspase-1 resulting in phagosome maturation arrest. However, the molecular mechanism of caspase-1 inhibition by Zmp1 is still elusive. Here, we identified GRIM-19 (also known as NDUFA13), an essential subunit of mitochondrial respiratory chain complex I, as a novel Zmp1-binding protein. Using the CRISPR/Cas9 system, we generated GRIM-19 knockout murine macrophage cell line J774.1 and found that GRIM-19 is essential for IL-1β production during mycobacterial infection as well as in response to NLRP3 inflammasome-activating stimuli such as extracellular ATP or nigericin. We also found that GRIM-19 is required for the generation of mitochondrial reactive oxygen species and NLRP3-dependent activation of caspase-1. Loss of GRIM-19 or forced expression of Zmp1 resulted in a decrease in mitochondrial membrane potential. Our study revealed a previously unrecognized role of GRIM-19 as an essential regulator of NLRP3 inflammasome and a molecular mechanism underlying Zmp1-mediated suppression of IL-1β production during mycobacterial infection.

DOI： 10.1096/fj.202101074RR

GRIM-19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation 査読

Tomomi Kurane, Tetsuro Matsunaga, Tomoaki Ida, Kazuko Sawada, Akira Nishimura, Masayuki Fukui, Masayuki Umemura, Masaaki Nakayama, Naoya Ohara, Sohkichi Matsumoto, Takaaki Akaike, Goro Matsuzaki, Giichi Takaesu

The FASEB Journal 2021年12月

フッ化ナトリウムによるCCNファミリー遺伝子制御を介した歯肉線維化抑制作用の検討

水川朋美, 西田崇, 明石翔, 大杉綾花, 大森一弘, 中山真彰, 高柴正悟, 上岡寛, 滝川正春, 久保田聡

岡山歯学会雑誌 40 ( 2 ) 34 - 35 2021年12月

Attempt of thyX gene silencing and construction of a thyX deleted clone in a Mycobacterium bovis BCG. 査読

Yuki Arimura, Yusuke Minato, Takayuki Wada, Masaaki Nakayama, Ayako Ryumon, Nao Hirata, Chie Nakajima, Yasuhiko Suzuki, Manabu Ato, Kazuo Kobayashi, Naoko Ohara, Seiji Iida, Naoya Ohara

Microbiol Immunol. 2021年9月

The fungal metabolite (+)-terrein abrogates ovariectomy-induced bone loss and receptor activator of nuclear factor-κB ligand–induced osteoclastogenesis by suppressing protein kinase-C α/βII phosphorylation. 査読国際誌

Kyosuke Sakaida, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Saki Nakagawa, Hidefumi Sako, Chiaki Kamei, Satoshi Yamamoto, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga and Shogo Takashiba

Frontiers in Pharmacology 12 674366 - 674366 2021年6月

Point mutation in the stop codon of MAV_RS14660 increases the growth rate of Mycobacterium avium subspecies hominissuis. 査読

Tomomi Kawakita, Tetsu Mukai, Mitsunori Yoshida, Hiroyuki Yamada, Masaaki Nakayama, Yuji Miyamoto, Masato Suzuki, Noboru Nakata, Takemasa Takii, Akihide Ryo, Naoya Ohara, Manabu Ato

Microbiology 167 ( 2 ) 2021年2月

Point mutation in the stop codon of MAV_RS14660 increases the growth rate of Mycobacterium avium subspecies hominissuis. 国際誌

Tomomi Kawakita, Tetsu Mukai, Mitsunori Yoshida, Hiroyuki Yamada, Masaaki Nakayama, Yuji Miyamoto, Masato Suzuki, Noboru Nakata, Takemasa Takii, Akihide Ryo, Naoya Ohara, Manabu Ato

Microbiology (Reading, England) 167 ( 2 ) 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

DOI： 10.1099/mic.0.001007

Construction and Characterization of the PGN_0296 Mutant of Porphyromonas gingivalis 査読

Abu Saleh Muhammad Shahriar, Shintaro Ono, Masaaki Nakayama, Naoko Ohara and Naoya Ohara

Journal of Oral Biosciences 2020年10月

The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1. 査読

Saki Nakagawa, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Satoshi Yamamoto, Hiroya Kobayashi, Hidefumi Sako, Kyosuke Sakaida, Hiroshi Yoshimura, Satoki Ishii, Soichiro Ibaragi, Kimito Hirai, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

Int Immunopharmacol. 83 2020年6月

The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1. 国際誌

Saki Nakagawa, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Satoshi Yamamoto, Hiroya Kobayashi, Hidefumi Sako, Kyosuke Sakaida, Hiroshi Yoshimura, Satoki Ishii, Soichiro Ibaragi, Kimito Hirai, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

International immunopharmacology 83 106429 - 106429 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease.

DOI： 10.1016/j.intimp.2020.106429

PCRをベースとしたLautropia mirabilisの簡便な検出法と分離法の検討

佐藤あやめ, 中山真彰, 中川美緒, 小崎弘貴, 室美里, 曽我賢彦, 大原直也

日本細菌学雑誌 75 ( 1 ) 66 - 66 2020年1月

Construction and characterization of a PGN_0297 mutant of Porphyromonas gingivalis: evidence for contribution of PGN_0297 to gingipain activity 査読

Shintaro Ono, Masaaki Nakayama, Masato Tachibana, Abu Saleh Muhammad Shahriar, Wang Heling, Shogo Takashiba, and Naoya Ohara

Acta Medica Okayama 2019年3月

Construction and characterization of a PGN_0297 mutant of Porphyromonas gingivalis: Evidence of the contribution of PGN_0297 to gingipain activity

Shintaro Ono, Masaaki Nakayama, Masato Tachibana, Abu Saleh Muhammad Shahriar, Wang Heling, Shogo Takashiba, Naoya Ohara

Acta Medica Okayama 73 ( 4 ) 315 - 323 2019年

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 University

The periodontal pathogen Porphyromonas gingivalis shows colonial pigmentation on blood agar and produces gingipains (Kgp, RgpA, and RgpB), cysteine proteases involved in an organism's virulence and pigmentation. We showed previously that deletion of the PGN_0300 gene abolished the pigmentation activity and reduced the proteolytic activity of gingipains. The role of the PGN_0297 gene, which consists of an operon with the PGN_0300 gene, is unclear. Herein we examined the effect of PGN_0297 gene deletion on the pigmentation and proteolytic activities and transcriptional levels of gingipains. A PGN_0297 gene deletion mutant (ΔPGN_0297) did not exhibit the pigmentation. The proteolytic activity of the gingipains was decreased in the culture supernatant and on the cell surface of ΔPGN_0297. The mutant ΔPGN_0297 failed to attenuate Akt phosphorylation at Thr308 and Ser473, but both phosphorylations were attenuated in the wild-type and its complementation strain. The deletion of PGN_0297 gene did not substantially affect the transcriptional levels of the gingipain genes kgp, rgpA, and rgpB. Taken together, these results indicate that PGN_0297 is closely involved in the secretion and maturation of gingipains.

Fungal metabolite (+)-terrein suppresses IL-6/sIL-6R-induced CSF1 secretion by inhibiting JAK1 phosphorylation in human gingival fibroblasts. 査読国際誌

Satoshi Yamamoto, Kazuhiro Omori, Hiroki Mandai, Masaaki Nakayama, Saki Nakagawa, Hiroya Kobayashi, Tadashi Kunimine, Hiroshi Yoshimura, Kyosuke Sakaida, Hidefumi Sako, Soichiro Ibaragi, Tadashi Yamamoto, Hiroshi Maeda, Seiji Suga, and Shogo Takashiba

Heliyon 4 ( 11 ) e00979 2018年11月

Fungal metabolite (

Satoshi Yamamoto, Kazuhiro Omori, Hiroki Mandai, Masaaki Nakayama, Saki Nakagawa, Hiroya Kobayashi, Tadashi Kunimine, Hiroshi Yoshimura, Kyosuke Sakaida, Hidefumi Sako, Soichiro Ibaragi, Tadashi Yamamoto, Hiroshi Maeda, Seiji Suga, Shogo Takashiba

HELIYON 4 ( 11 ) 2018年11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：ELSEVIER SCI LTD

Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.

DOI： 10.1016/j.heliyon.2018.e00979

Novel function of Porphyromonas gingivalis gingipains in the PI3K/Akt signaling pathway 招待査読

Nakayama Masaaki, Ohara Naoya

JOURNAL OF ORAL BIOSCIENCES 59 ( 3 ) 131 - 134 2017年8月

Involvement of an Skp-Like Protein, PGN_0300, in the Type IX Secretion System of Porphyromonas gingivalis 査読

Yuko Taguchi, Keiko Sato, Hideharu Yukitake, Tetsuyoshi Inoue, Masaaki Nakayama, Mariko Naito, Yoshio Kondo, Konami Kano, Tomonori Hoshino, Koji Nakayama, Shogo Takashiba, Naoya Ohara

INFECTION AND IMMUNITY 84 ( 1 ) 230 - 240 2016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 oral Gram-negative anaerobic bacterium Porphyromonas gingivalis is an important pathogen involved in chronic periodontitis. Among its virulence factors, the major extracellular proteinases, Arg-gingipain and Lys-gingipain, are of interest given their abilities to degrade host proteins and process other virulence factors. Gingipains possess C-terminal domains (CTDs) and are translocated to the cell surface or into the extracellular milieu by the type IX secretion system (T9SS). Gingipains contribute to the colonial pigmentation of the bacterium on blood agar. In this study, Omp17, the PGN_0300 gene product, was found in the outer membrane fraction. A mutant lacking Omp17 did not show pigmentation on blood agar and showed reduced proteolytic activity of the gingipains. CTD-containing proteins were released from bacterial cells without cleavage of the CTDs in the omp17 mutant. Although synthesis of the anionic polysaccharide (A-LPS) was not affected in the omp17 mutant, the processing of and A-LPS modification of CTD-containing proteins was defective. PorU, a C-terminal signal peptidase that cleaves the CTDs of other CTD-containing proteins, was not detected in any membrane fraction of the omp17 mutant, suggesting that the defective maturation of CTD-containing proteins by impairment of Omp17 is partly due to loss of function of PorU. In the mouse subcutaneous infection experiment, the omp17 mutant was less virulent than the wild type. These results suggested that Omp17 is involved in P. gingivalis virulence.

DOI： 10.1128/IAI.01308-15

BCG thyX欠損株の作製とその性状解析

有村友紀, 中山真彰, 妹尾昌紀, 田川淳平, 中山浩次, 飯田征二, 大原直也

Journal of Oral Biosciences Supplement 2015 330 - 330 2015年9月

BCGにおけるcyclic-di-GMP菌体内合成の影響

妹尾昌紀, 中山真彰, 有村友紀, 飯田征二, 大原直也

Journal of Oral Biosciences Supplement 2015 331 - 331 2015年9月

Involvement of an Skp-like protein, PGN_0300, in the type IX secretion system of Porphyromonas gingivalis 査読

Yuko Taguchi , Keiko Sato , Hideharu Yukitake , Tetsuyoshi Inoue , Masaaki Nakayama , Mariko Naito , Yoshio Kondo , Konami Kano , Tomonori Hoshino , Koji Nakayama , Shogo Takashiba and Naoya Ohara

Infection and Immunity 290 ( 8 ) 5190 - 5202 2015年2月

Attenuation of the phosphatidylinositol 3-Kinase/Akt signaling pathway by porphyromonas gingivalis gingipains RgpA, RgpB, and Kgp

Masaaki Nakayama, Tetsuyoshi Inoue, Mariko Naito, Koji Nakayama, Naoya Ohara

Journal of Biological Chemistry 290 ( 8 ) 5190 - 5202 2015年2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：American Society for Biochemistry and Molecular Biology Inc.

Background: The significance of gingipains on the PI3K/Akt signaling pathway is poorly understood.Results: The inactivation of PI3K and Akt was induced by P. gingivalis, which was associated with gingipains.Conclusion: Gingipains are critical for suppressing the PI3K/Akt signaling pathway via extracellular proteolysis independent of P. gingivalis invasion. Significance: This study shows the first evidence that the gingipains negatively regulate the PI3K/Akt signaling pathway.

DOI： 10.1074/jbc.M114.591610

Attenuation of the PI3 kinase/Akt signaling pathway by Porphyromonas gingivalis gingipains RgpA, RgpB, and Kgp 査読

Masaaki Nakayama, Tetsuyoshi Inoue, Mariko Naito, Koji Nakayama and Naoya Ohara

The Journal of Biological Chemistry 290 ( 8 ) 5190 - 5202 2015年1月

Characterization of the tripartite drug efflux pumps of Porphyromonas gingivalis ATCC 33277 査読

Tetsuyoshi Inoue, Masaaki Nakayama, Yuko Taguchi, Konami Kano, Miyuu Ono, Yurika Shimizu, Teruo Kuroda, Naoya Ohara

New Microbiologica 38 ( 1 ) 97 - 103 2015年1月

Role of extracytoplasmic function sigma factors in biofilm formation of Porphyromonas gingivalis 査読国際誌

Satosu Onozawa, Yuichiro Kikuchi, Kazuko Shibayama, Eitoyo Kokubu, Masaaki Nakayama, Tetsuyoshi Inoue, Keisuke Nakano, Yukinaga Shibata, Naoya Ohara, Koji Nakayama, Kazuyuki Ishihara, Toshiyuki Kawakami and Hiromasa Hasegawa

BMC Oral Health 15 4 - 4 2015年1月

Development of a novel plasmid vector pTIO-1 adapted for electrotransformation of Porphyromonas gingivalis 査読

Junpei Tagawa, Tetsuyoshi Inoue, Mariko Naito, Keiko Sato, Tomomi Kuwahara, Masaaki Nakayama, Koji Nakayama, Takashi Yamashiro, Naoya Ohara

JOURNAL OF MICROBIOLOGICAL METHODS 105 174 - 179 2014年10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：ELSEVIER SCIENCE BV

We report here the construction of a plasmid vector designed for the efficient electrotransformation of the periodontal pathogen Porphyromonas gingivalis. The novel Escherichia coli-Bacteroides/P. gingivalis shuttle vector, designated pTIO-1, is based on the 11.0-kb E. coli-Bacteroides conjugative shuttle vector, pVAL-1 (a pB8-51 derivative). To construct pTIO-1, the pB8-51 origin of replication and erythromycin resistance determinant of pVAL-1 were cloned into the E. coli cloning vector pBluescript II SK(-) and non-functional regions were deleted. pTIO-1 has an almost complete multiple cloning site from pBluescript II SK(-). The size of pTIO-1 is 4.5 kb, which is convenient for routine gene manipulation. pTIO-1 was introduced into P. gingivalis via electroporation, and erythromycin-resistant transformants carrying pTIO-1 were obtained. We characterized the transformation efficiency, copy number, host range, stability, and insert size capacity of pTIO-1. An efficient plasmid electrotransformation of P. gingivalis will facilitate functional analysis and expression of P. gingivalis genes, including the virulence factors of this bacterium. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.mimet.2014.07.032

Development of a novel plasmid vector pTIO-1 adapted for electrotransformation of Porphyromonas gingivalis 査読

Junpei Tagawa, Tetsuyoshi Inoue, Mariko Naito, Keiko Sato, Tomomi Kuwahara, Masaaki Nakayama, Koji Nakayama, Takashi Yamashiro, Naoya Ohara

Journal of Microbiological Methods 2014年8月

Hemoglobin receptor protein from Porphyromonas gingivalis induces interleukin-8 production in human gingival epithelial cells through stimulation of the mitogen-activated protein kinase and NF-κB signal transduction pathways. (共著) 査読

Yuki Fujita, Masaaki Nakayama, Mariko Naito, Eiki Yamachika, Tetsuyoshi Inoue, Koji Nakayama, Seiji Iida, and Naoya Ohara

Infection and Immunity 82 ( 1 ) 202 - 211 2014年1月

Porphyromonas gingivalisにおいて電気穿孔法で導入可能なプラスミドベクターの構築

田川淳平, 井上哲圭, 佐藤啓子, 内藤真理子, 中山真彰, 中山浩次, 山城隆, 大原直也

Journal of Oral Biosciences Supplement 2013 113 - 113 2013年9月

Porphyromonas gingivalisにおいて電気穿孔法で導入可能なプラスミドベクターの構築

田川淳平, 井上哲圭, 佐藤啓子, 内藤真理子, 中山真彰, 中山浩次, 山城隆, 大原直也

Journal of Oral Biosciences Supplement 2013 167 - 167 2013年9月

Interweaving MicroRNAs and Proinflammatory Cytokines in Gastric Mucosa with Reference to H. pylori Infection (共著) 査読

Journal of Clinical Immunology 2012年4月

Interweaving MicroRNAs and Proinflammatory Cytokines in Gastric Mucosa with Reference to H. pylori Infection 査読

Hajime Isomoto, Kayoko Matsushima, Naoki Inoue, Tomayoshi Hayashi, Toshiyuki Nakayama, Masaki Kunizaki, Shigekazu Hidaka, Masaaki Nakayama, Junzo Hisatsune, Masahiro Nakashima, Takeshi Nagayasu, Kazuhiko Nakao, Toshiya Hirayama

JOURNAL OF CLINICAL IMMUNOLOGY 32 ( 2 ) 290 - 299 2012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：SPRINGER/PLENUM PUBLISHERS

Using endoscopic biopsies, gastric mucosal expression levels of interleukin (IL)-1 beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and microRNAs (miRNAs) that were differentially expressed in association with Helicobacter pylori were assessed by quantitative reverse-transcriptase polymerase chain reaction. Among the H. pylori-positive mucosa, 17 out of 29 miRNAs had significant correlations with at least one of the four proinflammatory cytokines in expression. Among the 17 miRNAs, 15 were associated with the degree of neutrophil infiltration and, more prominently, the degree of mononuclear cell infiltration, according to the updated Sydney system. Persistent H. pylori infection may affect the mucosal expression profiles of miRNAs via chronic inflammation mediated by proinflammatory cytokines. There were significant positive correlations between certain miRNAs including the microRNA-200 family and IL-1 beta, IL-6, or TNF-alpha mRNA in H. pylori-negative gastric mucosa. Underscoring the causal association between miRNAs and proinflammatory cytokines may provide insights into the pathogenesis of H. pylori-associated gastritis linking to gastric carcinogenesis.

DOI： 10.1007/s10875-011-9626-3

Enhanced Expression of CXCL13 in Human Helicobacter pylori-Associated Gastritis (共著) 査読

Yujiro Nakashima, Hajime Isomoto, Kayoko Matsushima, Akira Yoshida, Toshiyuki Nakayama, Masaaki Nakayama, Junzo Hisatsune, Tatsuki Ichikawa, Fuminaoa Takeshima, TomayoshiHayashi, Kazuhiko Nakao, Toshiya Hirayama, and Shigeru Kohno

Digestive Diseases and Sciences 2011年11月

Enhanced Expression of CXCL13 in Human Helicobacter pylori-Associated Gastritis

Yujiro Nakashima, Hajime Isomoto, Kayoko Matsushima, Akira Yoshida, Toshiyuki Nakayama, Masaaki Nakayama, Junzo Hisatsune, Tatsuki Ichikawa, Fuminao Takeshima, Tomayoshi Hayashi, Kazuhiko Nakao, Toshiya Hirayama, Shigeru Kohno

DIGESTIVE DISEASES AND SCIENCES 56 ( 10 ) 2887 - 2894 2011年10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

Chemokine CXC ligand 13 (CXCL13) and CXC receptor type 5 (CXCR5) are constitutively expressed in tertiary lymphoid follicles where the CXCL13/CXCR5 system regulates B lymphocytes homing. In this study, we sought to examine CXCL13 expression in the H. pylori-infected and -uninfected gastric mucosa and to elucidate the implication in the pathogenesis of HAG in humans.Using endoscopic biopsies taken from the gastric antrum of 29 subjects infected with Helicobacter pylori and 22 uninfected subjects, mucosal CXCL13 mRNA and protein levels were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.The CXCL13 expression levels were significantly more elevated in H. pylori-positive patients than uninfected ones. The CXCL13 expression levels correlated with the degree of chronic gastritis and bacterial colonization. Immunohistochemistry and in vitro infection assay showed that CXCL13 was not produced by the gastric epithelium, but the alpha-smooth muscle antigen expressing mesenchymal cells were the possible source of CXCL13 within H. pylori-infected gastric mucosa. CXCR5 immunostaining was seen in the CD20-positive lymphoid aggregates.The enhanced induction of CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis.

DOI： 10.1007/s10620-011-1717-8

Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-XL, leading to apoptosis in gastric epithelial cells (共著) 査読

Ayako Matsumoto, Hajime Isomoto, Masaaki Nakayama, Junzo Hisatsune, Yoshito Nishi, Yujiro Nakashima, Kayoko Matsushima, Hisao Kurazono, Kazuhiko Nakao, Toshiya Hirayama, and Shigeru Kohno

Digestive Diseases and Sciences 2011年4月

Helicobacter pylori VacA Reduces the Cellular Expression of STAT3 and Pro-survival Bcl-2 Family Proteins, Bcl-2 and Bcl-X-L, Leading to Apoptosis in Gastric Epithelial Cells

Ayako Matsumoto, Hajime Isomoto, Masaaki Nakayama, Junzo Hisatsune, Yoshito Nishi, Yujiro Nakashima, Kayoko Matsushima, Hisao Kurazono, Kazuhiko Nakao, Toshiya Hirayama, Shigeru Kohno

DIGESTIVE DISEASES AND SCIENCES 56 ( 4 ) 999 - 1006 2011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：SPRINGER

Helicobacter pylori vacuolating cytotoxin, VacA, stimulates apoptosis via a mitochondria-dependent pathway. VacA induces apoptosis via activation of the pro-apoptotic B-cell lymphoma (Bcl)-2 family proteins, Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), while the implication of such pro-survival Bcl-2 family members as Bcl-2 and Bcl-X-L in the VacA-induced apoptosis remains unknown. Signal transduction and activator of transcription 3 (STAT3) is a pivotal transcription factor that upregulates Bcl-2 and Bcl-X-L.This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X-L in the intrinsic apoptosis.Immunoblot and reverse transcriptase real-time polymerase chain reaction (RT-PCR) were employed to assess the cellular expression of STAT3, Bcl-2, and Bcl-X-L in response to purified VacA in gastric adenocarcinoma cell lines. VacA-induced apoptosis was quantitated morphologically following knockdown by each specific small interfering RNA (siRNA) or in the presence of pharmacological inhibitors.VacA reduced STAT3, Bcl-2, and Bcl-X-L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X-L by siRNA induced apoptosis to a similar extent in the case of sufficient VacA inoculation. The VacA-mediated reduction of STAT3 expression was independent of cellular vacuolization, since a vacuolar-type ATPase inhibitor, bafilomycin A1, did not inhibit VacA-induced reduction of STAT3, Bcl-2, and Bcl-X-L expression. Instead, a c-JUN NH2-terminal kinase (JNK) inhibitor, SP600125, restored the VacA-induced reduction of STAT3 expression to the basal level.VacA-induced apoptosis may be, in part, implicated in the reduction of STAT3 linking to the downregulation of Bcl-2 and Bcl-X-L, in association with JNK activity.

DOI： 10.1007/s10620-010-1420-1

MicroRNA signatures in Helicobacter pylori-infected gastric mucosa (共著) 査読

Kayoko Matsushima, Hajime Isomoto, Naoki Inoue, Toshiyuki Nakayama, Tomayoshi Hayashi, Masaaki Nakayama, Kazuhiko Nakao, Toshiya Hirayama, and Shigeru Kohno

International journal of cancer 2011年1月

Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis (共著) 査読

Akira Yoshida, Hajime Isomoto, Junzo Hisatsune, Masaaki Nakayama, Yujiro Nakashima, Kayoko Matsushima, Yohei Mizuta, Tomayoshi Hayashi, Yoshio Yamaoka, Takeshi Azuma, Joel Moss, Toshiya Hirayama, and Shigeru Kohno

Clinical Immunology 130 290 - 297 2009年3月

Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway 査読

Masaaki Nakayama, Junzo Hisatsune, Eiki Yamasaki, Hajime Isomoto, Hisao Kurazono, Masanori Hatakeyama, Takeshi Azuma, Yoshio Yamaoka, Kinnosuke Yahiro, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry 284 ( 3 ) 1612 - 1619 2009年1月

Molecular Characterization of Helicobacter pylori VacA Induction of IL-8 in U937 Cells Reveals a Prominent Role for p38MAPK in Activating Transcription Factor-2, cAMP Response Element Binding Protein, and NF-κB Activation (共著) 査読

Junzo Hisatsune, Masaaki Nakayama, Hajime Isomoto, Hisao Kurazono, Naofumi Mukaida, Asish K. Mukhopadhyay, Takeshi Azuma, Yoshio Yamaoka, Jan Sap, Eiki Yamasaki, Kinnosuke Yahiro, Joel Moss, and Toshiya Hirayama

The Journal of Immunology 180 ( 7 ) 5017 - 5027 2008年4月

Molecular characterization of Helicobacter pylori VacA induction of IL-8 in U937 cells reveals a prominent role for p38MAPK in activating transcription factor-2, cAMP response element binding protein, and NF-kappa B activation 査読

Junzo Hisatsune, Masaaki Nakayama, Hajime Isomoto, Hisao Kurazono, Naofumi Mukaida, Asish K. Mukhopadhyay, Takeshi Azuma, Yoshio Yamaoka, Jan Sap, Eiki Yamasaki, Kinnosuke Yahiro, Joel Moss, Toshiya Hirayama

JOURNAL OF IMMUNOLOGY 180 ( 7 ) 5017 - 5027 2008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：AMER ASSOC IMMUNOLOGISTS

Helicobacterpylori VacA induces multiple effects on susceptible cells, including vacuolation, mitochondrial damage, inhibition of cell growth, and enhanced cyclooxygenase-2 expression. To assess the ability of H. pylori to modulate the production of inflammatory mediators, we examined the mechanisms by which VacA enhanced IL-8 production by promonocytic U937 cells, which demonstrated the greatest VacA-induced IL-8 release of the cells tested. Inhibitors of p38 MAPK (SB203580), ERK1/2 (PD98059), IKBa ((E)-3-(4-methylphenyisulfonyl)-2-propenenitrile), Ca2+ entry (SKF96365), and intracellular Ca 21 channels (dantrolene) blocked VacA-induced IL-8 production. Furthermore, an intracellular Ca2+ chelator (BAPTA-AM), which inhibited VacA-activated p38 MAPK, caused a dose-dependent reduction in VacA-induced IL-8 secretion by U937 cells, implying a role for intracellular Ca 21 in mediating activation of MAPK and the canonical NF-kappa B pathway. VacA stimulated translocation of NF-kappa Bp65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-kappa B pathway. In addition, small interfering RNA of activating transcription factor (ATF)-2 or CREB, which is a p38MAPK substrate and binds to the AP-1 site of the IL-8 promoter, inhibited VacA-induced IL-8 production. VacA activated an IL-8 promoter containing an NF-IL-6 site, but not a mutated AP-1 or NF-kappa B site, suggesting direct involvement of the ATF-2/CREB binding region or NF-kappa B-binding regions in VacA-induced IL-8 promoter activation. Thus, in U937 cells, VacA directly increases IL-8 production by activation of the p38 MAPK via intracellular Ca2+ release, leading to activation of the transcription factors, ATF-2, CREB, and NF-kappa B.

DOI： 10.4049/jimmunol.180.7.5017

Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells

Junzo Hisatsune, Eiki Yamasaki, Masaaki Nakayama, Daisuke Shirasaka, Hisao Kurazono, Yohtaro Katagata, Hiroyasu Inoue, Jiahuai Han, Jan Sap, Kinnosuke Yahiro, Joel Moss, Toshiya Hirayama

Infection and Immunity 75 ( 9 ) 4472 - 4481 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol- specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE 2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DOI： 10.1128/IAI.00500-07

Helicobacter pylori VacA enhances PGE2 production through induction of COX-2 expression via a p38 MAP kinase/ ATF-2 cascade in AZ-521 cells (共著) 査読

Junzo Hisatsune, Eiki Yamasaki, Masaaki Nakayama, Daisuke Shirasaka, Hisao Kurazono, Yohtaro Katagata, Hiroyasu Inoue, Jiahuai Han, Jan Sap, Kinnosuke Yahiro, Joel Moss, and Toshiya Hirayama

Infection and Immunity 75 ( 9 ) 4472 - 4481 2007年6月

Helicobacter pylori VacA clustering in lipid rafts, mediated by its receptor, RPTPβ, is required for VacA-induced vacuolation in AZ-521 cells. 査読

Masaaki Nakayama, Akihiro Wada, Junzo Hisatsune, Eiki Yamasaki, Yoshito Nishi, Kinnosuke Yahiro, Hisao Kurazono, Joel Moss, and Toshiya Hirayama

Infection and Immunity 74 ( 12 ) 6571 - 6580 2006年12月

Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. 査読

Eiki Yamasaki, Akihiro Wada, Atsushi Kumatori, Ichiro Nakagawa, Junko Funao, Masaaki Nakayama, Junzo Hisatsune, Miyuki Kimura, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry. 281 ( 16 ) 11250 - 11259 2006年4月

[Structure and intoxication of VacA].

Toshiya Hirayama, Akihiro Wada, Masaaki Nakayama, Yoshito Nishi, Jyunzo Hisatsune

Nihon rinsho. Japanese journal of clinical medicine 63 Suppl 11 53 - 7 2005年11月

Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPα and RPTPβ, by Helicobacter pylori m2VacA 査読国際誌

Blanquita B. De Guzman, Junzo Hisatsune, Masaaki Nakayama, Kinnosuke Yahiro, Akihiro Wada, Eiki Yamasaki, Yoshito Nishi, Shiho Yamazaki, Takeshi Azuma, Yoshiyuki Ito, Masahiro Ohtani, Thea van der Wijk, Jeroen den Hertog, Joel Moss, and Toshiya Hirayama

Cellular Microbiology 7 ( 9 ) 1285 - 1293 2005年9月

Essential Domain of Receptor Tyrosine Phosphatase β (RPTPβ) for Interaction with Helicobacter pylori Vacuolating Cytotoxin 査読国際誌

Kinnosuke Yahiro, Akihiro Wada, Eiki Yamasaki, Masaaki Nakayama, Yoshito Nishi, Jyunzou Hisatsune, Naoko Morinaga, Jan Sap, Masatoshi Noda, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry 279 ( 49 ) 51013 - 51021 2004年12月

Gangliosides act as co-receptors for Salmonella enteritidis FliC and promote FliC induction of human β-defensin-2 expression in Caco-2 cells. 査読

Ken-ichi Ogushi, Akihiro Wada, Takuro Niidome, Tatsuya Okuda, Rafael Llanes, Masaaki Nakayama, Yoshito Nishi, Hisao Kurazono, Kelly D. Smith, Alan Aderem, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry 279 ( 13 ) 12213 - 12219 2004年3月

Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells. 査読国際誌

Masaaki Nakayama, Miyuki Kimura, Akihiro Wada, Kinnosuke Yahiro, Ken-ichi Ogushi, Takuro Niidome, Akihiro Fujikawa, Daisuke Shirasaka, Nobuo Aoyama, Hisao Kurazono, Masaharu Noda, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry 279 ( 8 ) 7024 - 7028 2004年2月

Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. 査読

Kinnosuke Yahiro, Akihiro Wada, Masaaki Nakayama, Takahiro Kimura, Ken-ichi Ogushi, Takuro Niidome, Haruhiko Aoyagi, Ken-ichi Yoshino, Kazuyoshi Yonezawa, Joel Moss, and Toshiya Hirayama

The Journal of Biological Chemistry 278 ( 21 ) 19183 - 19189 2003年5月

High molecular weight factor in FCS inhibits Helicobacter pylori VacA-binding to its receptor, RPTPbeta, on AZ-521. 査読

Takahiro Kimura, Akihiro Wada, Masaaki Nakayama, Ken-ichi Ogushi, Yoshito Nishi, Blaquita B. De Guzman, Joel Moss, and Toshiya Hirayama

Microbiology and Immunology 47 ( 1 ) 105 - 107 2003年1月

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