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PARK Ah-Mee

    Department of Medicine　Lecturer
Last Updated :2024/04/19

Researcher Information

J-Global ID

Research Interests

  • intestinal ulcer   Alzheimer's disease   Infectious diseases   H. pylori   転写因子   

Research Areas

  • Life sciences / Immunology
  • Life sciences / Animals: biochemistry, physiology, behavioral science
  • Life sciences / Bacteriology
  • Life sciences / Laboratory animal science

Academic & Professional Experience

  • 2023/04 - Today  近畿大学医学部医学部教育センター医学基盤教育部門講師
  • 2013/01 - 2023/03  Kindai UniversityFaculty of Medicine講師
  • 2010/04 - 2012/12  Kindai UniversityFaculty of Medicine講師
  • 2007/11 - 2010/03  Kindai UniversityFaculty of Medicine助教
  • 2004/04 - 2007/10  Georgetown Univ.Medical center博士研究員

Education

  • 1999/04 - 2003/03  Osaka City University  Graduate School of Medicine

Association Memberships

  • 日本認知症学会   THE JAPANESE SOCIETY OF INFLAMMATION AND REGENERATION   THE MOLECULAR BIOLOGY SOCIETY OF JAPAN   

Published Papers

  • Ijaz Ahmad; Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Sundar Khadka; Felicity N. E. Gavins; Hiroki Tanaka; Motoko Y. Kimura; Ikuo Tsunoda
    International Journal of Molecular Sciences 2024/03
  • Kota Moriguchi; Yumina Nakamura; Ah-Mee Park; Fumitaka Sato; Motoi Kuwahara; Sundar Khadka; Seiichi Omura; Ijaz Ahmad; Susumu Kusunoki; Ikuo Tsunoda
    International Journal of Molecular Sciences MDPI AG 24 (16) 12937 - 12937 2023/08 
    Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain–Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35–55, MOG92–106, or myelin proteolipid protein (PLP)139–151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler’s murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139–151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies.
  • マウス胃のピロリ菌慢性感染は脳に神経炎症と遺伝子発現変化を誘導する
    朴 雅美; 尾村 誠一; 佐藤 文孝; 角田 郁生
    老年精神医学雑誌 (株)ワールドプランニング 33 (増刊II) 257 - 257 0915-6305 2022/11
  • MS3 異なる病型を示す多発性硬化症の動物モデルにおける抗糖脂質抗体の検討
    森口 幸太; 中村 優美和; 朴 雅美; 佐藤 文孝; 桑原 基; スンダル・カドカ; 尾村 誠一; イジャーズ・エフマド; 楠 進; 角田 郁生
    神経免疫学 (一社)日本神経免疫学会 27 (1) 164 - 164 0918-936X 2022/10
  • マウス胃のピロリ菌慢性感染は脳に神経炎症と遺伝子発現変化を誘導する
    朴 雅美; 尾村 誠一; 佐藤 文孝; 角田 郁生
    Dementia Japan (一社)日本認知症学会 36 (4) 758 - 758 1342-646X 2022/10
  • 神経免疫疾患のバリア破綻の病態と治療 バリア(腸管バリア、BBB)破綻を伴うCNS免疫性疾患における脳内の「菌の定着colonization」の注意点
    角田 郁生; 朴 雅美; 尾村 誠一; 堀田 芙美香; 城 玲央奈; Sundar Khadka; Ijaz Ahmad; 森口 幸太; 佐藤 文孝
    神経免疫学 (一社)日本神経免疫学会 27 (1) 79 - 79 0918-936X 2022/10
  • Ah-Mee Park; Ikuo Tsunoda
    Inflammation and Regeneration Springer Science and Business Media LLC 42 (1) 2022/09 
    Abstract Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since HP does not invade the central nervous system (CNS), it has been considered that systemic immunological changes induced by HP infection may play pathogenic roles in AD and PD. Here, we investigated the effects of HP infection on the CNS in vivo and in vitro. In the CNS, chronically HP-infected mice had microglial activation without HP colonization, although systemic immunological changes were not observed. This led us to explore the possibility that HP-derived outer membrane vesicles (HP-OMVs) could cause neuroinflammation. OMVs are small, spherical bilayer vesicles (20–500 nm) released into the extracellular space from the outer membrane of Gram-negative bacteria; OMVs contain lipopolysaccharide, proteins, peptidoglycan, DNA, and RNA. OMVs have also been shown to activate both innate and acquired immune cells in vitro, and to disrupt the tight junctions of the gastric epithelium (“leaky gut”) as well as cross the blood-brain barrier in vivo. Thus, in theory, OMVs can activate immune responses in the remote organs, including the lymphoid organs and CNS, if only OMVs enter the systemic circulation. From the exosome fraction of sera from HP-infected mice, we detected HP-specific DNA, suggesting the presence of HP-OMVs. We also found that microglia incubated with HP-OMVs in vitro increased the cell proliferation, inflammatory cytokine production, and migration. On the other hand, HP-OMVs suppressed the cell proliferation of neuroblastoma in vitro. Lastly, we found that AD model mice infected with HP had amyloid plaques adjacent to activated microglia and astrocytes in vivo. Based on the literature review and our experimental data, we propose our working hypothesis that OMVs produced in chronic HP infection in the gut induce neuroinflammation in the CNS, explaining the higher prevalence of AD in HP-infected people.
  • Tomoe Yoshikawa; Kosuke Minaga; Akane Hara; Ikue Sekai; Masayuki Kurimoto; Yasuhiro Masuta; Yasuo Otsuka; Ryutaro Takada; Ken Kamata; Ah-Mee Park; Shiki Takamura; Masatoshi Kudo; Tomohiro Watanabe
    International Immunology Oxford University Press (OUP) 34 (12) 621 - 634 2022/09 
    Abstract Autoimmune pancreatitis (AIP) and IgG4-related disease (IgG4-RD) are new disease entities characterized by enhanced IgG4 antibody responses and involvement of multiple organs, including the pancreas and salivary glands. Although the immunopathogenesis of AIP and IgG4-RD is poorly understood, we previously reported that intestinal dysbiosis mediates experimental AIP through the activation of IFN-α- and IL-33-producing plasmacytoid dendritic cells (pDCs). Because intestinal dysbiosis is linked to intestinal barrier dysfunction, we explored whether the latter affects the development of AIP and autoimmune sialadenitis in MRL/MpJ mice treated with repeated injections of polyinosinic–polycytidylic acid [poly (I:C)]. Epithelial barrier disruption was induced by the administration of dextran sodium sulfate (DSS) in the drinking water. Mice co-treated with poly (I:C) and DSS, but not those treated with either agent alone, developed severe AIP, but not autoimmune sialadenitis, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Sequencing of 16S ribosomal RNA revealed that Staphylococcus sciuri translocation from the gut to the pancreas was preferentially observed in mice with severe AIP co-treated with DSS and poly (I:C). The degree of experimental AIP, but not of autoimmune sialadenitis, was greater in germ-free mice mono-colonized with S. sciuri and treated with poly (I:C) than in germ-free mice treated with poly (I:C) alone, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Taken together, these data suggest that intestinal barrier dysfunction exacerbates AIP through the activation of pDCs and translocation of S. sciuri into the pancreas.
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Kazuki Hashiwaki; Ikuo Tsunoda
    Scientific reports 12 (1) 11361 - 11361 2022/07 
    The COVID-19 pandemic has led people to wear face masks daily in public. Although the effectiveness of face masks against viral transmission has been extensively studied, there have been few reports on potential hygiene issues due to bacteria and fungi attached to the face masks. We aimed to (1) quantify and identify the bacteria and fungi attaching to the masks, and (2) investigate whether the mask-attached microbes could be associated with the types and usage of the masks and individual lifestyles. We surveyed 109 volunteers on their mask usage and lifestyles, and cultured bacteria and fungi from either the face-side or outer-side of their masks. The bacterial colony numbers were greater on the face-side than the outer-side; the fungal colony numbers were fewer on the face-side than the outer-side. A longer mask usage significantly increased the fungal colony numbers but not the bacterial colony numbers. Although most identified microbes were non-pathogenic in humans; Staphylococcus epidermidis, Staphylococcus aureus, and Cladosporium, we found several pathogenic microbes; Bacillus cereus, Staphylococcus saprophyticus, Aspergillus, and Microsporum. We also found no associations of mask-attached microbes with the transportation methods or gargling. We propose that immunocompromised people should avoid repeated use of masks to prevent microbial infection.
  • Satoru Hagiwara; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Chishina; Yoriaki Komeda; Akihiro Yoshida; Ah-Mee Park; Masako Sato; Akira Kawada; Hajime Nakano; Hiroshi Nakagawa; Masatoshi Kudo
    Scientific Reports Springer Science and Business Media LLC 12 (1) 2022/04 
    Abstract Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.
  • スンダル・カドカ; 尾村 誠一; 佐藤 文孝; 中村 優美和; 甲木 蒼紫; 崎山 奈美江; 朴 雅美; 西尾 和人; 掛谷 秀昭; 角田 郁生
    近畿大学医学雑誌 近畿大学医学会 46 (3-4) 20A - 20A 0385-8367 2021/12
  • Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo; Kosuke Minaga; Yoriaki Komeda; Ken Kamata; Masatomo Kimura; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuomi Ueshima; Yasunori Minami; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Cishina; Hiroshi Ida; Ah-Mee Park; Naoshi Nishida
    Scientific Reports Springer Science and Business Media LLC 11 (1) 2021/12 
    AbstractImmune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
  • 胃粘膜ピロリ菌感染によるアルツハイマー病モデルマウスの脳内グリア細胞活性化
    朴 雅美; 佐藤 文孝; 中村 優美和; 角田 郁生
    Dementia Japan (一社)日本認知症学会 34 (4) 529 - 529 1342-646X 2020/10
  • 感染によって誘発される神経免疫病態 タイラーウイルスによる急性灰白脳脊髄炎・多発性硬化症動物モデル 分子相同性から腸内細菌叢まで
    角田 郁生; 尾村 誠一; 佐藤 文孝; 崎山 奈美江; Khadka Sundar; 中村 優美和; 朴 雅美; 藤田 貢
    神経免疫学 日本神経免疫学会 25 (1) 67 - 67 0918-936X 2020/10
  • プロドラッグ型クルクミンCMGによる実験的自己免疫性脳脊髄炎の抑制と小腸細菌叢変化
    佐藤 文孝; カドカ・スンダル; 尾村 誠一; 朴 雅美; 藤田 貢; 中村 優美和; 西尾 和人; 掛谷 秀昭; 角田 郁生
    神経免疫学 日本神経免疫学会 25 (1) 100 - 100 0918-936X 2020/10
  • 胃粘膜ヘリコバクター・ピロリ菌感染によるCNS内神経炎症の誘導
    朴 雅美; 角田 郁生
    Medical Science Digest (株)ニュー・サイエンス社 46 (10) 632 - 633 1347-4340 2020/09 
    ヘリコバクター・ピロリ菌(HP)は胃に感染するグラム陰性のらせん状桿菌で、消化性潰瘍・胃癌などの原因となる。近年、HP感染が遠隔臓器である中枢神経系(CNS)の疾患にも関連していることを示す報告が増加している。興味深いことに、多発性硬化症ではHPの感染率が一般人口と比べて低く、アルツハイマー型認知症では高いことが分かってきた。我々はHP感染がこれら二疾患にどのように関わりうるかをHP感染マウスモデルの神経炎症を調べることで明らかにしたいと考え、研究を実施している。HP感染マウスでは脳内や髄膜へのHP侵入は認められないにも関わらず、グリア細胞の活性化すなわち神経炎症が認められた。このメカニズムは未だに不明であるが、我々はHPが産生する外膜小胞(Outer Membrane Vesicle:OMV)が胃粘膜より血行性にCNSに到達することで神経炎症を引き起こしている可能性を示す結果を得た。(著者抄録)
  • 朴 雅美; 尾村 誠一; 佐藤 文孝; 藤田 貢; 角田 郁生
    腸内細菌学雑誌 (公財)腸内細菌学会 34 (2) 138 - 138 1343-0882 2020/04
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Daniel K Hsu; Fu-Tong Liu; Ikuo Tsunoda
    Frontiers in immunology 11 550366 - 550366 2020 
    Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03832946.
  • Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Mitsugu Fujita; Sundar Khadka; Yumina Nakamura; Aoshi Katsuki; Kazuto Nishio; Felicity N E Gavins; Ikuo Tsunoda
    Frontiers in immunology Frontiers Media SA 11 1138 - 1138 2020 [Refereed]
     
    Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.
  • Khadka Sundar; 尾村 誠一; 佐藤 文孝; 朴 雅美; 藤田 貢; 崎山 奈美江; 中村 優美和; 甲木 蒼紫; 角田 郁生
    近畿大学医学雑誌 近畿大学医学会 44 (3-4) 17A - 17A 0385-8367 2019/12
  • Ken Kamata; Tomohiro Watanabe; Kosuke Minaga; Akane Hara; Tomoe Yoshikawa; Ayana Okamoto; Kentaro Yamao; Mamoru Takenaka; Ah-Mee Park; Masatoshi Kudo
    International immunology 31 (12) 795 - 809 2019/11 [Refereed]
     
    Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
  • ウイルス性脳脊髄炎モデルにおける中枢神経病態と腸内細菌叢との関連性
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; カドカ・スンダル; 角田 郁生
    NEUROINFECTION 日本神経感染症学会 24 (2) 162 - 162 1348-2718 2019/09
  • MS/NMO1 多発性硬化症ウイルスモデルにおける腸内細菌叢の変化と中枢神経系炎症性脱髄病変との関連
    尾村 誠一; 佐藤 文孝; 藤田 貢; 朴 雅美; カドカ・スンダル; 角田 郁生
    神経免疫学 日本神経免疫学会 24 (1) 104 - 104 0918-936X 2019/09
  • 自己免疫性脳炎とてんかん ウイルス誘導性てんかん動物モデルと免疫系(Immune system and Theiler's virus-induced animal model for seizures/epilepsy)
    角田 郁生; 佐藤 文孝; 尾村 誠一; Khadka Sundar; 藤田 貢; 朴 雅美; 甲木 蒼紫; 中村 優美和; 崎山 奈美江; Lindeberg Felicia
    てんかん研究 (一社)日本てんかん学会 37 (2) 391 - 391 0912-0890 2019/09
  • Seiichi Omura; Fumitaka Sato; Nicholas E Martinez; Ah-Mee Park; Mitsugu Fujita; Nikki J Kennett; Urška Cvek; Alireza Minagar; J Steven Alexander; Ikuo Tsunoda
    Frontiers in immunology 10 516 - 516 2019 [Refereed]
     
    Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the homogeneity and heterogeneity of two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational analyses. We identified up-regulation of immune-related genes, including immunoglobulins, in the CNS of both models. Pro-inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-17, were associated with the disease progression in SJL/J mice, while the expression of both cytokines was detected only at the EAE onset in A.SW mice. Principal component analysis (PCA) of CNS transcriptome data demonstrated that down-regulation of prolactin may reflect disease progression. Pattern matching analysis of spleen transcriptome with CNS PCA identified 333 splenic surrogate markers, including Stfa2l1, which reflected the changes in the CNS. Among them, we found that two genes (PER1/MIR6883 and FKBP5) and one gene (SLC16A1/MCT1) were also significantly up-regulated and down-regulated, respectively, in human MS peripheral blood, using data mining.
  • Koji Sugioka; Aya Kodama-Takahshi; Tomoko Sato; Kiyotaka Okada; Junko Murakami; Ah-Mee Park; Hiroshi Mishima; Yoshikazu Shimomura; Shunji Kusaka; Teruo Nishida
    Investigative Opthalmology & Visual Science Association for Research in Vision and Ophthalmology (ARVO) 59 (12) 5098 - 5098 1552-5783 2018/10
  • Ah-Mee Park; Ikuo Tsunoda; Osamu Yoshie
    The Journal of biological chemistry Elsevier {BV} 293 (41) 15815 - 15826 0021-9258 2018/10 [Refereed]
     
    Heat shock protein 27 (HSP27) protects cells under stress. Here, we demonstrate that HSP27 also promotes cell cycle progression of MRC-5 human lung fibroblast cells. Serum starvation for 24 h induced G1 arrest in these cells, and upon serum refeeding, the cells initiated cell cycle progression accompanied by an increase in HSP27 protein levels. HSP27 levels peaked at 12 h, and transcriptional up-regulation of six G2/M-related genes (CCNA2, CCNB1, CCNB2, CDC25C, CDCA3, and CDK1) peaked at 24-48 h. siRNA-mediated HSP27 silencing in proliferating MRC-5 cells induced G2 arrest coinciding with down-regulation of these six genes. Of note, the promoters of all of these genes have the cell cycle-dependent element and/or the cell cycle gene-homology region. These promoter regions are known to be bound by the E2F family proteins (E2F-1 to E2F-8) and retinoblastoma (RB) family proteins (RB1, p107, and p130), among which E2F-4 and p130 were strongly up-regulated in HSP27-knockdown cells. E2F-4 or p130 knockdown concomitant with the HSP27 knockdown rescued MRC-5 cells from G2 arrest and up-regulated the six cell cycle genes. Moreover, we observed cellular senescence in MRC-5 cells on day 3 after the HSP27 knockdown, as evidenced by increased senescence-associated β-gal activity and up-regulated inflammatory cytokines. The cellular senescence was also suppressed by the concomitant knockdown of E2F-4/HSP27 or p130/HSP27. Our findings indicate that HSP27 promotes cell cycle progression of MRC-5 cells by suppressing expression of the transcriptional repressors E2F-4 and p130.
  • Ah-Mee Park; Ikuo Tsunoda
    BioTechniques 65 (4) 227 - 230 0736-6205 2018/10 [Refereed]
     
    Fecal occult blood (FOB) is a sign of gastrointestinal diseases, such as intestinal ulcers and colorectal cancer. In experimental animal studies, there is no standard method to detect FOB. Here, we present a simple protocol to detect FOB in mice, using the Luminol Reaction Experiment Kit® that was originally designed to detect bloodstains at a crime scene in criminal forensics. To obtain positive control bloody feces, we used an indomethacin-induced intestinal ulcer model in mice. By mixing small pieces of feces with a luminol solution, the fecal solution emitted visible blue-white chemiluminescence in dark field when feces contained hemoglobin. We also established a method for semi-quantification of hemoglobin content in the fecal solution, using a luminometer. This method is simple, quick, economical and semi-quantitative, allowing researchers to detect FOB in experimental mice.
  • Koji Sugioka; Aya Kodama-Takahshi; Tomoko Sato; Kiyotaka Okada; Junko Murakami; Ah-Mee Park; Hiroshi Mishima; Yoshikazu Shimomura; Shunji Kusaka; Teruo Nishida
    Investigative ophthalmology & visual science 59 (12) 5098 - 5107 0146-0404 2018/10 [Refereed]
     
    Purpose: Staphylococcus aureus is a common cause of corneal ulceration, and staphylokinase (SAK) produced by this bacterium is a plasminogen activator. To investigate the pathogenesis of corneal ulceration induced by S. aureus, we examined the effects of bacterial culture broth and SAK on collagen degradation in a culture model in which human corneal fibroblasts are embedded in a collagen gel. Methods: Corneal fibroblasts embedded in collagen were exposed to S. aureus culture broth or SAK. Collagen degradation was assessed by measurement of hydroxyproline in acid hydrolysates of culture supernatants. Expression of pro-matrix metalloproteinase-1 (pro-MMP-1) was detected by immunoblot analysis as well as reverse transcription and real-time polymerase chain reaction analysis. Results: Both S. aureus culture broth and SAK markedly increased collagen degradation in the presence of corneal fibroblasts and plasminogen. This effect of the culture broth was dependent on cell number to a greater extent than was that of SAK. Whereas the culture broth also increased the expression of pro-MMP-1 in corneal fibroblasts at both mRNA and protein levels, SAK did not. Conclusions: Our results suggest that S. aureus may promote collagen degradation both by upregulating pro-MMP1 expression in corneal fibroblasts, with pro-MMP-1 then being converted to active MMP-1 by plasmin, and by directing plasmin activity toward collagen in a SAK-dependent manner.
  • Ayuko Kishimoto; Shunsuke Kimura; Junko Nio-Kobayashi; Hiromi Takahashi-Iwanaga; Ah-Mee Park; Toshihiko Iwanaga
    Experimental eye research Academic Press 172 1 - 9 1096-0007 2018/07 [Refereed]
     
    The hyaloid vasculature constitutes a transitory system nourishing the internal structures of the developing eye, but the mechanism of vascular regression and its cell biological characteristics are not fully understood. The present study aimed to reveal the specificity of the hyaloid vessels by a systematic immunohistochemical approach for marker substances of myeloid cells and the extracellular matrix (ECM) in neonatal mice. Macrophages immunoreactive for F4/80, cathepsin D, and LYVE-1 gathered around the vasa hyaloidea propria (VHP), while small round cells in vascular lumen of VHP were selectively immunoreactive for galectin-3; their segmented nuclei and immunoreactivities for Ly-6G, CD11b, and myeloperoxidase indicated their neutrophilic origin. VHP possessed thick ECM and a dense pericyte envelope as demonstrated by immunostaining for laminin, type IV collagen, integrin β1, and NG2. The galectin-3+ cells loosely aggregated with numerous erythrocytes in the lumen of hyaloid vessels in a manner reminiscent of vascular congestion. Galectin-3 is known to polymerize and form a complex with ECM and NG2 as well as recruit leukocytes on the endothelium. Observation of galectin-3 KO mice implicated the involvement of galectin-3 in the regression of hyaloid vasculature. Since macrophages may play central roles including blocking of the blood flow and the induction of apoptosis in the regression, galectin-3+ neutrophils may play a supportive role in the macrophage-mediated involution of the hyaloid vascular system.
  • Kyosuke Kanai; Ah-Mee Park; Akiko Watanabe; Tomohiro Arikawa; Teruhito Yasui; Hiroki Yoshida; Ikuo Tsunoda; Osamu Yoshie
    Journal of immunology (Baltimore, Md. : 1950) American Association of Immunologists 200 (8) 2703 - 2713 1550-6606 2018/04 [Refereed]
     
    IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27-deficient mice), we examined the role of IL-27 in primary infection by murine γ-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27-deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27-deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27-deficient mice was characterized by more IFN-γ-producing CD8+ T cells and fewer IL-10-producing CD8+ T cells than that of wild-type mice. An infectious mononucleosis-like disease was also aggravated in IL-27-deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-γ-producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10-producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis.
  • Computational Analyses Associate the CNS Lymphatic Molecules with Disease Progression of a Viral Model for Multiple Sclerosis
    Seiichi Omura; Fumitaka Sato; Mitsugu Fujita; Ah-Mee Park; J. Steven Alexander, Phillip; C.S.R. Kilgore; Urska Cvek; Ikuo Tsunoda
    Neuroinfection 日本神経感染症学会 23 (1) 114 - 120 1348-2718 2018/04 [Refereed][Invited]
     
    多発性硬化症(MS)の発症要因はいまだ確定していないが、ウイルス感染がその一つと考えられている。MSの病理学的特徴は中枢神経系(CNS)への免疫細胞浸潤であり、接着分子の発現増加と血液脳関門の破綻が寄与している。一方、侵入した免疫細胞のCNSからの退出機序は不明であったが、近年CNS内リンパ管の存在が報告され、その役割が注目されている。本稿ではMSのウイルス感染モデルであるタイラーウイルス誘導性脱髄疾患マウスを用い、その脊髄トランスクリプトームデータのバイオインフォマティクス解析により、CNS内リンパ管の病態への寄与を検討した。タイラーウイルス感染群と対照群の接着分子、血液脳関門関連分子、リンパ管分子発現データを用いた主成分分析により、リンパ管分子の発現低下がリンパ球のCNSからの退出遅延に寄与することが示唆された。(著者抄録)
  • 尾村誠一; 清水和秋; 桑原基; 森川みゆき; 藤田貢; 朴雅美; 佐藤文孝; PEDIO Erika; 楠進; 角田郁生
    Neuroimmunology 日本神経免疫学会 23 (1) 103 - 103 0918-936X 2018
  • Satoru Hagiwara; Naoshi Nishida; Ah-Mee Park; Yoriaki Komeda; Toshiharu Sakurai; Tomohiro Watanabe; Masatoshi Kudo
    Scientific reports NATURE PUBLISHING GROUP 7 (1) 10440 - 10440 2045-2322 2017/09 [Refereed]
     
    Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV-related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of β-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis.
  • Fumitaka Sato; Eiichiro Kawai; Nicholas E Martinez; Seiichi Omura; Ah-Mee Park; Satoru Takahashi; Keigyou Yoh; Ikuo Tsunoda
    Scientific reports NATURE PUBLISHING GROUP 7 (1) 10496 - 10496 2045-2322 2017/09 [Refereed]
     
    Intracerebral Theiler's murine encephalomyelitis virus (TMEV) infection in mice induces inflammatory demyelination in the central nervous system. Although C57BL/6 mice normally resistant to TMEV infection with viral clearance, we have previously demonstrated that RORγt-transgenic (tg) C57BL/6 mice, which have Th17-biased responses due to RORγt overexpression in T cells, became susceptible to TMEV infection with viral persistence. Here, using T-bet-tg C57BL/6 mice and Gata3-tg C57BL/6 mice, we demonstrated that overexpression of T-bet, but not Gata3, in T cells was detrimental in TMEV infection. Unexpectedly, T-bet-tg mice died 2 to 3 weeks after infection due to failure of viral clearance. Here, TMEV infection induced splenic T cell depletion, which was associated with lower anti-viral antibody and T cell responses. In contrast, Gata3-tg mice remained resistant, while Gata3-tg mice had lower IFN-γ and higher IL-4 production with increased anti-viral IgG1 responses. Thus, our data identify how overexpression of T-bet and Gata3 in T cells alters anti-viral immunity and confers susceptibility to TMEV infection.
  • Ah-Mee Park; Seiichi Omura; Mitsugu Fujita; Fumitaka Sato; Ikuo Tsunoda
    Clinical & experimental neuroimmunology 8 (3) 215 - 232 2017/08 [Refereed]
     
    Alteration of microbiota has been associated with intestinal, inflammatory, and neurological diseases. Abundance of "good bacteria" such as Bifidobacterium, or their products have been generally believed to be beneficial for any diseases, while "bad bacteria" such as pathogenic Helicobacter pylori are assumed to be always detrimental for hosts. However, this is not the case when we compare and contrast the association of the gut microbiota with two neurological diseases, multiple sclerosis (MS) and Alzheimer's disease (AD). Following H. pylori infection, pro-inflammatory T helper (Th)1 and Th17 immune response are initially induced to eradicate bacteria. However, H. pylori evades the host immune response by inducing Th2 cells and regulatory T cells (Tregs) that produce anti-inflammatory interleukin (IL)-10. Suppression of anti-bacterial Th1/Th17 cells by Tregs may enhance gastric H. pylori propagation, followed by a cascade reaction involving vitamin B12 and folic acid malabsorption, plasma homocysteine elevation, and reactive oxygen species induction. This can damage the blood-brain barrier (BBB), leading to accumulation of amyloid-β in the brain, a hallmark of AD. On the other hand, this suppression of pro-inflammatory Th1/Th17 responses to H. pylori has protective effects on the hosts, since it prevents uncontrolled gastritis as well as suppresses the induction of encephalitogenic Th1/Th17 cells, which can mediate neuroinflammation in MS. The above scenario may explain why chronic H. pylori infection is positively associated with AD, while it is negatively associated with MS. Lastly, we list "10 pitfalls of microbiota studies", which will be useful for evaluating and designing clinical and experimental microbiota studies.
  • 感染因子による神経免疫疾患誘発のメカニズムと治療 ウイルス感染によって誘導される"軸索型"多発性硬化症動物モデル インサイド-アウト・モデル
    角田 郁生; 尾村 誠一; 佐藤 文孝; 崎山 奈美江; 朴 雅美; 藤田 貢
    NEUROINFECTION 日本神経感染症学会 22 (1) 28 - 35 1348-2718 2017/04 
    多発性硬化症(multiple sclerosis、MS)は中枢神経系の炎症性脱髄と軸索障害を主体とする神経変性疾患であり、全世界では200万人以上、日本では約1万人のMS患者が存在する。MS発症の原因としてはウイルス感染説と自己免疫説が提唱されている。その動物実験モデルとして、前者に対してはタイラーウイルス誘導性脱髄疾患[Theiler's murine encephalomyelitis virus(TMEV)-induced demyelinating disease、TMEV-IDD]が、後者に対しては実験的自己免疫性脳脊髄炎(experimental autoimmune encephalomyelitis、EAE)が、それぞれ頻用されている。両者ともT細胞が病変形成に関与するが、MS様病変である脱髄と軸索変性の進展様式は両者間で異なる。TMEV-IDDでは、病変は神経線維の内側(インサイド)の軸索障害に始まり、外側(アウトサイド)の髄鞘障害(=脱髄)へと進展する(インサイド-アウト・モデル)。一方、EAEでは外側の髄鞘障害が先行し、続いて内側の軸索障害が誘導される(アウトサイド-イン・モデル)。ヒトMSの病理像では、インサイド-アウト・モデルとアウトサイド-イン・モデルそれぞれに合致する病理像が報告されており、前者は"軸索型"MSといえるものであり、後者の古典的"脱髄型"MSとは異なる。また両者の病理像が同一個体でみられるMS症例も存在する。すなわち"インサイド-アウト"と"アウトサイド-イン"の進展様式は相反するものではなく、むしろ共存して悪循環を形成し病態進行に寄与しうると推測される。この悪循環を断つ方法としては、1)炎症抑制、2)軸索保護、3)軸索変性の抑制(ウイルス感染の場合は、ウイルス増殖抑制による)の三つが考えられる。理論的には、この悪循環のいずれかのステップに介入する治療法がMSの進行抑制を可能にする。実際、MS治療に作用点の異なる複数の薬剤が有効であるという臨床データが、MS症例の多くで前述二つの進展様式が共存しうることを示唆する。(著者抄録)
  • Mitsugu Fujita; Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Ikuo Tsunoda
    Anatomy & Physiology: Current Research 7 274  2017 [Refereed]
  • Identification of a HBx mutation that enhances human hepatocarcinogenesis through the activation of the JNK and Wnt pathways.
    Hagiwara S; Nishida N; Sakurai T; Park AM; Komeda Y; Kitano M; Kudo M
    BMC Cancer in press 2017 [Refereed]
  • Kyosuke Kanai; Ah-Mee Park; Hiroki Yoshida; Ikuo Tsunoda; Osamu Yoshie
    Journal of immunology (Baltimore, Md. : 1950) AMER ASSOC IMMUNOLOGISTS 198 (1) 119 - 127 0022-1767 2017/01 [Refereed]
     
    EBI3 functions as the subunit of immune-regulatory cytokines, such as IL-27 and IL-35, by pairing with p28 and p35, respectively. We treated wild-type and EBI3-deficient mice with intratracheal administration of LPS and obtained bronchoalveolar lavage fluid (BALF) 24 h later. Although neutrophils were the predominant cells in BALF from both groups of mice, eosinophils were highly enriched and there was increased production of eosinophil-attracting chemokines CCL11 and CCL24 in BALF of EBI3-deficient mice. The bronchial epithelial cells and alveolar macrophages were the major producers of CCL11 and CCL24. Because no such increases in eosinophils were seen in BALF of p28/IL-27-deficient mice or WSX-1/IL-27Rα subunit-deficient mice upon intratracheal stimulation with LPS, we considered that the lack of IL-35 was responsible for the enhanced airway eosinophilia in EBI3-deficient mice. In vitro, IL-35 potently suppressed production of CCL11 and CCL24 by human lung epithelial cell lines treated with TNF-α and IL-1β. IL-35 also suppressed phosphorylation of STAT1 and STAT3 and induced suppressor of cytokine signaling 3. In vivo, rIL-35 dramatically reduced LPS-induced airway eosinophilia in EBI3-deficient mice, with concomitant reduction of CCL11 and CCL24, whereas neutralization of IL-35 significantly increased airway eosinophils in LPS-treated wild-type mice. Collectively, our results suggest that IL-35 negatively regulates airway eosinophilia, at least in part by reducing the production of CCL11 and CCL24.
  • Ikuo Tsunoda; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Namie Sakiyama; Ah-Mee Park
    Clinical & experimental neuroimmunology 7 (4) 330 - 345 1759-1961 2016/11 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a viral model for multiple sclerosis (MS), as TMEV can induce chronic inflammatory demyelinating lesions with viral persistence in the spinal cord of SJL/J mice. In contrast, when C57BL/6 mice are infected with TMEV, the mice can clear the virus from the central nervous system (CNS), without viral persistence or demyelination, but develop seizures and hippocampal sclerosis, which has been used as a viral model for seizures/epilepsy. In the two TMEV-induced CNS disease models, not only viral infection, but also immune responses contribute to the pathogenesis. Interestingly, acquired immunity plays an effector role in the MS model, whereas innate immunity appears to contribute to the development of seizures. Recently, we have established the third TMEV-induced disease model, a mouse model for viral myocarditis, using C3H mice. TMEV-induced myocarditis is a triphasic disease, which mimics human myocarditis; phase I, mediated by viral replication in the heart and innate immunity; phase II, mediated by acquired immunity; and phase III, resulted from cardiac fibrosis. The genetic susceptibility to the aforementioned three models (MS, seizures and myocarditis) differs among mouse strains. We have compared and contrasted the three models induced by one single pathogen, TMEV, particularly in regard to the roles of T helper cells and natural killer T cells, which will give an insight into how interactions between the immune system and the host's genetic background determine the tissue tropism of virus and the development of virus-induced organ-specific immunopathology.
  • Ah-Mee Park; Satoru Hagiwara; Daniel K Hsu; Fu-Tong Liu; Osamu Yoshie
    Infection and immunity AMER SOC MICROBIOLOGY 84 (4) 1184 - 1193 0019-9567 2016/04 [Refereed]
     
    We studied the role of galectin-3 (Gal3) in gastric infection by Helicobacter pylori We first demonstrated that Gal3 was selectively expressed by gastric surface epithelial cells and abundantly secreted into the surface mucus layer. We next inoculated H. pylori Sydney strain 1 into wild-type (WT) and Gal3-deficient mice using a stomach tube. At 2 weeks postinoculation, the bacterial cells were mostly trapped within the surface mucus layer in WT mice. In sharp contrast, they infiltrated deep into the gastric glands in Gal3-deficient mice. Bacterial loads in the gastric tissues were also much higher in Gal3-deficient mice than in WT mice. At 6 months postinoculation,H. pylori had successfully colonized within the gastric glands of both WT and Gal3-deficient mice, although the bacterial loads were still higher in the latter. Furthermore, large lymphoid clusters mostly consisting of B cells were frequently observed in the gastric submucosa of Gal3-deficient mice.In vitro, peritoneal macrophages from Gal3-deficient mice were inefficient in killing engulfed H. pylori Furthermore, recombinant Gal3 not only induced rapid aggregation of H. pylori but also exerted a potent bactericidal effect on H. pylori as revealed by propidium iodide uptake and a morphological shift from spiral to coccoid form. However, a minor fraction of bacterial cells, probably transient phase variants of Gal3-binding sugar moieties, escaped killing by Gal3. Collectively, our data demonstrate that Gal3 plays an important role in innate immunity to infection and colonization of H. pylori.
  • Ikuo Tsunoda; Seiichi Omura; Fumitaka Sato; Susumu Kusunoki; Mitsugu Fujita; Ah-Mee Park; Faris Hasanovic; Richard Yanagihara; Satoshi Nagata
    Acta medica Kinki University 41 (2) 37 - 52 0386-6092 2016 [Refereed]
     
    Zika virus (ZIKV) is an enveloped, positive-sense, single-stranded RNA virus that belongs to the genus Flavivirus, family Flaviviridae, which includes many human and animal pathogens, such as dengue virus (DENV), West Nile virus, and Japanese encephalitis virus. In the original as well as subsequent experimental and clinical reports, ZIKV seems to have moderate neurotropism (in animal models) and neurovirulence (in human fetuses), but no neuroinvasiveness (in human adults). Intrauterine ZIKV infection (viral pathology) has been linked to an increased incidence of microcephaly, while increased Guillain-Barré syndrome (GBS) following ZIKV infection is likely immune-mediated (immunopathology). Clinically, in ZIKV infection, antibodies against other flaviviruses, such as DENV, have been detected; these antibodies can cross-react with ZIKV without ZIKV neutralization. In theory, such non-neutralizing antibodies are generated at the expense of decreased production of neutralizing antibodies ("antigenic sin"), leading to poor viral clearance, while the non-neutralizing antibodies can also enhance viral replication in Fc receptor (FcR)-bearing cells via antibody-dependent enhancement (ADE). Here, we propose three potential roles of the antibody-mediated pathogenesis of ZIKV infection: 1) cross-reactive antibodies that recognize ZIKV and neural antigens cause GBS; 2) ZIKV-antibody complex is transported transplacentally via neonatal FcR (FcRn), resulting in fetal infection; and 3) ZIKV-antibody complex is taken up at peripheral nerve endings and transported to neurons in the central nervous system (CNS), by which the virus can enter the CNS without crossing the blood-brain barrier.
  • Ah-Mee Park; Kyosuke Kanai; Tatsuki Itoh; Takao Sato; Tatsuya Tsukui; Yutaka Inagaki; Moises Selman; Kouji Matsushima; Osamu Yoshie
    PloS one 11 (2) e0148998  1932-6203 2016 [Refereed]
     
    Heat shock protein 27 (HSP27) is a member of the small molecular weight HSP family. Upon treatment with transforming growth factor β1 (TGF-β1), we observed upregulation of HSP27 along with that of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation, in cultured human and mouse lung fibroblasts. Furthermore, by using siRNA knockdown, we demonstrated that HSP27 was involved in cell survival and upregulation of fibronectin, osteopontin (OPN) and type 1 collagen, all functional markers of myofibroblast differentiation, in TGF-β1-treated MRC-5 cells. In lung tissues of bleomycin-treated mice, HSP27 was strongly upregulated and substantially co-localized with α-SMA, OPN and type I collagen but not with proSP-C (a marker of type II alveolar epithelial cells), E-cadherin (a marker of epithelial cells) or F4/80 (a marker of macrophages). A similar co-localization of HSP27 and α-SMA was observed in lung tissues of patients with idiopathic pulmonary fibrosis. Furthermore, airway delivery of HSP27 siRNA effectively suppressed bleomycin-induced pulmonary fibrosis in mice. Collectively, our findings indicate that HSP27 is critically involved in myofibroblast differentiation of lung fibroblasts and may be a promising therapeutic target for lung fibrotic diseases.
  • Satoru Hagiwara; Naoshi Nishida; Ah-Mee Park; Toshiharu Sakurai; Akira Kawada; Masatoshi Kudo
    Hepatology (Baltimore, Md.) WILEY-BLACKWELL 62 (5) 1638 - 9 0270-9139 2015/11 [Refereed]
  • Koji Yoshida; Ah-Mee Park; Shingen Ozaki; Hiroshi Munakata
    Advances in Biological Chemistry 4 59 - 66 2014/02 [Refereed]
  • EGCG suppresses TGF-bete signaling by interacting with TGF-beta type II receptor.
    Tabuchi M; Hayakawa S; Honda E; Ooshima K; Itoh I; Yoshida K; Park AM; Higashino H; Isemura M; Munakata H
    World Journal of Experimental Medicine 3 (4) 100 - 107 2013/11 [Refereed]
  • Masaki Tabuchi; Sumio Hayakawa; Eiko Honda; Kana Ooshima; Tatsuki Itoh; Koji Yoshida; Ah-Mee Park; Hideaki Higashino; Mamoru Isemura; Hiroshi Munakata
    World J Exp Med Baishideng Publishing Group Co. 3 (4) 100 - 107 2220-315X 2013/08
  • Eiko Honda; Ah-Mee Park; Koji Yoshida; Masaki Tabuchi; Hiroshi Munakata
    The Tohoku journal of experimental medicine TOHOKU UNIV MEDICAL PRESS 230 (2) 67 - 73 0040-8727 2013/06 [Refereed]
     
    Fibrosis is a state, in which excess amounts of extracellular matrix are deposited in the tissue. Fibrosis can occur in various organs, including the liver, lung, kidney and heart. The progression of fibrosis involves interstitial hypercellularity, accumulation of extracellular matrix, and atrophy of epithelial structures, resulting in a loss of normal function. Myofibroblasts play a crucial role in the development and progress of fibrosis. When stimulated, myofibroblasts actively synthesize connective tissue components and cause organ fibrosis. As a result, the process and the mechanism of myofibroblast activation represent a target for antifibrotic treatment. As yet, however, an effective treatment has not been developed, and new treatment modalities are expected. Because activation of myofibroblasts is a key event during fibrosis development, there is great interest in identifying and characterizing proteins whose expression is changed after this activation. In this review, fibrosis is outlined and the role of myofibroblasts in this disorder is described. Furthermore, the search for candidate proteins to target for treatment and the prospects of antifibrotic therapy are discussed.
  • Ah-Mee Park; Masatoshi Kudo; Satoru Hagiwara; Masaki Tabuchi; Tomohiro Watanabe; Hiroshi Munakata; Toshiharu Sakurai
    FREE RADICAL BIOLOGY AND MEDICINE ELSEVIER SCIENCE INC 52 (11-12) 2284 - 2291 0891-5849 2012/06 [Refereed]
     
    Mitogen-activated protein kinases (MAPKs) are ubiquitous proteins that function in both normal and stress-related pathophysiological states of the cell. This study aimed to analyze the importance of p38MAPK in pancreatic injury using WBN/Kob rats with spontaneous chronic pancreatitis. Male WBN/Kob rats were injected with the p38MAPK inhibitor SB203580, starting at the age of 4 weeks, and sacrificed 6 weeks later. Compared with vehicle-treated rats, p38 inhibitor-treated rats exhibited a significant increase in pancreatic cell death and inflammation as assessed by histologic examination and myeloperoxidase activity, respectively. p38 inhibition decreased the expression of heat shock protein 27 (HSP27), an antioxidant protein, and enhanced accumulation of reactive oxygen species (ROS). In addition, the proapoptotic protein BAD was increased in the pancreas of rats treated with p38 inhibitor. In a pancreatic cell line (PANC-1), HSP27 knockdown augmented reactive oxygen species accumulation and cell death induced by tumor necrosis factor-alpha plus actinomycin D. In conclusion, p38MAPK suppresses chronic pancreatitis by upregulating HSP27 expression and downregulating BAD expression. (C) 2012 Elsevier Inc. All rights reserved.
  • Satoru Hagiwara; Masatoshi Kudo; Hobyung Chung; Kazuomi Ueshima; Tatsuo Inoue; Seiji Haji; Tomohiro Watanabe; Ah-Mee Park; Hiroshi Munakata; Toshiharu Sakurai
    HEPATOLOGY RESEARCH WILEY-BLACKWELL 42 (4) 394 - 400 1386-6346 2012/04 [Refereed]
     
    Aim: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. Methods: From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross- sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. Results: Multivariate analysis using a Logistic regression model showed that JNK activity in non- cancerous liver tissue was correlated with postoperative late recurrence. (P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33- 25.36). Conclusions: JNK activity in non- cancerous liver tissue is considered as a reliable predictive biomarker for postoperative recurrence in HCC.
  • Ah-Mee Park; Sumio Hayakawa; Eiko Honda; Yoshihiro Mine; Koji Yoshida; Hiroshi Munakata
    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS ELSEVIER SCIENCE INC 518 (2) 133 - 141 0003-9861 2012/02 [Refereed]
     
    Pulmonary fibrosis is a devastating condition resulting from excess extracellular matrix deposition that leads to progressive lung destruction and scarring. In the pathogenesis of fibrotic diseases, activation of myofibroblasts by transforming growth factor-beta (TGF-beta) plays a crucial role. Since no effective therapy for pulmonary fibrosis is currently recognized, finding an effective antifibrotic agent is an important objective. One approach might be through identification of agents that inactivate myofibroblasts. In the current study we examined the potential of conditioned medium obtained from several types of cells to exhibit myofibroblast inactivating activity. Conditioned media from lung cancer cell lines A549 and PC9 were found to have this action, as shown by its ability to decrease alpha-smooth muscle actin expression in MRC-5 cells. Subsequently the inhibitory factor was purified from the medium and identified as 5'-deoxy-5'-methylthioadenosine (MTA), and its mechanism of action elucidated. Activation of protein kinase A and cAMP responsive element binding protein (CREB) were detected. MTA inhibited TGF-beta-induced mitogen-activated protein kinase activation. Furthermore, the gain-of-function mutant CREB caused inactivation of myofibroblasts. These results show that A549 and PC9 conditioned media have the ability to inactivate myofibroblasts, and that CREB-phosphorylation plays a central role in this process. (C) 2011 Elsevier Inc. All rights reserved.
  • Satoru Hagiwara; Toshiharu Sakurai; Shinichi Nishina; Kaoru Tanaka; Masafumi Ikeda; Kazuomi Ueshima; Yasunori Minami; Tatsuo Inoue; Norihisa Yada; Satoshi Kitai; Masahiro Takita; Tomoyuki Nagai; Sousuke Hayaishi; Tadaaki Arizumi; Ah-Mee Park; Hiroshi Munakata; Naoshi Nishida; Masatoshi Kudo
    Digestive diseases (Basel, Switzerland) KARGER 30 (6) 541 - 6 0257-2753 2012 [Refereed]
     
    OBJECTIVE: A number of studies have reported reactivation of hepatitis B during intensive immunosuppressive therapy such as cases of hematological malignancy, whereas little has been reported for characteristics of reactivation triggered by chemotherapy for solid cancer. METHODS: A total of 130 patients underwent chemotherapy for treatments of common solid cancer between May 2011 and May 2012 at Kinki University Hospital. Among them, 27 patients were suspected for a past infection of hepatitis B virus (HBV), showing positive for hepatitis B core antibody or surface antibody but negative for hepatitis B surface antigen, and were eligible for this study. RESULTS: Hepatitis B reactivation was observed in 2 of 27 cases (7.4%). The duration between the start of chemotherapy and increase of serum HBV load was 30 days in both cases. CONCLUSIONS: We reported the 2 cases of hepatitis B reactivation receiving chemotherapy for solid cancer in terms of patterns and characteristics of reactivation. Accumulation of such cases will help in clarifying the clinical importance of hepatitis B reactivation during treatment of solid malignancies.
  • Ah-Mee Park; Hiroko Nagase; Lingling Liu; Shilpashree Vinod Kumar; Nava Szwergold; Chi-Ming Wong; Yuichiro J. Suzuki
    CARDIOVASCULAR RESEARCH OXFORD UNIV PRESS 90 (1) 97 - 104 0008-6363 2011/04 [Refereed]
     
    Aims Anthracyclines such as daunorubicin (DNR) and doxorubicin are effective cancer chemotherapeutic agents, but can induce cardiotoxicity. GATA4 has been shown to serve as a survival factor of cardiac muscle cells, and anthracyclines promote apoptosis in part by down-regulating GATA4. The present study investigated the mechanism of anthracycline action to down-regulate GATA4. Methods and results DNR inhibited the transcriptional activity exhibited by the 250 bp conserved region immediately upstream from the transcriptional start site of the Gata4 gene. Mapping this region identified that the CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) binding to the CCAAT box was inhibited by DNR in HL-1 cardiac muscle cells and in perfused isolated mouse hearts. The DNR action on the Gata4 promoter was found to be dependent on p53, since DNR promoted nuclear binding of p53 to CBF/NF-Y and pifithrin-alpha (a p53 inhibitor) attenuated DNR down-regulation of GATA4. Conclusion Anthracycline down-regulation of GATA4 is mediated by the inhibition of Gata4 gene transcription via a novel mechanism that involves the p53-dependent inhibition of CBF/NF-Y binding to the CCAAT box within the Gata4 promoter.
  • Satoru Hagiwara; Masatoshi Kudo; Kazuomi Ueshima; Hobyung Chung; Mami Yamaguchi; Masahiro Takita; Seiji Haji; Masatomo Kimura; Tokuzo Arao; Kazuto Nishio; Ah-Mee Park; Hiroshi Munakata
    JOURNAL OF GASTROENTEROLOGY SPRINGER TOKYO 46 (2) 212 - 221 0944-1174 2011/02 [Refereed]
     
    Combination therapy with the oral fluoropyrimidine anticancer drug S1 and interferon is reportedly effective for the treatment of advanced hepatocellular carcinoma (HCC), but selection criteria for this therapy have not been clarified. In this study, we attempted to identify factors predicting the effectiveness of this combination therapy. Pathological specimens of HCC were collected before treatment from 31 patients with advanced HCC who underwent S1+ pegylated-interferon (PEG-IFN) alpha-2b therapy between January 2007 and January 2009. In these pathological specimens, the expression levels of CD133, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and interferon-receptor 2 (IFNR2) proteins were determined by Western blot assay. The presence or absence of p53 gene mutations was determined by direct sequencing. The relationships between these protein expression levels and the response rate (RR), progression-free survival (PFS), and overall survival (OS) were evaluated. The CD133 protein expression level was significantly lower in the responder group than in the nonresponder group. Comparing the PFS and OS between high- and low-level CD133 expression groups (n = 13 and 18, respectively) revealed that both parameters were significantly prolonged in the latter group. The expression levels of TS, DPD, and IFNR2 protein and the presence of p53 gene mutations did not correlate with the RR. CD133 was identified as a predictor of the therapeutic effect of S1+ PEG-IFN alpha-2b therapy against advanced HCC.
  • Toshiharu Sakurai; Masatoshi Kudo; Nobuhiro Fukuta; Tatsuya Nakatani; Masatomo Kimura; Ah-Mee Park; Hiroshi Munakata
    PANCREATOLOGY KARGER 11 (SUPPL. 2) 7 - 13 1424-3903 2011 [Refereed]
     
    Background: Pancreatic cancers often develop in the context of pancreatic fibrosis caused by chronic pancreas inflammation, which also results in the accumulation of reactive oxygen species (ROS), pancreatic parenchymal cell death, and stellate cell activation. Angiotensin II, which is converted from angiotensin I by the angiotensin-converting enzyme (ACE), stimulates ROS production via NADPH oxidase. In stellate cells, angiotensin II activates the stress-activated protein kinase p38. However, the molecular mechanism by which angiotensin II regulates pancreatic inflammation and fibrosis remains to be determined. Methods: Wistar Bonn/Kobori (WBN/Kob) rats spontaneously develop chronic pancreatic inflammation. To examine whether blockade of the renin-angiotensin system affects the development of pancreatic fibrosis, WBN/Kob rats were given angiotensin II type 1 receptor (AT1R) blocker or ACE inhibitor (ACEI). Next, we assessed the role of angiotensin II and its possible downstream target p38 alpha in stellate cell activation using primary stellate cells. Results: Treatment with AT1R blocker and ACEI prevented the development of chronic pancreatitis and fibrosis. In stellate cells, angiotensin II upregulated the expression of angiotensin II receptors, alpha-smooth muscle actin (SMA) and transforming growth factor-beta. In addition, p38 alpha was found to be essential to collagen type I production and alpha-SMA expression. ROS accumulation is enhanced in chronic pancreatic inflammation, which increases the risk of pancreatic cancer. Conclusions: Inhibition of the angiotensin II signaling pathway might be a promising strategy to prevent pancreatic fibrogenesis and subsequent carcinogenesis. Copyright (C) 2011 S. Karger AG, Basel and IAP
  • Ah-Mee Park; Chi-Ming Wong; Ludmila Jelinkova; Lingling Liu; Hiroko Nagase; Yuichiro J. Suzuki
    HYPERTENSION LIPPINCOTT WILLIAMS & WILKINS 56 (6) 1145 - 1151 0194-911X 2010/12 [Refereed]
     
    The major cause of death among pulmonary hypertension patients is right heart failure, but the biology of right heart is not well understood. Previous studies showed that mechanisms of the activation of GATA4, a major regulator of cardiac hypertrophy, in response to pressure overload are different between left and right ventricles. In the left ventricle, aortic constriction triggers GATA4 activation via posttranslational modifications without influencing GATA4 expression, while pulmonary artery banding enhances GATA4 expression in the right ventricle. We found that GATA4 expression can also be increased in the right ventricle of rats treated with chronic hypoxia to induce pulmonary hypertension and investigated the mechanism of increased GATA4 expression. Examination of Gata4 promoter revealed that CCAAT box plays an important role in gene activation, and hypoxic pulmonary hypertension promoted the binding of CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) to CCAAT box in the right ventricle. We found that CBF/NF-Y forms a complex with annexin A1, which inhibits DNA binding activity. In response to hypoxic pulmonary hypertension, annexin A1 gets degraded, resulting in CBF/NF-Y-dependent activation of Gata4 gene transcription. The right ventricle contains a higher level of CBF/NF-Y compared to the left ventricle, and this may allow for efficient activation in response to annexin A1 degradation. Signaling via iron-catalyzed protein oxidation mediates hypoxic pulmonary hypertension-induced annexin A1 degradation, Gata4 gene transcription, and right ventricular hypertrophy. These results establish a right heart-specific signaling mechanism in response to pressure overload, which involves metal-catalyzed carbonylation and degradation of annexin A1 that liberates CBF/NF-Y to activate Gata4 gene transcription. (Hypertension. 2010;56:1145-1151.) . Online Data Supplement
  • Kana Ooshima; Shingen Ozaki; Masaki Tabuchi; Hideaki Higashino; Eiko Honda; Ah-Mee Park; Shuji Arima; Hiroshi Munakata
    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE TOHOKU UNIV MEDICAL PRESS 219 (4) 331 - 336 0040-8727 2009/12 [Refereed]
     
    Essential hypertension is a disease of unknown pathogenesis, although renal function has been implicated as an important factor in its cause. Stroke-prone spontaneously hypertensive (SHRSP) rats provide an animal model of essential hypertension. To understand the cause of hypertension, identifying proteins that are differentially expressed between hypertensive and normotensive rats may provide a key. Here, proteins in the renal cortex from SHRSP rats, malignant stroke-prone spontaneously hypertensive (M-SHRSP) rats, and Wistar Kyoto (WKY) rats as a normotensive control were subjected to two-dimensional difference gel electrophoresis (2D-DIGE). After in-gel digestion by trypsin, proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Several proteins showed differential expression patterns between hypertensive and normotensive rats. Among them, we focused on catechol-O-methyltransferase (COMT) because this enzyme inactivates catecholamines, possibly affecting blood pressure. To confirm the differential expression of COMT in each animal, we conducted Western blot analysis, which revealed that the expression of COMT is lower in M-SHRSP rats than in control and SHRSP rats, indicating that blood pressure and expression of COMT are related. In fact, the blood pressure of M-SHRSP rats was significantly higher than that of SHRSP rats at age of 10 weeks. Immunohistochemical and immunofluorescence studies showed that COMT in renal cortex is localized in tubular epithelial cells. The expression of COMT is lower in the renal cortex tubular epithelium of M-SHRSP rats than in normotensive rats. These results suggest that the decreased expression of COMT may be an important factor leading to the development of hypertension.
  • Regina M. Day; Ismael A. Matus; Yuichiro J. Suzuki; Kyung-Jin Yeum; Jian Qin; Ah-Mee Park; Vivek Jain; Tunay Kuru; Guangwen Tang
    RESPIROLOGY WILEY-BLACKWELL PUBLISHING, INC 14 (8) 1134 - 1142 1323-7799 2009/11 [Refereed]
     
    Background and objective: OSA is associated with increased incidence of cardiovascular diseases. Pathogenic mechanisms of vascular diseases include thickened vascular walls due to the increased number of smooth muscle cells (SMC). Retinoic acid (RA) suppresses the growth of SMC, and reduced retinoid levels are associated with vascular diseases. Oxidant signalling promotes SMC growth, thus antioxidant levels may also influence the development of cardiovascular diseases. The present study tested the hypothesis that plasmas from OSA patients contain altered levels of retinoids, carotenoids and tocopherols. Methods: Plasma samples were taken before and after sleep from patients with OSA (mostly mild) without known cardiovascular diseases and from control subjects. Levels of retinoids, carotenoids and tocopherols were measured using sensitive gas chromatograph-mass spectrometry and high pressure liquid chromatography methods and total antioxidant capacity was assessed fluorometrically. Results: Results showed that plasmas from patients with OSA had significantly lower retinyl palmitate and 9-cis RA compared with control subjects, while levels of retinol, all-trans RA and 13-cis RA were indifferent. All trans beta-carotene and 9-cis beta-carotene were also lower in OSA patients. Levels of all-trans RA and 13-cis RA in OSA patients were reduced after sleep compared with before sleep. OSA patients showed significantly higher delta-tocopherol compared with controls. Treatment of cultured human vascular SMC with post-sleep OSA patient plasmas promoted cell growth, but not in controls. Conclusions: Mild OSA exhibits altered levels of specific retinoids, carotenoids and tocopherols, which may be markers and/or mediators for the increased susceptibility of patients to vascular diseases.
  • Lingling Liu; Lucia Marcocci; Chi Ming Wong; Ah-Mee Park; Yuichiro J. Suzuki
    FREE RADICAL BIOLOGY AND MEDICINE ELSEVIER SCIENCE INC 45 (6) 847 - 854 0891-5849 2008/09 [Refereed]
     
    Pulmonary hypertension is a devastating disease, which leads to right heart failure. Serotonin (5-HT) plays important roles in the pathogenesis Of Pulmonary hypertension and pulmonary vascular remodeling. The role of 5-HT in right heart failure. however, is unknown. Since oxidative stress may mediate heart failure the, present study examined the effects of 5-HT on protein oxidation in the adult rat right heart ventricle, Treatment of perfused isolated hearts with 5-HT resulted in the promotion of protein carbonylation, specifically in the right ventricle, but not in the left. While no differences between right and left ventricular antioxidant enzymes and 5-HT receptors/transporter were detected, monoamine oxidase A (MAO-A) expression and activity were found to be lower in the right ventricle compared to the left. These results indicate that differences in neither the reactive oxygen species (ROS) scavenging ability, 5-HT membrane signaling capacity, nor MAO-dependent production of hydrogen peroxide are responsible for varied 5-HT-mediated protein carbonylation in right and left ventricles. Rather, lower MAO-A in the right heart might preserve cytosolic 5-HT which triggers other mechanisms for ROS production. Consistently, inhibition of MAO-A resulted in the promotion of protein carbonylation. We propose that low MAO-A, thus reduced degradation of 5-HT, increases the intracellular 5-HT activity in the right ventricle, leading to the promotion of protein carbonylation. (C) 2008 Elsevier Inc. All rights reserved.
  • Yuichiro J. Suzuki; Hiroko Nagase; Chi Ming Wong; Shilpashree Vinod Kumar; Vivek Lain; Ah-Mee Park; Regina M. Day
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY AMER THORACIC SOC 36 (6) 678 - 687 1044-1549 2007/06 [Refereed]
     
    Pulmonary hypertension is characterized by thickened pulmonary arterial walls due to increased number of pulmonary artery smooth muscle cells (PASMC). Apoptosis of PASMC may play an important role in regulating the PASMC number and may be useful for reducing pulmonary vascular thickening. The present study examined the regulation of an anti-apoptotic protein Bcl-X-L. Bcl-X-L expression was found to be increased in the pulmonary artery of chronic hypoxia-treated rats with pulmonary vascular remodeling. Adenovirus-mediated gene transfer of Bcl-x(L) indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced BCl-X-L expression by targeting the bcl-x(L) promoter. The bCl-X-L promoter contains two GATA elements, and SNP decreases the GATA-4 DNA-binding activity. Overexpression of GATA-4 attenuated the SNP-mediated suppression of BCl-X-L expression, providing direct evidence for the role of GATA-4 in BCl-X-L gene transcription. We established that SNP targets the 250 proximal region of the gata4 promoter and suppresses its gene transcription. Thus, inducers of pulmonary hypertension enhance anti-apoptotic BCl-X-L gene transcription, which can be suppressed by targeting gata4 gene transcription.
  • Ah-Mee Park; Hiroko Nagase; Shilpashree Vinod Kumar; Yuichiro J. Suzuki
    ANTIOXIDANTS & REDOX SIGNALING MARY ANN LIEBERT, INC 9 (6) 723 - 729 1523-0864 2007/06 [Refereed]
     
    Obstructive sleep apnea (OSA) is associated with cardiovascular diseases such as hypertension through mechanisms involving intermittent hypoxia (IH). However, it is not yet clear whether IH directly affects the heart. In a mouse model of OSA, we found that IH causes time-dependent alterations of the susceptibility of the heart to oxidative stress. Acute IH can exert preconditioning-like cardioprotection, in part, through the transcriptional activation of genes such as bcl-x(L) and gata4. We cloned the mouse gata4 promoter and identified an IH-responsive region. The exposure of mice to prolonged IH results in the increased susceptibility of the heart to ischemia-reperfusion injury by increasing the oxidative stress status. This might resemble conditions of OSA patients. In our mouse model, further exposure to prolonged IH allowed reversal of the enhancement of myocardial damage. Understanding the complex effects of IH on the heart should help ultimately to develop therapeutic strategies against OSA-induced complications.
  • Ah-Mee Park; Yuichiro J. Suzuki
    JOURNAL OF APPLIED PHYSIOLOGY AMER PHYSIOLOGICAL SOC 102 (5) 1806 - 1814 8750-7587 2007/05 [Refereed]
     
    Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O-2 and 2 min 21% O-2) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H2O2 scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.
  • Ah-Mee Park; Hiroko Nagase; Shilpashree Vinod Kumar; Yuichiro J. Suzuki
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY AMER PHYSIOLOGICAL SOC 292 (2) H751 - H757 0363-6135 2007/02 [Refereed]
     
    Intermittent hypoxia ( IH) with repeated episodes of hypoxia-normoxia cycle has been shown to exert preconditioning-like cardioprotective effects. To understand the mechanism of these events, we investigated the changes in cardiac gene expression in response to acute IH. Mice were subjected to five cycles of 2 min of 10% O-2 plus 2 min of 21% O-2. RNA was isolated, and gene array analysis was performed. Results show that the expression of antiapoptotic genes, such as Bcl-2 and Bcl-x(L), were increased after acute IH. GATA-4 regulates transcription of these genes, and, consistently, GATA-4 activity was increased by acute IH. Although the phosphorylation of GATA-4 has been shown to regulate its activity, no changes in GATA-4 phosphorylation status by acute IH were noted. Gene transcription of gata4 was increased by acute IH, and this might be responsible for the enhanced GATA activity. To understand the mechanism of acute IH activation of gata4 gene transcription, we identified a promoter region of the mouse gata4 gene that is 1,000 bp immediately upstream from the transcriptional start site. In cardiac muscle cells, truncation of 1,000 to 250 bp did not alter the transcriptional activity, suggesting that the proximal 250-bp region contains important transcriptional regulatory sites. We further found that acute IH activates factors which bind to the proximal 100-bp region. Thus acute IH activates not yet identified factors that bind to the proximal 100-bp region of the gata4 promoter and, in turn, increases gata4 gene transcription, leading to enhanced expression of Bcl-2 and Bcl-x(L).
  • RM Day; YH Lee; AM Park; YJ Suzuki
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY AMER THORACIC SOC 34 (6) 695 - 703 1044-1549 2006/06 [Refereed]
     
    Airway remodeling in chronic asthma is characterized by increased smooth muscle mass that is associated with the reduction of the bronchial lumen as well as airway hyperresponsiveness. The development of agents that inhibit smooth muscle growth is therefore of interest for therapy to prevent asthma-associated airway remodeling. All-trans retinoic acid (ATRA) suppresses growth of vascular smooth muscle cells (SMCs) from the systemic and pulmonary circulation. The present study investigated the effects of ATRA on human bronchial (airway) SMCs. Human bronchial SMCs were found to express mRNAs for retinoic acid receptor (RAR)-alpha, -beta, -gamma, and retinoid X receptor (RXR)-alpha, -beta, but not RXR-gamma. Although ATRA was not effective in inhibiting proliferation or in inducing apoptosis in airway SMCs, we found that ATRA (0.2-2 mu M) inhibited the SMC migration in response to platelet-derived growth factor (PDGF), as determined in a modified Boyden chamber assay. Both RAR and RXR agonists also blocked PDGF-induced airway SMC migration. ATRA also inhibited PDGF-induced actin reorganization associated with migration. PDGF-induced actin reorganization and migration were blocked by inhibitors of phosphatidylinositol 3 kinase (PI3K) and Akt. However, migration was blocked by inhibitors of the MEK/ERK pathway, with no effect on cytoskeletal reorganization. ATRA suppressed PDGF-induced Akt activation without influencing ERK activation. RAR was found to form protein-protein interactions with the p85 PI3K subunit. These results suggest that retinoic acid inhibits airway SMC migration through the modulation of the PI3K/Akt pathway.
  • YJ Suzuki; Jain, V; AM Park; RM Day
    FREE RADICAL BIOLOGY AND MEDICINE ELSEVIER SCIENCE INC 40 (10) 1683 - 1692 0891-5849 2006/05 [Refereed]
     
    Obstructive sleep apnea (OSA) has emerged as a major public health problem and increasing evidence indicates that untreated OSA can lead to the development of various cardiovascular disorders. One important mechanism by which OSA may promote cardiovascular diseases is intermittent hypoxia, in which patients are subjected to repeated episodes of brief oxygen desaturation in the blood, followed by reoxygenation. Such cycles of hypoxia/reoxygenation may result in the generation of reactive oxygen species. Some studies have demonstrated the presence of oxidative stress in OSA patients as well as in animals subjected to intermittent hypoxia. Further, modulations of nitric oxide and biothiol status might also play important roles in the pathogenesis of OSA-associated diseases. Reactive oxygen species and redox events are also involved in the regulation of signal transduction for oxygen-sensing mechanisms. This review summarizes currently available information on the evidence for and against the occurrence of oxidative stress in OSA and the role of reactive oxygen species in cardiovascular changes associated with OSA. (c) 2006 Elsevier Inc. All rights reserved.
  • YJ Suzuki; H Nagase; K Nie; AM Park
    ANTIOXIDANTS & REDOX SIGNALING MARY ANN LIEBERT, INC 7 (5-6) 829 - 834 1523-0864 2005/05 [Refereed]
     
    Growth factors play vital roles in the regulation of various biologic processes, including those in cardiovascular and respiratory systems. Accumulating evidence suggests that reactive oxygen species mediate growth factor signal transduction. The discovery of reactive oxygen species production by angiotensin II in vascular smooth muscle cells via the activation of NAD(P)H oxidase promoted studies of redox control of growth factor signaling. In the past few years, there have been further advances in this field. In addition to established roles of reactive oxygen species in vascular smooth muscle growth, these species have been demonstrated to serve as second messengers for cardiac hypertrophy induced by angiotensin II. NAD(P)H oxidase also produces reactive oxygen species in response to endothelin-1 in vascular smooth muscle and cardiac muscle cells. These results suggest that inhibiting NAD(P)H oxidase might be a useful therapeutic strategy. In fact, adenovirus-mediated gene transfer appears to be an effective approach to prevent vascular hypertrophy in rodent models. Growth factors also induce survival signaling in cardiac and smooth muscle cells, and redox control may play a role in such events. It is likely that studies reporting the mechanisms of redox control of growth factor signaling will rapidly emerge in the next several years, and understanding of such regulation should help in the development of therapeutic strategies against heart and lung diseases.
  • Imada, I; EF Sato; R Konaka; M Nishikawa; Y Kira; AM Park; Q Li; M Inoue
    Bioluminescence & Chemiluminescence: Progress and Perspectives WORLD SCIENTIFIC PUBL CO PTE LTD 295 - 298 2005 [Refereed]
  • AM Park; CC Chou; PC Drury; Y Okuyama; A Peter; A Hamabe; Y Miyauchi; RM Kass; HS Karagueuzian; MC Fishbein; SF Lin; PS Chen
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY AMER PHYSIOLOGICAL SOC 286 (6) H2072 - H2077 0363-6135 2004/06 [Refereed]
     
    The thoracic vein hypothesis of chronic atrial fibrillation (AF) posits that rapid, repetitive activations from muscle sleeves within thoracic veins underlie the mechanism of sustained AF. If this is so, thoracic vein ablation should terminate sustained AF and prevent its reinduction. Six female mongrel dogs underwent chronic pulmonary vein (PV) pacing at 20 Hz to induce sustained (>48 h) AF. Bipolar electrodes were used to record from the atria and thoracic veins, including the vein of Marshall, four PVs, and the superior vena cava. Radio frequency (RF) application was applied around the PVs and superior vena cava and along the vein of Marshall until electrical activity was eliminated. Computerized mapping ( 1,792 electrodes, 1 mm resolution) was also performed. Sustained AF was induced in 30.6 +/- 6.5 days, and ablation was done 17.3 +/- 8.5 days afterward. Before ablation, the PVs had shorter activation cycle lengths than the atria, and rapid, repetitive activations were observed in the PVs. All dogs converted to sinus rhythm during (n = 4 dogs) or within 90 min of completion of RF ablation. Rapid atrial pacing afterward induced only nonsustained (< 60 s) AF in all dogs. Average AF cycle lengths after reinduction were significantly (P = 0.01) longer (183 &PLUSMN; 31.5 ms) than baseline (106 &PLUSMN; 16.2 ms). There were no activation cycle length gradients after RF application. We conclude that thoracic vein ablation converts canine sustained AF into sinus rhythm and prevents the reinduction of sustained AF. These findings suggest that thoracic veins are important in the maintenance of AF in dogs.
  • AM Park; Q Li; K Nagata; T Tamura; K Shimono; EF Sato; M Inoue
    FREE RADICAL BIOLOGY AND MEDICINE PERGAMON-ELSEVIER SCIENCE LTD 36 (9) 1126 - 1133 0891-5849 2004/05 [Refereed]
     
    Although both bacillary and coccoid forms of Helicobacter pylori reside in human stomach, the pathophysiological significance of the two forms remains obscure. The present work describes the effect of oxygen tension on the transformation and reactive oxygen species (ROS) metabolism of this pathogen. Most H. pylori cultured under an optimum O-2 concentration (7%) were the bacillary form, whereas about 80% of cells cultured under aerobic or anaerobic conditions were the coccoid form. The colony-forming unit of H. pylori decreased significantly under both aerobic and anaerobic culture conditions. The bacillary form of H. pylori generated predominantly superoxide radical, whereas the coccoid form generated preferentially hydroxyl radical. Specific activities of cellular respiration, urease, and superoxide dismatase decreased markedly after transformation of the bacillary form to the coccoid form, with concomitant generation of protein carbonyls and 8-hydroxyguanine. The frequency of mutation of cells increased significantly during culture under nonoptimum O-2 conditions. These results indicate that ROS generated by H. pylori catalyze the oxidative modification of cellular DNA, thereby enhancing the transformation from the bacillary to the coccoid form. The enhanced generation of mutagenic hydroxyl radicals in the coccoid form might accelerate mutation and increase the genetic diversity of H. pylori. (C) 2004 Elsevier Inc. All rights reserved.
  • M Inoue; EF Sato; M Nishikawa; AM Park; Y Kira; Imada, I; K Utsumi
    CURRENT MEDICINAL CHEMISTRY BENTHAM SCIENCE PUBL LTD 10 (23) 2495 - 2505 0929-8673 2003/12 [Refereed]
     
    Mitochondria are the major site for the generation of ATP at the expense of molecular oxygen. Significant fractions (similar to2%) of oxygen are converted to the superoxide radical and its reactive metabolites (ROS) in and around mitochondria. Although ROS have been known to impair a wide variety of biological molecules including lipids, proteins and DNA, thereby causing various diseases, they also play critical roles in the maintenance of aerobic life. Because mitochondria are the major site of free radical generation, they are highly enriched with antioxidants including GSH and enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase, on both sides of their membranes to minimize oxidative stress in and around this organelle. The present work reviews the sites and mechanism of ROS generation by mitochondria, mitochondrial localization of Mn-SOD and Cu,Zn-SOD which has been postulated for a long time to be a cytosolic enzyme. The present work also describes that a cross-talk of molecular oxygen, nitric oxide (NO) and superoxide radicals regulates the circulation, energy metabolism, apoptosis, and functions as a major defense system against pathogens. Pathophysiological significance of ROS generation by mitochondria in the etiology of aging, cancer and degenerative neuronal diseases is also described.
  • M Inoue; EF Sato; M Nishikawa; AM Park; Y Kira; Imada, I; K Utsumi
    ANTIOXIDANTS & REDOX SIGNALING MARY ANN LIEBERT, INC 5 (4) 475 - 484 1523-0864 2003/08 [Refereed]
     
    Although oxygen is required for the energy metabolism in aerobic organisms, it generates reactive oxygen and nitrogen species that impair a wide variety of biological molecules, including lipids, proteins, and DNA, thereby causing various diseases. Because mitochondria are the major site of free radical generation, they are highly enriched with enzymes, such as Mn-type superoxide dismutase in matrix, and antioxidants including GSH on both sides of inner membranes, thus minimizing oxidative stress in and around this organelle. We recently showed that a cross talk of nitric oxide and oxygen radicals regulates the circulation, energy metabolism, reproduction, and remodeling of cells during embryonic development, and functions as a major defense system against pathogens. The present work shows that Cu/Zn-type superoxide dismutase, which has been postulated for a long time to be a cytosolic enzyme, also localizes bound to inner membranes of mitochondria, thereby minimizing oxidative stress in and around this organelle, while mitochondrial association decreases markedly with the variant types of the enzyme found in patients with familial amyotrophic lateral sclerosis. We also report that a cross talk of nitric oxide, superoxide, and molecular oxygen cooperatively regulates the fates of pathogens and their hosts and that oxidative stress in and around mitochondria also determines cell death in the development of animals and tissue injury caused by anticancer agents by some carnitine-inhibitable mechanism.
  • AM Park; K Nagata; EF Sato; T Tamura; K Shimono; M Inoue
    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS ACADEMIC PRESS INC ELSEVIER SCIENCE 411 (1) 129 - 135 0003-9861 2003/03 [Refereed]
     
    The aim of the present work is to elucidate the mechanism by which the respiration of Helicobacter pylori but not of Escherichia coli shows a strong resistance to nitric oxide (NO). Nitric oxide strongly but reversibly inhibited the oxygen consumption by sonicated membranes from H. pylori and Triton X-100-treated cells. Although the sensitivity of the H. pylori respiration to cyanide was low, it also increased after the treatment with Triton X-100. Kinetic analyses revealed that NO was rapidly degraded by E coli and the Triton X-100-treated H. pylori, but not by the intact H. pylori. Thus, the low sensitivity to NO might reflect the low affinity of the cytochrome c oxidase for this radical within the membrane/lipid bilayers of H. pylori. Such properties of the oxidase in H. pylori membranes may, at least in part, underlie the mechanism by which this bacterium thrives in NO-enriched gastric juice. (C) 2002 Elsevier Science (USA). All rights reserved.
  • M Miyoshi; E Kasahara; AM Park; K Hiramoto; Y Minamiyama; S Takemura; EF Sato; M Inoue
    FREE RADICAL RESEARCH TAYLOR & FRANCIS LTD 37 (1) 85 - 90 1071-5762 2003 [Refereed]
     
    Dietary nitrate is reduced to nitrite by some oral bacteria and the resulting nitrite is converted to nitric oxide (NO) in acidic gastric juice. The aim of this study is to elucidate the pathophysiological role of dietary nitrate in the stomach. Intragastric administration of nitrate rapidly increased nitrate and NO in plasma and the gastric headspace, respectively. Water-immersion-restraint stress (WIRS) increased myeloperoxidase (MPO) activity in gastric mucosa and induced hemorrhagic erosions by a nitrate-inhibitable mechanism. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit WIRS-induced mucosal injury. WIRS decreased gastric mucosal blood flow by a mechanism which was inhibited by administration of nitrate. These data suggested that the enterosalivary cycle of nitrate and related metabolites consisted of gastrointestinal absorption and salivary secretion of nitrate, its conversion to nitrite by oral bacteria and then to NO in the stomach might play important roles in the protection of gastric mucosa from hazardous stress.
  • M Inoue; E Sato; M Nishikawa; AM Park; K Maeda; E Kasahara
    SUPEROXIDE DISMUTASE ACADEMIC PRESS INC 349 346 - 354 0076-6879 2002 [Refereed]
  • A Nakamura; AM Park; K Nagata; EF Sato; M Kashiba; T Tamura; M Inoue
    FREE RADICAL BIOLOGY AND MEDICINE PERGAMON-ELSEVIER SCIENCE LTD 28 (11) 1611 - 1618 0891-5849 2000/06 [Refereed]
     
    Exposure to unfavorable conditions results in the transformation of Helicobacter pylori, a gastric pathogen, from a bacillary form to a coccoid form. The mechanism and pathophysiological significance of this transformation remain unclear. The generation of the superoxide radical by H. pylori has previously been shown to inhibit the bactericidal action of nitric oxide, the concentration of which is relatively high in gastric juice. With the use of chemiluminescence probes, both the qualify and quantity of reactive oxygen species generated by H, pylori have now been shown to change markedly during the transformation from the bacillary form to the coccoid form. The transformation of H. pylori was associated with oxidative modification of cellular proteins, including urease, an enzyme required for the survival of this bacterium in acidic gastric juice. Although the cellular abundance of urease protein increased during the transformation, the specific activity of the enzyme decreased and it underwent aggregation. Specific activities of both superoxide dismutase and catalase in H. pylori also decreased markedly during the transformation. The transformation of H. pylori was also associated with oxidative modification of DNA, as revealed by the generation of 8-hydroxyguanine, and subsequent DNA fragment. These observations indicate that oxidative stress elicited by endogenously generated reactive oxygen species might play an important role in the transformation of H. pylori from the bacillary form to the coccoid form. (C) 2000 Elsevier Science Inc.
  • M Inoue; EF Sato; AM Park; M Nishikawa; E Kasahara; M Miyoshi; A Ochi; K Utsumi
    FREE RADICAL RESEARCH HARWOOD ACAD PUBL GMBH 33 (6) 757 - 770 1071-5762 2000 [Refereed]
     
    Mammalian tissues have large amounts of available ATP which are generated by oxidative phosphorylation in mitochondria. For the maintenance of the human body, a large amount of oxygen is required to regenerate these ATP molecules. A small fraction of the inspired oxygen is converted to superoxide radical and related metabolites even under physiological conditions. Most reactive oxygen species react rapidly with a variety of molecules thereby interfering with cellular functions and induce various diseases. Nitric oxide (NO) is an unstable gaseous radical with high affinity for various molecules, such as hemeproteins, thiols, and related radicals. NO easily penetrates through cell membrane/lipid bilayers, forms dissociable complexes with these molecules and modulates cellular metabolism and functions. Because NO has an extremely high affinity for the superoxide radical, the occurrence of the latter might decrease the biological function of NO. Thus, superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension and vasogenic tissue injury. Because NO also reacts with molecular oxygen, it rapidly loses its biological activity, particularly under ambient atmospheric conditions where the oxygen tension is unphysiologically high. Thus, biological functions of NO are determined by the local concentrations of molecular oxygen and superoxide radicals. NO also inhibits electron transfer reaction and ATP synthesis in mitochondria and aerobic bacteria, such as E. coli; the inhibitory effects are also enhanced by hypoxia. Thus, the cross-talk between NO, molecular oxygen and oxyradicals play critical roles in the regulation of energy metabolism, fates and the survival of aerobic organisms. The present work describes the pathophysiological significance of the supersystem driven by the cross-talk between NO and oxyradicals.

Books etc

  • Key Word 高血圧
    萩原俊男; 朴雅美 他 (Joint workp182-183)先端医学社 2002
  • サイトプロテクション
    井上正康; 朴雅美ほか (Joint workp137-142)がんと化学療法社 2002
  • レドックス制御と抗酸化治療戦略
    井上正康; 朴雅美ほか (Joint translationp31-54)医薬ジャーナル 2000
  • 酸化ストレス・レドックスの生化学
    谷口直之; 朴雅美他 (Joint workp.129-136)共立出版 2000
  • NOの生理作用と疾患
    谷口直之; 朴雅美他 (Joint workp.85)羊土社 1999

Conference Activities & Talks

  • マウス胃のピロリ菌慢性感染は脳に神経炎症と遺伝子発現変化を誘導する
    朴雅美; 尾村誠一; 佐藤文孝; 角田郁生
    第41回日本認知症学会学術集会/第37回日本老年精神医学会  2022/11
  • バリア（腸管バリア、BBB）破綻を伴うCNS免疫性疾患における脳内の「菌の定着 colonization」データの注意点
    角田 郁生; 朴 雅美; 尾村 誠一; 堀田芙美香; 城玲央奈; スンダル・カドカ; イジャーズ・エフマド; 森口 幸太; 佐藤 文孝
    第34回日本神経免疫学会学術集会  2022/10
  • 異なる病型を示す多発性硬化症の動物モデルにおける抗糖脂質抗体の検討
    森口 幸太; 中村 優美和; 朴 雅美; 佐藤 文孝; 桑原 基; スンダル・カドカ; 尾村 誠一; イジャーズ・エフマド; 楠 進; 角田 郁生
    第34回日本神経免疫学会学術集会  2022/10
  • ピロリ菌の外膜小胞は神経炎症を誘導する：アルツハイマー型認知症との関連
    朴雅美; 角田郁生
    第44回日本分子生物学会年会  2021/12
  • 胃粘膜ピロリ菌感染マウス脳内免疫細胞活性化：アルツハイマー型認知症との関連
    朴雅美; 岩室優; 角田郁生
    第42回日本炎症・再生医学会  2021/07
  • プロドラッグ型クルクミンCMGによる実験的自己免疫性脳脊髄炎の抑制と小腸細菌叢変化
    佐藤文孝; カドカ・スンダル; 尾村誠一; 朴雅美; 藤田貢; 中村優美和; 西尾和人; 掛谷秀昭; 角田郁生
    第32回日本神経免疫学会学術集会  2020/10
  • タイラーウイルスによる急性灰白脳脊髄炎・多発性硬化症動物モデル：分子相同性から腸内細菌叢まで
    角田郁生; 尾村誠一; 佐藤文孝; 崎山奈美江; Sundar Khadka; 中村優美和; 朴雅美; 藤田貢
    第32回日本神経免疫学会学術集会  2020/10
  • ガレクチン-3は腸内細菌叢に影響し，NSAIDsによる小腸潰瘍の増悪因子として働く
    朴雅美; 尾村誠一; 佐藤文孝; 藤田貢; 角田郁生
    第24回腸内細菌学会学術集会  2020/06
  • ピロリ菌が神経細胞・中枢神経に及ぼす影響
    朴雅美; 佐藤文孝; 甲木蒼紫; 中村優美和; 角田郁生
    第42回日本分子生物学会年会  2019/12
  • ウイルス誘導性てんかん動物モデルと免疫系
    角田郁生; 佐藤文孝; 尾村誠一; Sundar Khadka; 藤田貢; 朴雅美; 甲木蒼紫; 中村優美和; 崎山奈美江; Felicia Lindeberg
    第53回日本てんかん学会学術集会  2019/10
  • 尾村誠一、佐藤文孝、藤田貢、朴雅美、カドカ スンダル、角田郁生
    尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; スンダル・カドカ; 角田郁生
    第24回日本神経感染症学会総会学術大会  2019/10
  • 多発性硬化症ウイルスモデルにおける腸内細菌叢の変化と中枢神経系炎症性脱髄病変との関連
    尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; カドカ スンダル; 角田郁生
    第31回日本神経免疫学会学術集会  2019/09
  • 多発性硬化症ウイルスモデルにおける中枢神経系炎症性病態と腸内細菌叢変化との関連性の検討
    尾村誠一; 佐藤文孝; 朴 雅美; 藤田 貢; 角田郁生
    第23回腸内細菌学会  2019/06
  • Galectin-3 intensifies NSAIDs-induced small intestinal ulcer.  [Not invited]
    Ah-Mee Park; Ikuo Tsunoda
    第41回日本分子生物学会年会  2018/11
  • 転写因子Ｔ－ｂｅｔ過剰発現は神経向性ウイルス感染において致死的となる  [Not invited]
    佐藤文孝; 川合英一郎; Nicholas E. Martinez; 尾村誠一; 藤田貢; 朴雅美; 高橋智; 楊景堯; 角田郁生
    第23回日本神経感染症学会総会・学術大会  2018/10
  • ギラン・バレー症候群における抗糖脂質抗体産生に関連する潜在因子の探索型因子分析による同定
    尾村誠一; 清水和秋; 桑原基; 森川みゆき; 藤田貢; 朴雅美; 佐藤文孝; Pedio Erika; 楠進; 角田郁生
    第30回日本神経免疫学会学術集会．  2018/09
  • グライコアレイデータの探索型因子分析によるギラン・バレー症候群診断に関連する潜在因子の同定因子分析による同定
    尾村誠一; 清水和秋; 桑原基; 森川みゆき; 藤田貢; 朴雅美; 佐藤文孝; Pedio Erika; 楠進; 角田郁生
    第77回近畿大学医学会学術講演会  2018/07
  • A novel function of p130 protein in pulmonary fibrosis.  [Not invited]
    Ah-Mee Park; Ikuo Tsunoda
    ConBio2017 生命科学系学会合同年次大会  2017/12
  • 肺線維化における細胞周期制御因子の役割  [Not invited]
    朴雅美; 角田郁生; 義江修
    第38回 日本炎症・再生医学会  2017/07
  • マウスγヘルペスウイルスを用いた Epstein-Barr virus 肝炎の発症機序の研究  [Not invited]
    金井亨輔; 朴雅美; 渡部明子; 有川智博; 安居輝人; 吉田裕樹; 角田郁生; 義江修
    第32回中国四国ウイルス研究会  2017/06
  • HSP27ノックダウンによる線維芽細胞の細胞周期停止におけるE2F-4の役割.  [Not invited]
    朴雅美
    第39回日本分子生物学会  2016/11
  • ヘリコバクター・ピロリ菌感染おけるガレクチン-3の生体防御的役割  [Not invited]
    朴雅美
    第81回日本インターフェロン･サイトカイン学会  2016/05

MISC

Awards & Honors

  • 2017/07 日本炎症・再生医学会 優秀演題賞
     肺線維化における細胞周期制御因子の役割 
    受賞者: 朴雅美
  • 2007/04 METROPOLITAN DC THORACIC SOCIETY ANNUAL MEETING First Prize
     
    受賞者: Ah-Mee Park
  • 2006/05 American Thoracic Society Annual meetin Travel Award
     
    受賞者: Ah-Mee Park

Research Grants & Projects

  • 日本学術振興会 科学研究費助成事業：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 朴 雅美
     
    In vivo study アルツハイマーモデル（AD）マウスと野生型(WT)マウスにヘリコバクター・ピロリ菌（HP）を長期間（10ヶ月）感染させ、新奇物体探索テストにより認知行動/運動量の解析後に血液、脳と胃を回収した。コントロールとして、同齢のHP非感染ADマウスとWTマウスを用いた（AD±HP, WT±HPの4群）。 新奇物体探索テストでの認知行動には4群間で差が見られなかったが、ADマウスでは運動量が亢進しており、特にAD+HPではWT＋HPに比べ有意に増加していた。これは認知症に見られる徘徊行動に類似する状態であるといえる。HP＋マウスでは血中エンドトキシン濃度が有意に増加していた事からHP感染によって消化管がリーキーな状態になっていることが分かった。HP+マウス脳内ではミクログリアの活性化が認められたが、HP-との差は以前に解析した感染5ヶ月後の方が顕著であった。 In vitro study これまでの動物実験解析からHP感染による脳ミクログリアの活性化にはHPが産生する外膜小胞（OMV）が影響している事が考えられたため、ピロリ菌からOMVを回収し、脳の細胞への影響を調べた。WTマウスから脳グリア細胞を回収し、OMVを暴露したところ、IL-6, IL-1bなどの炎症性サイトカインが増加した。脳グリア細胞には主に3種の細胞（ミクログリア、アストロサイト、オリゴデンドロサイト）が混在しているため、それぞれへの影響を調べるため細胞株にOMVを暴露しサイトカインのmRNAを調べた結果、オリゴデンドロサイトは全く反応せず、ミクログリアが最も強く反応した。このことは動物実験結果と一致していた。
  • 新しい生活スタイルのための抗微生物マスク開発
    近畿大学：「"オール近大"新型コロナウイルス感染症対策支援プロジェクト
    Date (from‐to) : 2021/04 -2022/03
  • 近畿大学：「"オール近大"新型コロナウイルス感染症対策支援プロジェクト
    Date (from‐to) : 2020/07 -2021/03
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : Park Ah-Mee
     
    Epidemiological studies have reported that the infection rate of H. pylori is significantly higher in Alzheimer's disease. However, there have been few reports that have shown a relationship between them in animal experiments that are not affected by environmental factors. In this study, we found that H. pylori chronic infected mice showed significantly increase of central nervous system inflammation than non-infected mice. Although the mechanism of this increase is not clear at present, we found that the outer membrane vesicles produced by H. pylori may be involved.
  • 肺線維化におけるエピジェネティクス解析
    ノバルティスファーマ：ノバルティスファーマ研究助成
    Date (from‐to) : 2017/04 -2018/03 
    Author : 朴雅美
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : PARK Ah-Mee; TSUNODA Ikuo
     
    The purpose of this study is to clarify the role of Galectin-3 (Gal3) on NSAIDs-induced intestinal ulcer. By using Gal3 knockout mice, we found that Gal-3 is a worsen factor of NSAIDs-induced intestinal ulcer. There are two possible mechanism for this negative effect of Gal3. The first one is a role of Gal3 as danger signal of activated macrophages. This molecule might cause sever inflammation. The another one is changes of intestinal bacterial flora with or without Gal-3. We found obvious differences of small intestinal flora population between wildtype mice and Gal3 mice. Those differences might affect to the ulceration by NSAIDs.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2012/04 -2015/03 
    Author : PARK Ah-mee
     
    The object of this study is to clarify the epigenetic changes in pulmonary fibrosis. In vivo study using silica-induced mouse fibrosis model revealed that the DNA methylation level was unchanged, but the protein level of DNMT3B, which catalysis DNA methylation, was increased in fibrosis lung. In vitro study also showed the increase of this protein. The increase of DNMT3B protein may play important role in pulmonary fibrosis.
  • 炎症の慢性化機構の解明と制御に向けた基盤技術の創出
    科学技術振興機構：戦略的創造研究推進事業 CREST
    Date (from‐to) : 2011/04 -2015/03 
    Author : 松島綱治
  • ヘリコバクターピロリ菌感染予防におけるガレクチン-3の役割
    近畿大学：学内研究助成金
    Date (from‐to) : 2013/04 -2014/03 
    Author : 朴雅美
  • 肺筋線維芽細胞に対する5’-メチルチオアデノシンの抑制作用について
    近畿大学：学内研究助成金
    Date (from‐to) : 2009/04 -2010/03 
    Author : 朴雅美

Media Coverage

Others

  • 2020/07 -2021/03  “オール近大”新型コロナウイルス感染症対策支援プロジェクト 
    “オール近大”新型コロナウイルス感染症対策支援プロジェクト 研究助成 カテゴリー：研究 企画題目：継続使用マスクに付着した微生物の調査

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