トップ›研究者一覧›千田淳司

研究者を探す

研究者にアプローチする
更新情報を通知する

千田淳司

徳島大学

プロフィール
教育活動
研究活動
社会活動
リサーチマップ・
Jグローバル
KAKEN
注目研究

研究者総覧で最新データを確認する

2024年5月17日更新

職名: 講師
電話: 088-633-7424
電子メール: j-chida@ier.tokushima-u.ac.jp
学歴: 2003/3: 東北大学大学院生命科学研究科生命機能科学専攻修士課程修了
2006/3: 東北大学大学院生命科学研究科生命機能科学専攻博士課程修了
学位: 理学博士 (東北大学) (2006年3月)
理学修士 (東北大学) (2003年3月)
職歴・経歴: 2006/4: 徳島大学分子酵素学研究センター科学技術振興研究員 (特任助教)
2008/2: 徳島大学分子酵素学研究センター助教

専門分野・研究分野: 小児感染症学
生化学 (Biochemistry)

研究者総覧で最新データを確認する

2024年5月17日更新

専門分野・研究分野: 小児感染症学
生化学 (Biochemistry)
担当経験のある授業科目: プロテオミクス医科学特論 (大学院)
応用分子酵素学・病態学特論 (大学院)
指導経験: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2024年5月17日更新

専門分野・研究分野: 小児感染症学
生化学 (Biochemistry)

研究テーマ: インフルエンザ脳症発症の分子機序に関する研究 (インフルエンザ脳症 (influenza-associated encephalopathy), ミトコンドリア (mitochondria), アデノシン三リン酸 (adenosine triphosphate))
患者の末梢血中の ATP レベルを測定する診断キットの開発 (アデノシン三リン酸 (adenosine triphosphate), 多臓器不全 (multiple organ failure)) (Measurements of adenylate nucleotides (i.e., ATP, ADP) are used extensively to monitor energy stasis in broad range of cell types and tissues. For applications involving mammalian and other animal tissue, ATP are commonly extracted with chaotropic reagents particularly trichloroacetic acid (TCA) and perchloric acid (PCA). Physical methods for disintegration (boiling, sonic disintegration) have also used. As expected, these methods are suitable for measurements of cellular ATP, however these methods are inappropriate for histionic ATP because of the inefficiency of nucleotides extraction. Consequently, we have developed an integrated kit that includes software programs measuring tissue or total blood ATP. As the first step, we have evaluated the clinically usefulness of this system for determining blood ATP levels in patients with acute disease such as influenza-associated encephalopathy. It was found that various patients with severe disease have decreased blood ATP levels. It can be anticipated that in the abovementioned disease states, ATP measurement will become a valuable clinical parameter of great potential clinical importance.)

著書

研究者総覧に該当データはありませんでした。

論文

Dini Agriani Pasiana, Hironori Miyata, Junji Chida, Hideyuki Hara, Morikazu Imamura, Ryuichiro Atarashi and Suehiro Sakaguchi :
Central residues in prion protein PrPC are crucial for its conversion into the pathogenic isoform,
The Journal of Biological Chemistry, Vol.298, No.9, 102381, 2022.

(キーワード): prion / Mice / Prion Diseases / Prion Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jbc.2022.102381
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35973512; ● Search Scopus @ Elsevier (PMID): 35973512; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jbc.2022.102381

(DOI: 10.1016/j.jbc.2022.102381, PubMed: 35973512) Keiji Uchiyama, Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Morikazu Imamura, Tsuyoshi Mori, Hanae Takatsuki, Ryuichiro Atarashi and Suehiro Sakaguchi :
Ethanolamine Is a New Anti-Prion Compound,
International Journal of Molecular Sciences, Vol.22, No.21, 11742, 2021.

(要約): Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrP. PrP is produced through conformational conversion of the cellular isoform of prion protein, PrP, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrP levels when cultured in advanced Dulbecco's modified eagle medium (DMEM) but not in classic DMEM. PrP levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrP levels in N2aC24L1-3 cells, but not PrP levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.
(キーワード): Animals / Brain / Cell Line, Tumor / Ethanolamine / Mice / Mice, Inbred ICR / PrPSc Proteins / Prion Diseases
(徳島大学機関リポジトリ): ● Metadata: 117551
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms222111742
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34769172; ● Summary page in Scopus @ Elsevier: 2-s2.0-85118175726

(徳島大学機関リポジトリ: 117551, DOI: 10.3390/ijms222111742, PubMed: 34769172, Elsevier: Scopus) Hideyuki Hara, Junji Chida, Keiji Uchiyama, Dini Agriani Pasiana, Etsuhisa Takahashi, Hiroshi Kido and Suehiro Sakaguchi :
Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells.,
Scientific Reports, Vol.11, No.1, 10109, 2021.

(徳島大学機関リポジトリ): ● Metadata: 117718
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-021-89586-6
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33980968; ● Search Scopus @ Elsevier (PMID): 33980968; ● Search Scopus @ Elsevier (DOI): 10.1038/s41598-021-89586-6

(徳島大学機関リポジトリ: 117718, DOI: 10.1038/s41598-021-89586-6, PubMed: 33980968) Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Keiji Uchiyama, Yutaka Kikuchi, Tomoko Naito, Yuichi Takahashi, Junji Yamamura, Hisashi Kuromatsu and Suehiro Sakaguchi :
Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire.,
International Journal of Molecular Sciences, Vol.22, No.6, 3268, 2021.

(要約): Prions are infectious agents causing prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans. Several cases have been reported to be transmitted through medical instruments that were used for preclinical CJD patients, raising public health concerns on iatrogenic transmissions of the disease. Since preclinical CJD patients are currently difficult to identify, medical instruments need to be adequately sterilized so as not to transmit the disease. In this study, we investigated the sterilizing activity of two oxidizing agents, ozone gas and vaporized hydrogen peroxide, against prions fixed on stainless steel wires using a mouse bioassay. Mice intracerebrally implanted with prion-contaminated stainless steel wires treated with ozone gas or vaporized hydrogen peroxide developed prion disease later than those implanted with control prion-contaminated stainless steel wires, indicating that ozone gas and vaporized hydrogen peroxide could reduce prion infectivity on wires. Incubation times were further elongated in mice implanted with prion-contaminated stainless steel wires treated with ozone gas-mixed vaporized hydrogen peroxide, indicating that ozone gas mixed with vaporized hydrogen peroxide reduces prions on these wires more potently than ozone gas or vaporized hydrogen peroxide. These results suggest that ozone gas mixed with vaporized hydrogen peroxide might be more useful for prion sterilization than ozone gas or vaporized hydrogen peroxide alone.
(キーワード): Animals / Brain / Disease Models, Animal / Dose-Response Relationship, Drug / Hydrogen Peroxide / Mice / Ozone / PrPC Proteins / Prion Diseases / Prions / Stainless Steel
(徳島大学機関リポジトリ): ● Metadata: 116339
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms22063268
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33806892; ● Summary page in Scopus @ Elsevier: 2-s2.0-85102845949

(徳島大学機関リポジトリ: 116339, DOI: 10.3390/ijms22063268, PubMed: 33806892, Elsevier: Scopus) Keiji Uchiyama, Miyata Hironori, Yamaguchi Yoshitaka, Imamura Morikazu, Okazaki Mariya, Pasiana Dini Agriani, Junji Chida, Hideyuki Hara, Atarashi Ryuichiro, Watanabe Hitomi, Kondoh Gen and Suehiro Sakaguchi :
Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91-106.,
International Journal of Molecular Sciences, Vol.21, No.19, 7260, 2020.

(要約): Conformational conversion of the cellular prion protein, PrP, into the abnormally folded isoform, PrP, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91-106 were generated in the absence of endogenous PrP, designated Tg(PrP∆91-106)/ mice and intracerebrally inoculated with various prions. Tg(PrP∆91-106)/ mice were resistant to RML, 22L and FK-1 prions, neither producing PrP∆91-106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrP∆91-106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrP∆91-104 after incubation with BSE-PrP-prions but not with RML- and 22L-PrP-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91-104 into PrP∆91-104 even after incubation with RML- and 22L-PrP-prions. These results suggest that residues 91-106 or 91-104 of PrP are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrP into PrP.
(徳島大学機関リポジトリ): ● Metadata: 115634
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms21197260
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33019549; ● Summary page in Scopus @ Elsevier: 2-s2.0-85091919621

(徳島大学機関リポジトリ: 115634, DOI: 10.3390/ijms21197260, PubMed: 33019549, Elsevier: Scopus) Junji Chida, Hideyuki Hara, Keiji Uchiyama, Etsuhisa Takahashi, Hironori Miyata, Hidetaka Kosako, Yukiko Tomioka, Toshihiro Ito, Hiroyuki Horiuchi, Haruo Matsuda, Hiroshi Kido and Suehiro Sakaguchi :
Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice.,
PLoS Pathogens, Vol.16, No.8, e1008823, 2020.

(要約): The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.
(徳島大学機関リポジトリ): ● Metadata: 115613
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1008823
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32845931; ● Search Scopus @ Elsevier (PMID): 32845931; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1008823

(徳島大学機関リポジトリ: 115613, DOI: 10.1371/journal.ppat.1008823, PubMed: 32845931) Suehiro Sakaguchi and Junji Chida :
Prion Protein Is a Novel Modulator of Influenza: Its Potential Implications for Anti-Influenza Therapeutics.,
Current Issues in Molecular Biology, Vol.37, 21-32, 2019.

(徳島大学機関リポジトリ): ● Metadata: 115747
(出版サイトへのリンク): ● Publication site (DOI): 10.21775/cimb.037.021
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31814573; ● Summary page in Scopus @ Elsevier: 2-s2.0-85078510915

(徳島大学機関リポジトリ: 115747, DOI: 10.21775/cimb.037.021, PubMed: 31814573, Elsevier: Scopus) Nandita Rani Das, Hironori Miyata, Hideyuki Hara, Junji Chida, Keiji Uchiyama, Kentaro Masujin, Hitomi Watanabe, Gen Kondoh and Suehiro Sakaguchi :
The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region,
Molecular Neurobiology, Vol.57, 1203-1216, 2019.

(要約): Conformational conversion of the cellular isoform of prion protein, designated PrP, into the abnormally folded, amyloidogenic isoform, PrP, is an essential pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Lines of evidence indicate that the N-terminal domain, which includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region, is important for PrP to convert into PrP after infection with prions. To further gain insights into the role of the polybasic region and the OR region in prion pathogenesis, we generated two different transgenic mice, designated Tg(PrP3K3A)/Prnp and Tg(PrP3K3A∆OR)/Prnp mice, which express PrP with lysine residues at codons 23, 24, and 27 in the polybasic region mutated with or without a deletion of the OR region on the Prnp background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp mice were highly resistant to the prions, indicating that lysine residues at 23, 24, and 27 could be important for the polybasic region to support prion infection. Tg(PrP3K3A∆OR)/Prnp mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp mice. The pre-OR region, including the polybasic region, of PrP3K3A∆OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrP3K3A∆OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrP into PrP, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s12035-019-01804-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31707632; ● Summary page in Scopus @ Elsevier: 2-s2.0-85074844020

(DOI: 10.1007/s12035-019-01804-5, PubMed: 31707632, Elsevier: Scopus) Jun Oda, Yukioka Tetsu, Kazunari Azuma, Takao Arai, Junji Chida and Hiroshi Kido :
Endogenous genetic risk factor for serious heatstroke: the thermolabile phenotype of carnitine palmitoyltransferase II variant.,
Acute Medicine & Surgery, Vol.6, No.1, 25-29, 2018.

(要約): In serious heatstroke, elevated body temperature (>40°C) is considered the main cause of illness. Mitochondrial carnitine palmitoyltransferase II (CPT II) plays an important role in adenosine triphosphate (ATP) generation from long-chain fatty acids, and its thermolabile phenotype of polymorphisms leads to ATP production loss under high fever. Whether by heatstroke or influenza, high fever suppresses mitochondrial ATP production in patients with the thermolabile phenotype of polymorphisms. We investigated the relation between polymorphism and severity of heatstroke with a body temperature of over 40°C. We analyzed blood chemistry test results, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC), Acute Physiologic and Chronic Health Evaluation II, and Sequential Organ Failure Assessment (SOFA) scores, and polymorphisms in 24 consecutive patients with severe heatstroke at two university hospitals. Eleven patients carried thermolabile CPT II variants (rs2229291; c.1055T G [p.Phe352Cys]) (F352C), and the genotype frequency was greater in heatstroke patients than in healthy volunteers. There was no significant difference in body temperature or blood chemistry data at emergency room arrival between patients with and without the CPT II variants. However, hospital days were longer and initial antithrombin activity was significantly lower in the variant group, suggesting a possible link with early phase vascular endothelial cell dysfunction. The JAAM DIC diagnostic criteria and SOFA scores were also higher in the group. There were no differences in the serum albumin, serum creatine kinase, and fibrin degradation product levels, and platelet counts. In addition to known risks (e.g., environmental temperature and old age), the CPT II polymorphism [F352C] can be a predisposing genetic risk factor for serious heatstroke with organ disfunction, and lower antithrombin activity.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ams2.373
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30651994; ● Search Scopus @ Elsevier (PMID): 30651994; ● Search Scopus @ Elsevier (DOI): 10.1002/ams2.373

(DOI: 10.1002/ams2.373, PubMed: 30651994) Suehiro Sakaguchi and Junji Chida :
Roles of Prion Protein in Virus Infections.,
DNA and Cell Biology, Vol.37, No.10, 808-811, 2018.

(要約): The normal cellular prion protein, designated PrP, is a membrane glycoprotein expressed most abundantly in brains, particularly by neurons, and to a lesser extent in non-neuronal tissues including lungs. Conformational conversion of PrP into the amyloidogenic isoform is a key pathogenic event in prion diseases. We recently found that PrP has a protective role against infection with influenza A viruses (IAVs) in mice by reducing reactive oxygen species in the lungs after infection with IAVs. The antioxidative activity of PrP is probably attributable to its function to activate antioxidative enzyme Cu/Zn-superoxide dismutase, or SOD1, through regulating Cu content in lungs infected with IAVs. Oxidative stress could play a pivotal role in the pathogenesis of a wide range of viral infections. Here, we introduce our and others' studies on the role of PrP in viral infections, and raise the attractive possibility that PrP might be a novel target molecule for development of antioxidative therapeutics against not only IAV infection but also other viral infections.
(キーワード): Animals / Copper / Enzyme Activation / Epithelial Cells / Gene Expression Regulation / Heat-Shock Proteins / Influenza A virus / Lung / Mice / Orthomyxoviridae Infections / Oxidative Stress / PrPC Proteins / Protective Factors / Reactive Oxygen Species / Superoxide Dismutase-1
(徳島大学機関リポジトリ): ● Metadata: 112207
(出版サイトへのリンク): ● Publication site (DOI): 10.1089/dna.2018.4402
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30222366; ● Search Scopus @ Elsevier (PMID): 30222366; ● Search Scopus @ Elsevier (DOI): 10.1089/dna.2018.4402

(徳島大学機関リポジトリ: 112207, DOI: 10.1089/dna.2018.4402, PubMed: 30222366) Junji Chida, Hideyuki Hara, Masashi Yano, Keiji Uchiyama, Rani Nandita Das, Etsuhisa Takahashi, Hironori Miyata, Yukiko Tomioka, Toshihiro Ito, Hiroshi Kido and Suehiro Sakaguchi :
Prion protein protects mice from lethal infection with influenza A viruses.,
PLoS Pathogens, Vol.14, No.5, e1007049, 2018.

(要約): The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPC is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp0/0 mice from the lethal infection with IAV. Moreover, Prnp0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPOR)/Prnp0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrPC has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp0/0 and Tg(PrPOR)/Prnp0/0 lungs than in WT lungs. It is thus conceivable that PrPC functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrPC in protection against IAV infection, and suggest that PrPC might be a novel target molecule for anti-influenza therapeutics.
(キーワード): Animals / Brain / Copper / Disease Susceptibility / Influenza A virus / Lung / Mice / Mice, Inbred C57BL / Mice, Knockout / Neurons / PrPC Proteins / Prion Diseases / Prion Proteins / Prions / Reactive Oxygen Species / Superoxide Dismutase
(徳島大学機関リポジトリ): ● Metadata: 112206
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1007049
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29723291; ● Search Scopus @ Elsevier (PMID): 29723291; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1007049

(徳島大学機関リポジトリ: 112206, DOI: 10.1371/journal.ppat.1007049, PubMed: 29723291) Junji Chida and Suehiro Sakaguchi :
Cellular prion protein-mediated protection against influenza A virus infection.,
Future Virology, Vol.14, No.1, 31-37, 2018.

(徳島大学機関リポジトリ): ● Metadata: 113067
(出版サイトへのリンク): ● Publication site (DOI): 10.2217/fvl-2018-0146
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.2217/fvl-2018-0146

(徳島大学機関リポジトリ: 113067, DOI: 10.2217/fvl-2018-0146) Hideyuki Hara, Miyata Hironori, Das Rani Nandita, Junji Chida, Yoshimochi Tatenobu, Keiji Uchiyama, Watanabe Hitomi, Kondoh Gen, Yokoyama Takashi and Suehiro Sakaguchi :
Prion Protein Devoid of the Octapeptide Repeat Region Delays BSE Pathogenesis in Mice.,
Journal of Virology, Vol.92, No.1, pii:e01368-17, 2018.

(要約): Conformational conversion of the cellular isoform of prion protein, PrP, into the abnormally folded, amyloidogenic isoform, PrP, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrP into PrP after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/ mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPΔOR in their brains. We show here that Tg(PrPΔOR)/ mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrP into PrP after infection with BSE prions. However, Tg(PrPΔOR)/ mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/ mice than PrP in control wild-type mice. Taken together, these results indicate that the OR region of PrP could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions. Structure-function relationship studies of PrP conformational conversion into PrP are worthwhile to understand the mechanism of the conversion of PrP into PrP We show here that, by inoculating Tg(PrPΔOR)/ mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrP into PrP after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrP into PrP after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.
(キーワード): Animals / Brain / Cattle / Disease Susceptibility / Encephalopathy, Bovine Spongiform / Humans / Mice / Mice, Transgenic / Oligopeptides / PrPC Proteins / Prion Diseases / Prions / Sequence Deletion
(徳島大学機関リポジトリ): ● Metadata: 111465
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/JVI.01368-17
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29046443; ● CiNii @ 国立情報学研究所 (CRID): 1050845762396495104; ● Search Scopus @ Elsevier (PMID): 29046443; ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.01368-17

(徳島大学機関リポジトリ: 111465, DOI: 10.1128/JVI.01368-17, PubMed: 29046443, CiNii: 1050845762396495104) Keiji Uchiyama, Mitsuru Tomita, Masashi Yano, Junji Chida, Hideyuki Hara, Nandita Rani Das, Anders Nykjaer and Suehiro Sakaguchi :
Prions amplify through degradation of the VPS10P sorting receptor sortilin.,
PLoS Pathogens, Vol.13, No.6, e1006470, 2017.

(要約): Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.
(キーワード): prion / Sortilin / VPS10P
(徳島大学機関リポジトリ): ● Metadata: 110433
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1006470
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28665987; ● Search Scopus @ Elsevier (PMID): 28665987; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1006470

(徳島大学機関リポジトリ: 110433, DOI: 10.1371/journal.ppat.1006470, PubMed: 28665987) Das Rani Nandita, Miyata Hironori, Hideyuki Hara, Keiji Uchiyama, Junji Chida, Masashi Yano, Watanabe Hitomi, Kondoh Gen and Suehiro Sakaguchi :
Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.,
Archives of Virology, Vol.162, No.7, 1867-1876, 2017.

(要約): The N-terminal polybasic region of the normal prion protein, PrP(C), which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrP(C) into the pathogenic isoform, PrP(Sc). We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrPpreOR)/Prnp (0/0) mice. Here, we produced two new lines of Tg(PrPpreOR)/Prnp (0/0) mice, each expressing the mutant protein, PrPpreOR, 1.1 and 1.6 times more than PrP(C) in wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrPpreOR)/Prnp (0/0) mice against full-length PrP(Sc). PrP(Sc)preOR accumulated in the brains of infected Tg(PrPpreOR)/Prnp (0/0) mice less than PrP(Sc) in control wild-type mice, although lower in RML-infected Tg(PrPpreOR)/Prnp (0/0) mice than in 22L-infected mice. Prion infectivity in infected Tg(PrPpreOR)/Prnp (0/0) mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrP(C) into PrP(Sc), and prion infectivity in a strain-specific way. PrPpreOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.
(キーワード): Amino Acid Sequence / Animals / Disease Susceptibility / Mice / Mice, Inbred C57BL / Mice, Transgenic / Prion Diseases / Prion Proteins / Repetitive Sequences, Amino Acid / Sequence Deletion
(徳島大学機関リポジトリ): ● Metadata: 110119
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s00705-017-3295-3
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28255815; ● Summary page in Scopus @ Elsevier: 2-s2.0-85014121673

(徳島大学機関リポジトリ: 110119, DOI: 10.1007/s00705-017-3295-3, PubMed: 28255815, Elsevier: Scopus) Keiji Uchiyama, Miyata Hironori, Masashi Yano, Yoshitaka Yamaguti, Imamura Morikazu, Muramatsu Naomi, Das Rani Nandita, Junji Chida, Hideyuki Hara and Suehiro Sakaguchi :
Mouse-Hamster Chimeric Prion Protein (PrP) Devoid of N-terminal Residues 23-88 Restores Susceptibility to 22L Prions, But Not to RML Prions in PrP-Knockout Mice.,
PLoS ONE, Vol.9, No.10, e109737, 2014.

(要約): Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) mice transgenically reconstituted with a mouse-hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM223-88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2Sc23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM223-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2Sc23-88 in their brains. These results indicate that MHM223-88 itself might either lose or greatly reduce the converting capacity to MHM2Sc23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM223-88 to MHM2Sc23-88 in trans. In the present study, we confirmed that Tg(MHM223-88)/Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM223-88)/Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2Sc23-88 in their brains. We also found accelerated conversion of MHM223-88 into MHM2Sc23-88 in the brains of RML- and 22L-inoculated Tg(MHM223-88)/Prnp 0/+ mice. However, wild-type PrPSc accumulated less in the brains of these inoculated Tg(MHM223-88)/Prnp 0/+ mice, compared with RML- and 22L-inoculated Prnp 0/+ mice. These results show that MHM223-88 itself can convert into MHM2Sc23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM223-88 into MHM2Sc23-88, but to the contrary, the co-expressing MHM223-88 disturbs the conversion of wild-type PrPC into PrPSc.
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0109737
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25330286; ● Search Scopus @ Elsevier (PMID): 25330286; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.pone.0109737

(DOI: 10.1371/journal.pone.0109737, PubMed: 25330286) Yamane Kazuhiro, Indalao L. Irene, Junji Chida, Yamamoto Yoshikazu, Hanawa Masaaki and Hiroshi Kido :
Diisopropylamine dichloroacetate, a novel pyruvate dehydrogenase kinase 4 inhibitor, as a potential therapeutic agent for metabolic disorders and multiorgan failure in severe influenza,
PLoS ONE, Vol.9, No.5, e98032, 2014.

(要約): Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-cytokine cycle, which is closely linked to the influenza virus-cytokine-trypsin cycle, resulting in prevention of multiorgan failure in severe influenza.
(キーワード): Animals / Blotting, Western / Enzyme-Linked Immunosorbent Assay / Female / Glucose / Influenza A Virus, H1N1 Subtype / Lipid Metabolism / Metabolic Diseases / Mice / Mice, Inbred C57BL / Multiple Organ Failure / Orthomyxoviridae Infections / Oxidation-Reduction / Phosphorylation / Protein Kinase Inhibitors / Protein Kinases / Pyruvic Acid / Quaternary Ammonium Compounds / RNA, Messenger / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction
(徳島大学機関リポジトリ): ● Metadata: 106308
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0098032
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24865588; ● Summary page in Scopus @ Elsevier: 2-s2.0-84901477996

(徳島大学機関リポジトリ: 106308, DOI: 10.1371/journal.pone.0098032, PubMed: 24865588, Elsevier: Scopus) Junji Chida, Rie Ono, Kazuhiko Yamane, Mineyoshi Hiyoshi, Masaji Nishimura, Mutsuo Onodera, Emiko Nakataki, Shichijo Koichi, Matsushita Masatomo and Hiroshi Kido :
Blood lactate/ATP ratio, as an alarm index and real-time biomarker in critical illness,
PLoS ONE, Vol.8, No.4, e60561, 2013.

(要約): The acute physiology, age and chronic health evaluation (APACHE) II score and other related scores have been used for evaluation of illness severity in the intensive care unit (ICU), but there is still a need for real-time and sensitive prognostic biomarkers. Recently, alarmins from damaged tissues have been reported as alarm-signaling molecules. Although ATP is a member of the alarmins and its depletion in tissues closely correlates with multiple-organ failure, blood ATP level has not been evaluated in critical illness. To identify real-time prognostic biomarker of critical illness, we measured blood ATP levels and the lactate/ATP ratio (ATP-lactate energy risk score, A-LES) in critically ill patients. Blood samples were collected from 42 consecutive critically ill ICU patients and 155 healthy subjects. The prognostic values of blood ATP levels and A-LES were compared with APACHE II score. The mean ATP level (SD) in healthy subjects was 0.62 (0.19) mM with no significant age or gender differences. The median ATP level in severely ill patients at ICU admission was significantly low at 0.31 mM (interquartile range 0.25 to 0.44) than the level in moderately ill patient at 0.56 mM (0.38 to 0.70) (P<0.01). Assessment with ATP was further corrected by lactate and expressed as A-LES. The median A-LES was 2.7 (2.1 to 3.3) in patients with satisfactory outcome at discharge but was significantly higher in non-survivors at 38.9 (21.0 to 67.9) (P<0.01). Receiver operating characteristic analysis indicated that measurement of blood ATP and A-LES at ICU admission are as useful as APACHE II score for prediction of mortality. Blood ATP levels and A-LES are sensitive prognostic biomarkers of mortality at ICU admission. In addition, A-LES provided further real-time evaluation score of illness severity during ICU stay particularly for critically ill patients with APACHE II scores of ≥20.0.
(キーワード): アデノシン三リン酸 (adenosine triphosphate) / Adolescent / Adult / Age Factors / Aged / Aged, 80 and over / Arteries / Biomarkers / Blood Chemical Analysis / 子ども (children) / Child, Preschool / Critical Illness / エネルギー代謝 (energy metabolism) / Female / Hemoglobins / Humans / 小児 (infant) / Infant, Newborn / Intensive Care Units / Lactic Acid / Male / Middle Aged / Prognosis / Reference Values / リスク (risk) / Time Factors / Veins / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0060561
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23577122; ● Summary page in Scopus @ Elsevier: 2-s2.0-84875942564

(DOI: 10.1371/journal.pone.0060561, PubMed: 23577122, Elsevier: Scopus) Etsuhisa Takahashi, Kosuke Kataoka, Irene L. Indalao, Keiko Konoha, Kazuyuki Fujii, Junji Chida, Dai Mizuno, Kohtaro Fujihashi and Hiroshi Kido :
Oral clarithromycin enhances airway IgA immunity through induction of IgA class switching recombination and B-cell activating factor of the tumor necrosis factor family molecule on mucosal dendritic cells in mice infected with influenza A virus,
Journal of Virology, Vol.86, No.20, 10924-1093, 2012.

(要約): We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.
(キーワード): Administration, Oral / Animals / Antibodies, Neutralizing / Antiviral Agents / B-Cell Activating Factor / Bronchi / Clarithromycin / Cytidine Deaminase / Dendritic Cells / 女性 (female) / Immunity, Mucosal / Immunoglobulin A / Immunoglobulin Class Switching / Influenza A Virus, H1N1 Subtype / Mice / Mice, Inbred BALB C / Orthomyxoviridae Infections / Oseltamivir / Spleen / Tumor Necrosis Factor-alpha
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/JVI.01207-12
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22896605; ● Summary page in Scopus @ Elsevier: 2-s2.0-84869061538

(DOI: 10.1128/JVI.01207-12, PubMed: 22896605, Elsevier: Scopus) Masaya Kubota, Junji Chida, Hideki Hoshino, Hiroshi Ozawa, Ayaka Koide, Hirohumi Kashii, Akiko Koyama, Yoko Mizuno, Ai Hoshino, Yamaguchi Miyoko, Dengbing Yao, Min Yao and Hiroshi Kido :
Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children,
Brain & Development, Vol.34, No.1, 20-27, 2012.

(要約): Despite the decrease in Reye syndrome after the discontinuation of aspirin, acute encephalopathy (non-Reye syndrome type) has been continually reported in Japan. Recent studies suggested that the thermolabile phenotype of carnitine palmitoyltransferase II (CPT II) variation [F352C] was closely related to the pathomechanism of influenza-associated encephalopathy (IAE) in Japanese, causing mitochondrial ATP utilization failure during periods of high fever, resulting in brain edema. So, we analyzed CPT II polymorphism and peripheral blood ATP levels as a signal of "energy crisis" in 12 and 10 patients with acute encephalopathy, respectively. Out of the 12 patients with acute encephalopathy, six showed thermolabile CPT II variants [F352C], and of these six, two patients died in spite of intensive care. In contrast, the remaining six patients with no thermolabile CPT II variant [F352C] showed a relatively mild clinical course. Blood ATP levels of the 10 patients in the acute phase of encephalopathy were significantly lower than those during the convalescent phase and also those of patients with febrile seizure status. Our data suggest that the thermolabile F352C CPT II variant, found only in Japanese, might be one of the predisposing factors to trigger the pathomechanism of acute encephalopathy in the Japanese population, and that it is causally related to the severity of disease. The decreased blood ATP level seems to reflect systemic mitochondrial dysfunction including the blood brain barrier during the acute phase of encephalopathy.
(キーワード): Adenosine Triphosphate / Carnitine O-Palmitoyltransferase / Child / Child, Preschool / Encephalitis, Viral / Genetic Predisposition to Disease / Genotype / Humans / Infant / Japan / Luminescent Measurements / Phenotype / Polymerase Chain Reaction / Polymorphism, Single Nucleotide
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.braindev.2010.12.012
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21277129; ● CiNii @ 国立情報学研究所 (CRID): 1570854176176565632; ● Search Scopus @ Elsevier (PMID): 21277129; ● Search Scopus @ Elsevier (DOI): 10.1016/j.braindev.2010.12.012

(DOI: 10.1016/j.braindev.2010.12.012, PubMed: 21277129, CiNii: 1570854176176565632) Hiroshi Kido, Yuushi Okumura, Etsuhisa Takahashi, Haiyan Pan, Siye Wang, Dengbing Yao, Min Yao, Junji Chida and Mihiro Yano :
Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure,
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol.1824, No.1, 186-194, 2012.

(要約): Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus-cytokine-protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
(キーワード): Animals / Antigen Presentation / Birds / Capillary Permeability / Host-Pathogen Interactions / Humans / Immune System / Influenza A virus / Influenza in Birds / Influenza, Human / Models, Biological / Multiple Organ Failure / Peptide Hydrolases
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbapap.2011.07.001
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21801859; ● Search Scopus @ Elsevier (PMID): 21801859; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbapap.2011.07.001

(DOI: 10.1016/j.bbapap.2011.07.001, PubMed: 21801859) Min Yao, Dengbing Yao, Miyoko Yamaguchi, Junji Chida, Dengfu Yao and Hiroshi Kido :
Bezafibrate upregulates carnitine palmitoyltransferase II expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza-associated encephalopathy,
Molecular Genetics and Metabolism, Vol.104, No.3, 265-272, 2011.

(要約): Influenza-associated encephalopathy (IAE) is characterized by persistently high fever, febrile convulsions, severe brain edema and high mortality. We reported previously that a large proportion of patients with disabling or fatal IAE exhibit a thermolabile phenotype of compound variants for [1055T>G/F352C] and [1102G>A/V368I] of carnitine palmitoyltransferase II (CPT II) and mitochondrial energy crisis during high fever. In the present study, we studied the effect of bezafibrate, a hypolipidemic pan-agonist of peroxisome proliferator-activated receptor (PPAR), on CPT II expression and mitochondrial energy metabolism in fibroblasts of IAE patients and wild type (WT) fibroblasts from a healthy volunteer at 37°C and 41°C. Although heat stress markedly upregulated CPT II, CPT IA and PPAR-δ mRNA expression levels, CPT II activity, β-oxidation and ATP levels in WT and IAE fibroblasts at 41°C were paradoxically downregulated probably due to the thermal instability of the corresponding enzymes. Bezafibrate significantly enhanced the expression levels of the above mRNAs and cellular functions of these enzymes in fibroblasts at 37°C. Bezafibrate-induced increase in CPT II activity also tended to restore the downregulated ATP levels, though moderately, and improved mitochondrial membrane potential even at 41°C to the levels at 37°C in fibroblasts of IAE patients. L-carnitine, a substrate of CPT II, boosted the effects of bezafibrate on cellular ATP levels in WT and IAE fibroblasts, even in severe IAE fibroblasts with thermolabile compound variations of F352C+V368I at 37°C and 41°C. The results suggest the potential usefulness of bezafibrate for the treatment of IAE.
(キーワード): Adenosine Triphosphate / Base Sequence / Bezafibrate / Blotting, Western / Brain Diseases, Metabolic / Carnitine / Carnitine O-Palmitoyltransferase / DNA Primers / Energy Metabolism / Fibroblasts / Gene Expression Regulation / Genomics / Hot Temperature / Humans / Influenza, Human / Japan / Membrane Potential, Mitochondrial / Microscopy, Fluorescence / Mitochondria / Molecular Sequence Data / Peroxisome Proliferator-Activated Receptors / RNA, Messenger / Real-Time Polymerase Chain Reaction / Sequence Analysis, DNA / Time Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ymgme.2011.07.009
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21816645; ● Search Scopus @ Elsevier (PMID): 21816645; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ymgme.2011.07.009

(DOI: 10.1016/j.ymgme.2011.07.009, PubMed: 21816645) Dengbing Yao, Min Yao, Miyoko Yamaguchi, Junji Chida and Hiroshi Kido :
Characterization of compound missense mutation and deletion of carnitine palmitoyltransferase II in a patient with adenovirus-associated encephalopathy,
The Journal of Medical Investigation : JMI, Vol.58, No.3,4, 210-218, 2011.

(要約): In mammals, carnitine palmitoyltransferase (CPT) system is a pivotal component of energy metabolism through mitochondrial fatty acid oxidation. The majority of patients with fatal or handicapped influenza-associated encephalopathy exhibit thermolabile compound homo/heterozygous mutations of CPT II. Compound CPT II mutations, [c.647A>G (p.Q216R)], [c.1102G>A (p.V368I)], [c.1939A>G (p.M647V)] and [c.745delG (p.G249EfsX16)], were found in a patient with adenovirus-associated encephalopathy and his family. The properties of these CPT II mutations were analyzed in COS-7 cells. CPT II mutations in the patient and his family were expressed in COS-7 cells and their molecular masses, enzyme activities, thermal instabilities and half-lives were analyzed. We identified two novel CPT II mutations in the patient, [c.647A>G (p.Q216R)] and [c.745delG (p.G249EfsX16)]. The CPT II Q216R mutation showed mild reduction of activity, thermal instability and short half-life but compound mutations with Q216R+V368I+M647V showed further enhancement of these disabilities, although mutations V368I and M647V had no such effects. CPT II mutation [c.745delG (p.G249EfsX16)] abolished enzyme activity and showed short half-life. The thermal instability and short half-life of the novel CPT II mutations, [c.647A>G (p.Q216R)] and [c.745delG (p.G249EfsX16)], could play important roles in energy crisis in the pathogenesis of virus-associated encephalopathy.
(キーワード): Adenosine Triphosphate / Adenoviridae Infections / Amino Acid Sequence / Animals / Base Sequence / Blotting, Western / COS Cells / Carnitine O-Palmitoyltransferase / Cercopithecus aethiops / Child, Preschool / Encephalitis, Viral / Enzyme Stability / Gene Deletion / Humans / Molecular Sequence Data / Mutation, Missense
(徳島大学機関リポジトリ): ● Metadata: 83835
(出版サイトへのリンク): ● Publication site (DOI): 10.2152/jmi.58.210
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21921422; ● Search Scopus @ Elsevier (PMID): 21921422; ● Search Scopus @ Elsevier (DOI): 10.2152/jmi.58.210

(徳島大学機関リポジトリ: 83835, DOI: 10.2152/jmi.58.210, PubMed: 21921422) Junji Chida, Siye Wang, Pan Hai-Yan, Le Quang Trong and Hiroshi Kido :
Influenza virus-cytokine-protease cycles are principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches,
Influenza and Other Respiratory Viruses, Vol.5, No.1, 281-286, 2011. Hai-Yan Pan, Hirotsugu Yamada, Junji Chida, Siye Wang, Mihiro Yano, Min Yao, Jianhua Zhu and Hiroshi Kido :
Up-regulation of ectopic trypsins in the myocardium by influenza A virus infection triggers acute myocarditis,
Cardiovascular Research, Vol.89, No.3, 595-603, 2010.

(要約): Influenza A virus (IAV) infection markedly up-regulates ectopic trypsins in various organs, viral envelope glycoprotein processing proteases, which are pre-requisites for virus entry and multiplication. We investigated the pathological roles of trypsin up-regulation in the progression of IAV-induced myocarditis, cytokine induction, and viral replication in the hearts, and also investigated the protective effects of trypsin inhibitor on cardiac dysfunction in vivo and selective knockdown of trypsin on IAV-induced cellular damage in cardiomyoblasts. The relationship of the expression among IAV RNA, trypsins, matrix metalloproteinase (MMP)-9, MMP-2, pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and tumour necrosis factor-α was analysed in mice hearts and cardiomyoblasts after IAV infection. The severity of myocarditis was most noticeable during Day 6-9 post-infection, along with peak expression of viral RNA, trypsins, particularly trypsin , MMPs, and cytokines. Cardiac ATP levels were the lowest at Day 9. Up-regulated trypsins, viral protein, and tissue-injured loci in the myocardium were closely localized. Trypsin inhibitor aprotinin treatment in vivo and selective trypsin - and trypsin -knockdown, particularly the latter, in H9c2 cardiomyoblasts significantly suppressed viral replication, up-regulation of MMPs, and production of active MMP-9 and cytokines, resulting in marked protection against cellular damage, ATP depletion, and apoptosis. IAV infection-induced cardiac dysfunction monitored by echocardiography was improved significantly by aprotinin treatment. IAV-induced trypsins, particularly trypsin , in the myocardium trigger acute viral myocarditis through stimulation of IAV replication, proMMP-9 activation, and cytokine induction. These results suggest that up-regulation of trypsins is one of the key host pathological findings in IAV-induced myocarditis.
(キーワード): Myocarditis / トリプシン (trypsin) / Influenza virus / 細胞質分裂 (cytokinesis) / Matrix metalloproteases
(出版サイトへのリンク): ● Publication site (DOI): 10.1093/cvr/cvq358
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21084314; ● Search Scopus @ Elsevier (PMID): 21084314; ● Search Scopus @ Elsevier (DOI): 10.1093/cvr/cvq358

(DOI: 10.1093/cvr/cvq358, PubMed: 21084314) Siye Wang, Le Quang Trong, Kurihara Naoki, Junji Chida, Youssouf Cisse, Mihiro Yano and Hiroshi Kido :
Influenza Virus Cytokine Protease Cycle in the Pathogenesis of Vascular Hyperpermeability in Severe Influenza,
The Journal of Infectious Diseases, Vol.202, No.7, 991-1001, 2010.

(要約): Severe influenza is characterized by cytokine storm and multiorgan failure with edema. The aim of this study was to define the impact of the cytokine storm on the pathogenesis of vascular hyperpermeability in severe influenza. Weanling mice were infected with influenza A WSN/33(H1N1) virus. The levels of proinflammatory cytokines, tumor necrosis factor (TNF) alpha, interleukin (IL) 6, IL-1beta, and trypsin were analyzed in the lung, brain, heart, and cultured human umbilical vein endothelial cells. The effects of transcriptional inhibitors on cytokine and trypsin expressions and viral replication were determined. Influenza A virus infection resulted in significant increases in TNF-alpha, IL-6, IL-1beta, viral hemagglutinin-processing protease trypsin levels, and viral replication with vascular hyperpermeability in lung and brain in the first 6 days of infection. Trypsin upregulation was suppressed by transcriptional inhibition of cytokines in vivo and by anti-cytokine antibodies in endothelial cells. Calcium mobilization and loss of tight junction constituent, zonula occludens-1, associated with cytokine- and trypsin-induced endothelial hyperpermeability were inhibited by a protease-activated receptor-2 antagonist and a trypsin inhibitor. The influenza virus-cytokine-protease cycle is one of the key mechanisms of vascular hyperpermeability in severe influenza.
(キーワード): Animals / Brain Chemistry / Capillary Permeability / Cells, Cultured / Cytokines / Endothelial Cells / Female / Humans / Influenza A Virus, H1N1 Subtype / Lung / Mice / Mice, Inbred C57BL / Myocardium / Orthomyxoviridae Infections / Peptide Hydrolases
(出版サイトへのリンク): ● Publication site (DOI): 10.1086/656044
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20731583; ● Search Scopus @ Elsevier (PMID): 20731583; ● Search Scopus @ Elsevier (DOI): 10.1086/656044

(DOI: 10.1086/656044, PubMed: 20731583) Etsuhisa Takahashi, Kosuke Kataoka, Kazuyuki Fujii, Junji Chida, Dai Mizuno, Makoto Fukui, Hiro-O Ito, Kohtaro Fujihashi and Hiroshi Kido :
Attenuation of inducible respiratory immune responses by oseltamivir treatment in mice infected with influenza A virus.,
Microbes and Infection, Vol.12, No.10, 778-783, 2010.

(要約): The antiviral neuraminidase inhibitor oseltamivir (OSV) is widely used to suppress viral replication in the treatment of influenza. Here, we report that OSV administration significantly suppressed respiratory mucosal secretory IgA responses with respect to antigen (Ag)-specific antibody (Ab) production and also the induction of Ag-specific IgA Ab-forming cells, but not systemic IgG responses, in weanling mice as a model of pediatric influenza. Neutralizing activities of the airway fluids in oral OSV-treated mice were significantly less than those of sham-treated mice. Our findings suggest the risk of re-infection in patients showing a low mucosal response following OSV treatment.
(キーワード): Animals / Antibodies, Viral / Antiviral Agents / Female / Immunity, Mucosal / Immunoglobulin A / Immunoglobulin G / Immunosuppression / Immunosuppressive Agents / Influenza A virus / Mice / Mice, Inbred BALB C / Orthomyxoviridae Infections / Oseltamivir
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.micinf.2010.04.013
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20452454; ● Search Scopus @ Elsevier (PMID): 20452454; ● Search Scopus @ Elsevier (DOI): 10.1016/j.micinf.2010.04.013

(DOI: 10.1016/j.micinf.2010.04.013, PubMed: 20452454) Siye Wang, Le Quang Trong, Junji Chida, Youssouf Cisse, Mihiro Yano and Hiroshi Kido :
Meckanisms of matrix metallo protease-9 wuregulation and tissue desfruction in rarious organs in influenza A virus infection,
The Journal of Medical Investigation : JMI, Vol.57, No.1,2, 26-34, 2010.

(要約): Severe influenza is characterized clinicopathologically by multiple organ failure, although the relationship amongst virus and host factors that influence this morbid outcome and the underlying mechanisms of action remain unclear. The present study identified marked upregulation of matrix metalloproteinase (MMP)-9 and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in various organs after intranasal infection of influenza A WSN virus. MMP-9 and TNF-alpha were upregulated in the lung, the site of initial infection, as well as in the brain and heart. The infection-induced MMP-9 upregulation was inhibited by anti-TNF-alpha antibodies and by anti-oxidative reagents pyrrolidine dithiocarbamate and N-acetyl-L-cysteine, which inhibit activation of nuclear factor kappa B (NF-kappaB), as well as by nordihydroguaiaretic acid, which inhibits activation of activator protein 1 (AP-1). In addition, MMP-9 upregulation via TNF-alpha was also suppressed by inhibitors of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase 1/2 and p38, and partly by a c-Jun N-terminal kinase inhibitor. These results indicated that the influenza-induced MMP-9 upregulation in various organs is mediated through MAPK-NF-kappaB- and/or AP-1-dependent mechanisms. Strategies that neutralize TNF-alpha as well as inhibitors of MAPK-NF-kappa B- and/or AP-1-dependent pathways may be useful for suppressing the MMP-9 effect and thus preventing multiple organ failure in severe influenza.
(キーワード): Animals / Influenza A virus / Lung / MAP Kinase Signaling System / Matrix Metalloproteinase 9 / Mice / Mice, Inbred C57BL / NF-kappa B / Orthomyxoviridae Infections / Phosphorylation / Transcription Factor AP-1 / Tumor Necrosis Factor-alpha
(出版サイトへのリンク): ● Publication site (DOI): 10.2152/jmi.57.26
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20299740; ● Search Scopus @ Elsevier (PMID): 20299740; ● Search Scopus @ Elsevier (DOI): 10.2152/jmi.57.26

(DOI: 10.2152/jmi.57.26, PubMed: 20299740) Sawabuchi Takako, Suzuki Satoshi, Isase Kazuhiro, Ito Chika, Dai Mizuno, Todari Hajime, Watanabe Isamu, Talukder R. Sadiqur, Junji Chida and Hiroshi Kido :
Boost of mucosal secretory immunoglobulin A response by clarithromycin in paediatric influenza,
Respirology, Vol.14, No.8, 1173-1179, 2009.

(要約): The antiviral neuraminidase inhibitor oseltamivir (OSV) is used to treat influenza. The macrolide clarithromycin (CAM) is used to treat bacterial infections and has anti-inflammatory and immunomodulatory activities. This retrospective study investigated the immunomodulatory effects of CAM in children presenting with influenza A. The study recruited 40 children with acute influenza, and grouped them according to the treatment received: 5-day treatment with OSV (n = 14), CAM (n = 8), OSV + CAM (n = 12) and untreated (n = 6). The before and after treatment comparisons were made of the level of secretory IgA (sIgA) against influenza A virus (H3N2) and (H1N1), total sIgA, viral RNA copy numbers in nasopharyngeal aspirates and disease symptoms. Infection induced anti-viral mucosal sIgA in the nasopharyngeal aspirates of most patients of all treatment groups. Particularly prominent increases in the levels were found in the CAM and OSV + CAM groups. Low induction of anti-viral sIgA was observed in the OSV group, but the addition of CAM to OSV augmented sIgA production and restored local mucosal sIgA levels. The frequency of residual cough in the OSV + CAM group was significantly lower than in the other groups including the group treated with OSV. CAM boosted the nasopharyngeal mucosal immune response in children presenting with influenza A, even in those treated with OSV who had low production of mucosal anti-viral sIgA, and alleviated the symptoms of influenza.
(キーワード): Adolescent / Anti-Bacterial Agents / Antiviral Agents / Child / Child, Preschool / Clarithromycin / Cough / Drug Therapy, Combination / Humans / Immunoglobulin A / Infant / Influenza A virus / Influenza, Human / Nasal Mucosa / Oseltamivir / Prevalence / RNA, Viral / Retrospective Studies / Treatment Outcome
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.1440-1843.2009.01639.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19909463; ● Search Scopus @ Elsevier (PMID): 19909463; ● Search Scopus @ Elsevier (DOI): 10.1111/j.1440-1843.2009.01639.x

(DOI: 10.1111/j.1440-1843.2009.01639.x, PubMed: 19909463) Hiroshi Kido, Yuushi Okumura, Etsuhisa Takahashi, HY Pan, Siye Wang, Junji Chida, Le Trong Quang and Mihiro Yano :
Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses.,
Journal of Molecular and Genetic Medicine, Vol.3, No.1, 167-175, 2009.

(要約): Influenza A virus (IAV) is one of the most common infectious pathogens in humans and causes considerable morbidity and mortality. The recent spread of highly-pathogenic avian IAV H5N1 viruses has reinforced the importance of pandemic preparedness. In the pathogenesis of IAV infection, cellular proteases play critical roles in the process of viral entry into cells that subsequently leads to tissue damage in the infected organs. Since there are no processing protease for the viral membrane fusion glycoprotein hemagglutinin precursor (HA(0)) in IAV, entry of the virus into cells is determined primarily by the host cellular HA(0) processing proteases that proteolytically activate membrane fusion activity. HA(0) of seasonal human IAV has the consensus cleavage site motif Q(E)-T/X-R and is selectively processed by at least seven different trypsin-type processing proteases identified to-date in animal model experiments using mouse-adapted IAV or gene expression system in MDCK cells. As is the case for the highly pathogenic avian influenza (HPAI) A virus, endoproteolytic processing of the HA(0) occurs through ubiquitous cellular processing proteases, which selectively recognize the multi-basic consensus cleavage site motifs, such as R-X-K/R-R, and K-X-K/R-R. The cleavage enzymes for the R-X-K/R-R motif, but not K-X-K/R-R motif, have been reported to be furin and pro-protein convertase (PC)5/6 in the trans-Golgi network. Here we report new members of type II transmembrane serine proteases of the cell membrane, mosaic serine protease large form (MSPL) and its splice variant TMPRSS13, which recognize and cleave both R-X-K/R-R and K-X-K/R-R motifs without calcium. Furthermore, IAV infection significantly up-regulates a latent ectopic pancreatic trypsin, one of the potent HA processing proteases, and pro-matrix metalloprotease-9, in various organs. These proteases may synergistically damage the blood-brain barrier in the brain and basement membrane of blood vessels in various organs, resulting in severe edema and multiple organ failure. In this review, we discuss these proteases as new drug target molecules for IAV treatment acting by inhibition of IAV multiplication and prevention of multiple organ failure, other than anti-viral agents, viral neuraminidase inhibitors.
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19565019; ● Search Scopus @ Elsevier (PMID): 19565019

(PubMed: 19565019) Dengbing Yao, Hiroshi Mizuguchi, Miyoko Yamaguchi, Hiroshi Yamada, Junji Chida, Koji Shikata and Hiroshi Kido :
Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.,
Human Mutation, Vol.29, No.5, 718-727, 2008.

(要約): Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homo-/heterozygous variants of carnitine palmitoyltransferase II (CPT II, gene symbol CPT2). We characterized the enzymatic properties of five single and three compound CPT II variants in patients with IAE. The kinetic characteristics of WT and variant CPT IIs, expressed in COS-7 cells, indicated that the variants exert a dominant-negative effect on the homotetrameric protein of the enzyme. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the WT. Like other disease-causing mutant proteins, these variant proteins were poly-ubiquitinated and rapidly degraded by a lactacystin-sensitive proteasome pathway. COS-7 cells transfected with the compound variants had their fatty acid beta-oxidation decreased to 30-59% and intracellular ATP levels to 48-79%, and a marked reduction of mitochondrial membrane potential at 41 degrees C, compared with control cells transfected with WT at 37 degrees C. The unstable CPT II variants with decreased enzymatic activities may bring mitochondrial fuel utilization below the phenotypic threshold during high fever, and thus may play an important etiopathological role in the development of brain edema of IAE.
(キーワード): ミトコンドリア (mitochondria) / カルニチンパルミトイルトランスフェラーゼ 2 (carnitine palmitoyltransferase 2) / インフルエンザ脳症 (influenza-associated encephalopathy)
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/humu.20717
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18306170; ● Search Scopus @ Elsevier (PMID): 18306170; ● Search Scopus @ Elsevier (DOI): 10.1002/humu.20717

(DOI: 10.1002/humu.20717, PubMed: 18306170) Junji Chida, Aiko Amagai, Masashi Tanaka and Yasuo Maeda :
Establishment of a new method for precisely determining the functions of individual mitochondrial genes, using Dictyostelium cells.,
BMC Genetics, Vol.9, 25, 2008.

(要約): Disruption of mitochondrial genes may become a powerful tool for elucidating precisely the functions of individual mitochondrial genes. However, it is generally difficult to manipulate genetically mitochondrial genes, because 1) a mitochondrion is surrounded by inner and outer membranes, and 2) there are a large number of mtDNA copies in a single cell. This is the reason why we tried to establish a novel method for disrupting a certain mitochondrial gene (rps4), using Dictyostelium cells. Here, we have developed a new method for specifically disrupting a mitochondrial gene (rps4 ; ribosomal protein subunit S4), by a combination of homologous recombination and delivery of an appropriate restriction endonuclease (SfoI) into mitochondria. First, mitochondrially targeted SfoI whose expression is under control of the tetracycline (Tet)-regulated gene expression system was introduced into cells heteroplasmic with respect to the rps4 gene. Then, the heteroplasmic cells were produced by homologous recombination by use of the construct in which the unique SfoI site and the 5'-half of the rps4 coding region were deleted not to be digested by SfoI, and therefore their mitochondria have both the wild-type mtDNA and the mutant mtDNA with the disrupted rps4 gene. In response to removal of Tet from growth medium, SfoI was selectively delivered into mitochondria and digested only the wild-type mtDNA but not the mutated rps4. Thus one can gain rps4-null cells with only the mutated mtDNA, under the Tet-minus condition. The mitochondrial gene-disruption method presented here must be widely useful for precisely determining the functions of individual mitochondrial genes. This is the first report to demonstrate complete and specific mitochondrial gene disruption.
(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 遺伝子相同組換え
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/1471-2156-9-25
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18366713; ● Search Scopus @ Elsevier (PMID): 18366713; ● Search Scopus @ Elsevier (DOI): 10.1186/1471-2156-9-25

(DOI: 10.1186/1471-2156-9-25, PubMed: 18366713) Junji Chida, Hitomi Yamaguchi, Aiko Amagai and Yasuo Maeda :
The necessity of mitochondrial genome DNA for normal developmental of Dictyostelium cells.,
Journal of Cell Science, Vol.117, No.Pt 15, 3141-3152, 2004.

(要約): Most unexpectedly, there is now increasing evidence that mitochondria have novel and crucial functions in the regulatory machinery of the growth/differentiation transition, cell-type determination, cellular movement and pattern formation. Here we created rho delta cells with a reduced amount (about 1/4) of mitochondrial DNA (mtDNA) from Dictyostelium discoideum Ax-2 cells, by exposing Ax-2 cells to ca. 30 microg/ml of ethidium bromide (EtBr) in axenic growth medium. Importantly, the rho delta cells exhibited a series of fascinating behaviors: when they were starved, they showed a marked delay of differentiation and stopped their development at the slug stage, thus failing to construct fruiting bodies. Moreover, cell patterning and cell-type proportioning were found to be greatly modified in slugs (referred to as rho delta slugs) derived from rho delta cells. That is, prestalk differentiation was significantly enhanced in rho delta slugs, while prespore differentiation was markedly inhibited. In addition, the clear anterior prestalk/posterior prespore pattern was considerably disturbed in rho delta slugs, presumably because of incomplete sorting between the two types of differentiated cells. After the assay of phototaxis, rho delta slugs also exhibited highly disordered movement towards the light source. Taken together, these results suggest that mtDNA might have important multiple functions in a variety of cellular processes during Dictyostelium development.
(キーワード): ミトコンドリアDNA (mitochondrial DNA) / アデノシン三リン酸 (adenosine triphosphate) / 細胞性粘菌 (Dictyostelium discoideum)
(出版サイトへのリンク): ● Publication site (DOI): 10.1242/jcs.01140
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15226392; ● Search Scopus @ Elsevier (PMID): 15226392; ● Search Scopus @ Elsevier (DOI): 10.1242/jcs.01140

(DOI: 10.1242/jcs.01140, PubMed: 15226392) Kou-ichi Hosoya, Aiko Amagai, Junji Chida and Yasuo Maeda :
Unique behavior and function of the mitochondrial ribosomal protein S4 (RPS4) in early Dictyostelium development.,
Zoological Science, Vol.20, No.12, 1455-1465, 2003.

(要約): Certain proteins encoded by mitochondrial DNA (mt-DNA), including mt-ribosomal protein S4 (rps4), appear to play important roles in the initiation of cell differentiation. Partial disruption of rps4 in Dictyostelium discoideum Ax-2 cells by means of homologous recombination greatly impairs the progression of differentiation, while the the rps4(OE) cells in which the rps4 mRNA was overexpressed in the extra-mitochondrial cytoplasm exhibit enhanced differentiation (Inazu et al., 1999). We have prepared a specific anti-RPS4 antibody and generated transformants (rps4(AS) cells) by antisense-mediated gene inactivation of rps4. Surprisingly, in the rps4(AS) cells the progress of differentiation was found to be markedly inhibited, suggesting that the antisense rps4 RNA synthesized in the extra-mitochondrial cytoplasm might be as effective as the partial disruption of rps4 gene. Immunostaining of the rps4(OE) cells with the anti-RPS4 antibody demonstrated that the RPS4 protein synthesized in the extra-mitochondrial cytoplasm is capable of moving to the nucleus, as predicted by PSORTII. Taken together with the results obtained using immunostained Ax-2 cells, we propose a possible pathway of RPS4 translocation coupled with differentiation.
(キーワード): ミトコンドリアDNA (mitochondrial DNA) / リボソームタンパク質 / 細胞性粘菌 (Dictyostelium discoideum)
(出版サイトへのリンク): ● Publication site (DOI): 10.2108/zsj.20.1455
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 14709810; ● Search Scopus @ Elsevier (PMID): 14709810; ● Search Scopus @ Elsevier (DOI): 10.2108/zsj.20.1455

(DOI: 10.2108/zsj.20.1455, PubMed: 14709810)

MISC

Junji Chida and Hiroshi Kido :
Extraction and quantification of adenosine triphosphate in mammalian tissues and cells.,
Methods in Molecular Biology, Vol.1098, 21-32, 2014.

(要約): Adenosine 5'-triphosphate (ATP) is the "energy currency" of organisms and plays central roles in bioenergetics, whereby its level is used to evaluate cell viability, proliferation, death, and energy transmission. In this chapter, we describe an improved and efficient method for extraction of ATP from tissues and cells using phenol-based reagents. The chaotropic extraction reagents reported so far co-precipitate ATP with insoluble proteins during extraction and with salts during neutralization. In comparison, the phenol-based reagents extract ATP well without the risks of co-precipitation. The extracted ATP can be quantified by the luciferase assay or high-performance liquid chromatography.
(キーワード): Adenosine Triphosphate / Animals / Chemical Fractionation / Chromatography, High Pressure Liquid / Ethylene Glycol / Indicators and Reagents / Luciferases, Firefly / Luminescent Measurements / Mice / Phenols / Trichloroacetic Acid
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-62703-718-1_2
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24166365; ● Summary page in Scopus @ Elsevier: 2-s2.0-84934435958

(DOI: 10.1007/978-1-62703-718-1_2, PubMed: 24166365, Elsevier: Scopus) 木戸博, 千田淳司 :
インフルエンザ脳症の発症機序, --- CPT2遺伝子多型が解き明かす発症リスク ---,
医学のあゆみ, Vol.241, No.1, 23-28, 2012年.

(要約): インフルエンザ脳症は，インフルエンザ感染による脳の血管内皮細胞膜の透過性亢進による脳浮腫の重篤な病態である．発症機序の解析から，インフルエンザ感染の高熱時に脳の血管内皮細胞膜の透過性が亢進しやすい患者のリスク因子として遺伝子多型が解明された．脳の血管内皮細胞は全身の血管内皮細胞のなかでもとくにエネルギー代謝の活発な細胞で，そのエネルギー源の約70%は脂肪酸代謝に依存している特徴をもつ．そのため重症化患者では，長鎖脂肪酸代謝酵素Calnitine Palmitoyltransferase 2 の熱不安定性遺伝子多型がリスク因子として集中していることが判明した．血管内皮細胞のエネルギークライシスが，脂肪代謝改善薬bezafibrate で改善されることが明らかになった．今後，脳症のリスク回避薬として期待される．
(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy)
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1524232505307507072

(CiNii: 1524232505307507072) 木戸博, Yao Dengbing, 千田淳司, Cisse Youssouf, Yao Min :
インフルエンザ脳症の発症原因 -ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-,
最新医学, Vol.65, No.1, 52-60, 2010年.

(キーワード): インフルエンザ脳症 / ミトコンドリア / 脂肪酸代謝障害 / 血管透過性亢進 / 遺伝子多型
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1522543654897644800

(CiNii: 1522543654897644800) Junji Chida, Aiko Amagai and Yasuo Maeda :
Validity of Dictyostelium mitochondrial DNA-less cells for elucidating the regulatory mechanisms of development.,
Journal of Plant Research, Vol.116, 149-150, 2003.

(キーワード): ミトコンドリアDNA (mitochondrial DNA) / 分化・形態形成 / 細胞性粘菌 (Dictyostelium discoideum)

総説・解説

千田淳司, 木戸博, 坂口末廣 :
宿主因子を標的にした新たなインフルエンザ治療の試み,
BIO Clinica, Vol.256, No.33, 52-55, 2018年2月. 木戸博, 千田淳司 :
インフルエンザ脳症への新たな対応策は?,
インフルエンザの最新知見 Q & A 2012, 171-172, 2012年5月. 水野葉子, 久保田雅也, 柏井洋文, 宮田理英, 田沼直之, 林雅晴, 千田淳司, 山口美代子, Yao Dengbing, Yao Min, 木戸博 :
Carnitine palmitoyltransferase II (CPT II) の熱不安定性遺伝子多型を持った急性脳症の1例,
小児科臨床, Vol.65, No.5, 1057-1062, 2012年. 木戸博, 千田淳司 :
インフルエンザ脳症の発症機序ー遺伝子多型が解き明かす発症基盤ー,
インフルエンザ, Vol.44, No.12(3), 225-232, 2011年10月.

(キーワード): インフルエンザ脳症 / サイトカイン / 遺伝子多型 / 血管透過性亢進
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1520291856148604032

(CiNii: 1520291856148604032) 木戸博, 千田淳司, 姚敏, Yao Dengbing, 山根一彦 :
遺伝子多型解析が解き明かすインフルエンザ脳症と多臓器不全,
実験医学, Vol.28, No.18, 2927-2933, 2010年11月. 木戸博, 千田淳司 :
インフルエンザ感染の重症化機序, --- インフルエンザ脳症の発症機序と遺伝的素因 ---,
Neuroinfection, Vol.15, No.1, 66-73, 2010年9月. 木戸博, 千田淳司, Min Yao, Wang Siye :
インフルエンザ感染の重症化，多臓器不全の発症メカニズム,
日本臨牀, Vol.68, No.8, 1565-1573, 2010年8月.

(要約): Severe influenza is characterized by cytokine storm and multi-organ failure with edema. We found that the "influenza virus-cytokine-trypsin/MMP-9 cycle" in the endothelial cells is one of the key mechanisms of vascular hyperpermeability, the major pathogen of multi-organ failure. Upregulated TNF-alpha, IL-6 and IL-beta induce ectopic pancreatic trypsin and pro-MMP-9 in the endothelial cells and in various organs. Trypsin mediates the viral hemagglutinin processing, which is crucial for viral entry and multicycles of replication. In addition, trypsin is the most potent pro-MMP-9 convertase to form active MMP-9 and both proteases synergistically destruct matrix around blood vessels. In addition upregulated trypsin triggers through its receptor, PAR-2, the modification of cellular functions, such as increase in calcium mobilization and mitochondrial membrane permeability, suppression of ATP generation and loss of tight junction constituent, zonula occludens-1. High risk patients who have impaired mitochondrial fuel utilization will easy get into energy crisis, resulting in vascular hyperpermeability in severe influenza.
(キーワード): cytokine storm / trypsin / influenza / multi-organ failure / vascular hyperpermeability
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20715496; ● CiNii @ 国立情報学研究所 (CRID): 1521136280984508800; ● Search Scopus @ Elsevier (PMID): 20715496

(PubMed: 20715496, CiNii: 1521136280984508800) 木戸博, 千田淳司, Yao Min, Wang Siye :
最近のインフルエンザ治療の動向とクラリスロマイシン投与の意義,
大阪府内科医会誌, Vol.19, No.1, 47-54, 2010年4月. 千田淳司, Yao Dengbing, Wang Siye, 山口美代子, 木戸博 :
インフルエンザの重症化をめぐって, --- インフルエンザ脳症発症の機序の解明 ---,
The Japanese Journal of Antibiotics, (in-press), 2009年.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ミトコンドリア (mitochondria) / カルニチンパルミトイルトランスフェラーゼ 2 (carnitine palmitoyltransferase 2)

木戸博, 水野大, 武井恒知, 西野真紀, 千田淳司, Cisse Youssof :
インフルエンザ経鼻ワクチン -肺サーファクタント粘膜免疫-,
小児科, Vol.48, No.12, 1837-1844, 2007年11月. 木戸博, 水野大, 武井恒知, 西野真紀, 千田淳司, Cisse Youssouf :
インフルエンザ経鼻ワクチン, --- 肺サーファクタントと粘膜免疫 ---,
小児科, Vol.48, No.12, 1837-1844, 2007年11月. 木戸博, Yao Dengbing, Quang Trong Le, 塚根真理子, 千田淳司 :
インフルエンザ脳症の発症原因を遺伝子多型と酵素機能から解析, --- 高熱で誘発されるミトコンドリア脂肪酸代謝障害 ---,
日本臨牀, Vol.64, No.10, 101-109, 2007年10月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / 多臓器不全 (multiple organ failure) / ミトコンドリア (mitochondria) / カルニチンパルミトイルトランスフェラーゼ 2 (carnitine palmitoyltransferase 2) / アデノシン三リン酸 (adenosine triphosphate)

木戸博, Yao Dengbing, Quang Trong Le, 千田淳司, 奥村裕司, 山田博司 :
インフルエンザ感染, --- インフルエンザ脳症の制圧に向けて ---,
化学療法の領域, Vol.23, No.7, 101-109, 2007年7月.

(キーワード): インフルエンザ (influenza) / インフルエンザ脳症 (influenza-associated encephalopathy) / 粘膜ワクチン

木戸博, Yao Dengbing, Le Quang Trong, 千田淳司, 奥村裕司, 山田博司 :
インフルエンザ感染，インフルエンザ脳症の制圧に向けて，科学治療の領域,
Antibiotics & Chemotherapy, Vol.23, No.7, 101-109, 2007年.

講演・発表

Etsuhisa Takahashi, HY Pan, IL Indalao, Junji Chida and Hiroshi Kido :
TRYPSIN KOCKDOWN AND TRYPSIN INHIBITOR ADMINISTRATION SUPPRESSED INFLUENZA VIRAL REPLICATION AND VIRUS-INDUCES MYOCARDITIS IN THE HEARTS AND CARDIOMYOBLAST CELLS,
7th General Meeting of the International Proteolisis, San Diego, Oct. 2011. Hiroshi Kido, Junji Chida, Siye Wang, Hai-Yan Pan and Min Yao :
Influenza-Cytokine-Protease Cycle in the pathogenesis of vascular hyperpermeability in severe influenza and its possible treatments,
BMB2010, Dec. 2010. Junji Chida, Siye Wang, Haiyan Pan, Min Yao, Dengbing Yao, Kazuhiko Yamane and Hiroshi Kido :
Influenza virus-cytokine-protease cycle and mitochondrial ATP depletion are the principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches,
Options for the Control of Influenza VII, China, Hong Kong, Sep. 2010. Junji Chida, Siye Wang, Hai-Yan Pan, Min Yao, Dengbing Yao, Kazuhiko Yamane and Hiroshi Kido :
Influenza virus-cytokine-protease cycle and mitochondrial ATP depletion are the principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches.,
Oprions for the Control of Influenza, Hong Kong, Sep. 2010. Junji Chida, Siye Wang, Tadashi Enomoto, Yuushi Ohnishi and Hiroshi Kido :
Up-regulations of ectopic pancreatic trypsin mRNAs by influenza virus infection and pathological role of them in multi-organ failure after virus infection.,
5th International Proteolysis Society, Patras, Oct. 2007.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / 多臓器不全 (multiple organ failure) / ミトコンドリア (mitochondria)

Junji Chida, Masashi Tanaka, Aiko Amagai and Yasuo Maeda :
A new approach to disrupt certain mitochondrial genes in Dictyostelium cells.,
International Conference on Mitochondria and Life 2005, Tokyo, Dec. 2005.

(キーワード): ミトコンドリア (mitochondria) / アデノシン三リン酸 (adenosine triphosphate) / 細胞性粘菌 (Dictyostelium discoideum)

Junji Chida, Masashi Tanaka, Aiko Amagai and Yasuo Maeda :
Unexpected and novel functions of mitochondria, revealed by Dictyostelium cells.,
International Conference on Mitochondria and Life 2005, Tokyo, Dec. 2005.

(キーワード): ミトコンドリア (mitochondria) / アデノシン三リン酸 (adenosine triphosphate) / 細胞性粘菌 (Dictyostelium discoideum)

Junji Chida, Masashi Tanaka, Aiko Amagai and Yasuo Maeda :
Establishment of a system for elucidating precisely the function of individual mitochondrial genes.,
18th Annual International Dictyostelium Conference, Lyon, Aug. 2005.

(キーワード): ミトコンドリア (mitochondria) / アデノシン三リン酸 (adenosine triphosphate) / 細胞性粘菌 (Dictyostelium discoideum)

Junji Chida, Hitomi Yamaguchi, Aiko Amagai and Yasuo Maeda :
Contributions of mitochondrial DNA to cell differentiation and pattern formation in Dictyostelium development.,
16th Annual International Dictyostelium Conference, Melbourne, Jul. 2003.

(キーワード): ミトコンドリアDNA (mitochondrial DNA) / アデノシン三リン酸 (adenosine triphosphate) / 細胞性粘菌 (Dictyostelium discoideum)

Chad Shaw, Nancy Van Driessche, Miroslava Ibarra, Sujata Sharma, Engi Okyay, Takahiro Morio, Mariko Katoh, Hideko Urushihara, Yoshimasa Tanaka, Junji Chida, Aiko Amagai, Yasuo Maeda, Dana Mahadeo, David Cotter, Adam Kusupa and Gad Shaulsky :
Beyond development: transcriptional profiling of the Dictyostelium cell cycle, spore germination and de-differentiation.,
15th Annual International Dictyostelium Conference, Sicilla, Sep. 2002. 原英之, 千田淳司, 坂口末廣 :
ネクロトーシスをトリガーとした異常型プリオン蛋白質産生の分子機構,
第45回日本分子生物学会年会, 2022年11月. 原英之, 千田淳司, 坂口末廣 :
インフルエンザウイルス感染は神経細胞において感染性プリオンの産生を引き起こす,
第44回日本分子生物学会年会, 2021年12月. 千田淳司, 原英之, 坂口末廣 :
プリオン蛋白質はインフルエンザ A ウイルス感染による重症化を軽減する,
第42回日本分子生物学会年会, 2019年12月. 原英之, 千田淳司, 坂口末廣 :
ウイルス感染を用いたプリオン病発症機構の解明,
第42回日本分子生物学会年会, 2019年12月. 原英之, 千田淳司, 坂口末廣 :
インフルエンザウイルス感染は神経細胞において異常型プリオン産生のトリガーとなる,
第41回日本分子生物学会年会, 2018年11月. 千田淳司, 原英之, 坂口末廣 :
プリオン蛋白質はインフルエンザAウイルス感染に防御的に機能する,
第66回日本ウイルス学会学術集会, 2018年10月. 千田淳司, 原英之, 坂口末廣 :
Prion protein protects mice from lethal infection with Influenza A virues,
2017年度生命科学系学会合同年次大会 (ConBio2017) 第 40回日本分子生物学会年会/第90回日本生化学会大会, 2017年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザウイルス活性機構,
2017年度生命科学系学会合同年次大会 (ConBio2017) 第 40回日本分子生物学会年会/第90回日本生化学会大会, 2017年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザウイルス活性機構の解明,
第39回日本分子生物学会年会, 2016年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザ活性の発見,
第38回日本分子生物学会年会第88回日本生化学会大会合同大会, 2015年12月. 小野寺睦雄, 中瀧恵実子, 千田淳司, 今中秀光, 木戸博, 西村匡司 :
ICU入室患者における末梢血アデノシン三リン酸(ATP)と転帰との関係,
第39回日本集中治療医学会総会, 2012年2月. 小野理恵, 西村匡司, 大藤純, 今中秀光, 千田淳司, 木戸博 :
重症患者の末梢血ATP乳酸値比,
日本麻酔科学会第58回学術集会，神戸, 2011年5月. Min Yao, Junji Chida, Hiyan Pan, Siye Wang and Hiroshi Kido :
Effect of Bezafibrate on mitochondrial energy crisis in the fibroblast of severe influenza-associated encephalopathy patients,
第33回日本分子生物学会年会第83回日本生化学会大会合同大会,, Dec. 2010. Junji Chida, Min Yao, Dengbing Yao, Miyoko Yamaguchi and Hiroshi Kido :
Pathogenesis of impaired systemic energy metabolism by severe influenza virus infection Analysis using mouse models of defect in mitochondrial -oxidation of long-chain fatty acids,
第33回日本分子生物学会年会第83回日本生化学会大会合同大会,, Dec. 2010. Hiroshi Kido, Junji Chida, Siye Wang, Hiyan Pan and Min Yao :
Influenza-Cytokine-Protease Cycle in the pathogenesis of vascular hyper-permeability in severe influenza and its possible treatment,
第33回日本分子生物学会年会第83回日本生化学会大会合同大会,, Dec. 2010. Yao Min, 高橋悦久, Pan Haiyan, 千田淳司, 木戸博 :
A Type II Transmembrane Serine Protease Serase-1B, a New Splice Variant of Polyserase-1/TMPRSS9, Plays a Role in Adipogenesis.,
第83回日本生化学会大会, 2010年12月. Pan Hai-Yan, 千田淳司, 木戸博 :
Up-regulation of ectopic trypsin in myocardium triggers acute myocarditis in severe influenza,
生化学, 2010年12月. Yao Min, 千田淳司, Pan Hai-Yan, Wang Siye, 木戸博 :
Effect of Bezafibrate on mitochondrial energy crisis in the fibroblast of severe influenza-associated encephalopathy patients,
生化学, 2010年12月. 千田淳司, Yao Min, Yao Dengbing, Miyoko Yamaguchi, 木戸博 :
Pathogenesis of impaired systemic energy metabolism by severe influenza virus infection Analysis using mouse models of defect in mitochondrial -oxidation of long-chain fatty acids-,
生化学, 2010年12月. Hiroshi Kido, Junji Chida, Siye Wang, Hai-Yan Pan and Min Yao :
Influenza-Cytokine-Protease Cycle in the pathogenesis of vascular hyper-permeability in severe influenza and its possible treatment.,
Seikagaku, Dec. 2010. 千田淳司, Wang Siye, Yao Dengbing, Yao Min, Miyoko Yamaguchi, 木戸博 :
インフルエンザ脳症の発症メカニズムの酵素学的な解析, --- ウイルス罹患後に高熱で誘発されるミトコンドリアの長鎖脂肪酸代謝障害 ---,
温熱生理研究会, 2010年9月. 千田淳司 :
インフルエンザ脳症のリスク診断を可能にする DNA チップの開発と患者の重症度をモニターする末梢血の ATP 測定システムの開発,
第9回次世代医療システム産業化フォーラム, 2008年12月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / DNA 診断チップ / アデノシン三リン酸 (adenosine triphosphate)

Junji Chida, Tadashi Enomoto, Hiroki Arase and Hiroshi Kido :
Molecular pathogenesis and multiplicity of influenza virus A/WSN/33 in plasminogen deficient mice.,
第81回日本生化学会大会, Dec. 2008.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ノックアウトマウス (knockout mice)

Yuuji Onishi, Junji Chida, Youssouf Cisse and Hiroshi Kido :
Molecular mechanism of the decrease in ATP levels by influenza virus infection.,
第81回日本生化学会大会, Dec. 2008.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ミトコンドリア (mitochondria) / アデノシン三リン酸 (adenosine triphosphate) / 血液脳関門 (blood-brain barrier) / 多臓器不全 (multiple organ failure)

Min Yao, Dengbing Yao, Miyoko Yamaguchi, Junji Chida and Hiroshi Kido :
Effect of bezafibrate on mitochondrial energy crisis in the fibroblasts of severe influenza-associated encephalopathy patients.,
第81回日本生化学会大会, Dec. 2008.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / カルニチンパルミトイルトランスフェラーゼ 2 (carnitine palmitoyltransferase 2)

千田淳司, Talukder R Sadiqur, 奥村裕司, 木戸博 :
インフルエンザ感染後に発現誘導されるトリプシン遺伝子群の転写制御ネットワーク,
第13回病態と治療におけるプロテアーゼとインヒビター学会, 2008年8月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / 炎症性サイトカイン受容体の情報伝達 (Signal transduction of proinflammatory cytokine receptors)

荒瀬裕己, 千田淳司, 榎本匡志, 木戸博 :
インフルエンザウイルスの活性化・増殖仮説のプラスミノーゲン KO マウスを用いた検証,
第13回病態と治療におけるプロテアーゼとインヒビター学会, 2008年8月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ノックアウトマウス (knockout mice) / ヘマグルチニン (Hemagglutinin)

千田淳司, Yao Dengbing, Wang Siye, 山口美代子, 木戸博 :
インフルエンザ脳症発症の分子機序の解明,
第15回マクロライド新作用研究会, 2008年7月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ミトコンドリア (mitochondria) / アデノシン三リン酸 (adenosine triphosphate)

Tadashi Enomoto, Hiroshi Yamada, Junji Chida, Siye Wang and Hiroshi Kido :
Mechanism of augmentation of symptomatic of influenza virus infection by antipyretic, diclophenac.,
第30回日本分子生物学会，第80回日本生化学会大会, Dec. 2007.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / サイトカイン (cytokine) / 血液脳関門 (blood-brain barrier)

Junji Chida, Tadashi Enomoto, Yuushi Ohnishi, Mariam Nasreen and Hiroshi Kido :
Down-regulation of mitochondrial related-genes by influenza virus infection and pathological role of them in multi-organ failure after virus infection.,
第30回日本分子生物学会年会，第80回日本生化学会大会, Dec. 2007.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / 多臓器不全 (multiple organ failure) / ミトコンドリア (mitochondria)

千田淳司, 榎本匡志, 山口美代子, 岡田清考, 木戸博 :
プラスミノーゲン欠損マウスを用いたインフルエンザウイルスの増殖機構の解析,
第12回病態と治療におけるプロテアーゼとインヒビター学会, 2007年6月.

(キーワード): インフルエンザ脳症 (influenza-associated encephalopathy) / ノックアウトマウス (knockout mice) / トリプシン (trypsin)

前田靖男, 千田淳司, 平田香, 森田強, 山口ひとみ, 雨貝愛子 :
細胞性粘菌を用いた研究で明らかになったミトコンドリアの多彩な機能,
第18回日本植物支部大会, 2005年12月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 田中雅嗣, 雨貝愛子, 前田靖男 :
MtDNA による増殖/分化の統御, --- 細胞性粘菌の発生系を用いた研究 ---,
第69回日本植物学会大会, 2005年9月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 田中雅嗣, 雨貝愛子, 前田靖男 :
粘菌細胞の分化・パターン形成におけるミトコンドリア遺伝子 (mtDNA) の重要性,
第38回日本発生生物学会大会, 2005年6月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 田中雅嗣, 雨貝愛子, 前田靖男 :
ミトコンドリア遺伝子の機能解析を実現するシステムの確立, --- 細胞性粘菌を用いた研究 ---,
第17回日本植物支部大会, 2004年12月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 山口ひとみ, 雨貝愛子, 前田靖男 :
細胞性粘菌の分化統御面における mtDNA の多面的な機能,
第16回日本植物支部大会, 2003年12月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 永井大樹, 前田靖男, 浅井圭介 :
酸素消光を利用した生体組織内におけるモルフォゲン分布パターンの可視化法の確立,
第31回可視化情報学会, 2003年11月.

(キーワード): 酸素センサー / ミトコンドリア (mitochondria) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 山口ひとみ, 雨貝愛子, 前田靖男 :
分化・パターン形成の制御における mtDNA の必要性, --- ρΔ 細胞を用いた解析 ---,
第15回日本植物形態学会大会, 2003年9月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 山口ひとみ, 雨貝愛子, 前田靖男 :
Dictyostelium discoideum の分化・形態形成における mtDNA の多面的な機能,
第67回日本植物学会大会, 2003年9月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 雨貝愛子, 田中雅嗣, 前田靖男 :
発生研究モデルとしての細胞性粘菌ミトコンドリアゲノム欠損株の有用性,
第2回日本ミトコンドリア学会, 2002年12月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 雨貝愛子, 田中雅嗣, 前田靖男 :
発生研究のシステムとしての細胞性粘菌 mt ゲノム欠損株の有用性,
第15回日本植物学会支部大会, 2002年11月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

研究会・報告書

千田淳司, 原英之, 坂口末廣 :
肺で発現する正常プリオン蛋白質の機能解析,
第32回中国四国ウイルス研究会, 2017年6月. 千田淳司, 永井大樹, 瀧浦晃基, 雨貝愛子, 前田靖男, 浅井圭介 :
粘菌の細胞集団における酸素圧の部域的差異, --- 光学的酸素センサーによる可視化と分化との相関 ---,
第8回細胞性粘菌研究会, 2005年11月.

(キーワード): 酸素センサー / ミトコンドリア (mitochondria) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 田中雅嗣, 雨貝愛子, 前田靖男 :
細胞性粘菌を用いた研究で明らかになったミトコンドリアの多彩な機能,
第8回細胞性粘菌研究会, 2005年11月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

千田淳司, 山口ひとみ, 雨貝愛子, 前田靖男 :
Mitochondrial genome DNA (mtDNA) is required for normal development of Dictyostelium discoideum cells.,
第6回細胞性粘菌研究会, 2004年3月.

(キーワード): ミトコンドリア (mitochondria) / ミトコンドリアDNA (mitochondrial DNA) / 細胞性粘菌 (Dictyostelium discoideum)

森尾貴広, Chad Shaw, 千田淳司, Nancy Van Driessche, 加藤真理子, Miroslava Ibarra, Sujata Sharma, Engi Okyay, 雨貝愛子, 漆原秀子, Adam Kusupa, 前田靖男, Gad Shaulsky :
細胞性粘菌の細胞周期における遺伝子発現プロファイルの解析,
第5回細胞性粘菌研究会, 2003年3月.

(キーワード): 細胞性粘菌 (Dictyostelium discoideum)

特許: 坂口末廣, 千田淳司 : 非アルコール性脂肪肝炎を治療または予防するための医薬組成物, (2022年1月), (2023年8月), 特許第2022-008773号 (2022年1月). 坂口末廣, 千田淳司 : 抗プリオン蛋白質抗体とその用途, (2015年4月), 特許第2015-077742号 (2015年4月). 石田晃彦, 花田祐紀, 木戸博, 千田淳司, 谷博文, 渡慶次学 : 血液検体のATP測定方法及びキット, 特願2013-174874 (2013年8月), 特開2015-42156 (2015年3月), 特許第2013-174874号 (2013年8月). 木戸博, 千田淳司, 山根一彦, 大村智, 中野洋文, 山地賢三郎, 山本剛 : PDK4阻害剤及びその利用, (2012年4月), 特開WO2013/153821 A1 (2013年10月), 特許第PCT/JP2013/002500号 (2013年4月). 木戸博, 西村匡司, 千田淳司 : 病気の重症度の検査方法, 特願PCT/JP2011/002979 (2011年5月), 特開WO2011/152012 A1 (2011年12月), 特許第2010-125354号 (2010年5月). 木戸博, 千田淳司, 塙雅明, 山本善一, 井紀孝, 角田健司 : インフルエンザの治療剤または予防剤, 特願2011-15729 (2011年1月), 特開WO2012/101846 (2012年8月), 特許第PCT/JP2011/067321号 (2011年7月). 木戸博, 千田淳司, 武井恒知 : ヌクレオチドの抽出方法, 特願PCT/JP2009/51364 (2009年1月), 特開WO 2009/096429 A1 (2009年8月), 特許第2008-017863号 (2008年1月).
作品: 研究者総覧に該当データはありませんでした。
補助金・競争的資金: プリオン病の予防・治療法開発を目指したプリオン以外の病原体の究明と病態解明研究 (研究課題/領域番号: 23H02798 )
宿主の炎症性マクロファージを標的とした新興感染症に対する原因療法の開発 (研究課題/領域番号: 22K08600 )
プリオン蛋白質を分子標的としたインフルエンザ重症化の新規治療法の開発 (研究課題/領域番号: 19K08930 )
プリオン病の神経細胞障害のメカニズム解明とその障害を改善する化合物の探索 (研究課題/領域番号: 19H03548 )
微生物に由来する新規ガン抑制因子の作用機構の解析 (研究課題/領域番号: 16K15130 )
肺のプリオン蛋白質を分子標的としたインフルエンザ重症化予防の確立 (研究課題/領域番号: 16K10029 )
プリオン病の新規病態として発見した細胞膜蛋白質の小胞輸送障害のメカニズム解明 (研究課題/領域番号: 26293212 )
プリオン蛋白質欠損マウスを用いた、インフルエンザ脳症の発症機序の解明 (研究課題/領域番号: 25461596 )
インフルエンザ重症患児で認められる体内代謝破綻の修復を目指す新規治療法の開発 (研究課題/領域番号: 23791180 )
集中治療患者の重症度診断リアルタイム・バイオマーカーの創出と診断機器開発研究 (研究課題/領域番号: 23659846 )
インフルエンザとエイズ感染の重症化を決定する致死的宿主応答因子の解析と治療法開発 (研究課題/領域番号: 23591477 )
インフルエンザ脳症を誘発する感受性因子の解明を基盤にした診断・治療法の開発 (研究課題/領域番号: 21790992 )
高病原性鳥インフルエンザウイルスの細胞侵入、感染増悪機序を基盤とした新治療法開発 (研究課題/領域番号: 21249061 )
インフルエンザ脳症発症を誘起する感受性因子の解明を基盤にした治療法の開発 (研究課題/領域番号: 19790724 )
研究者番号（20437651）による検索

その他: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2024年5月17日更新

専門分野・研究分野: 小児感染症学
生化学 (Biochemistry)
所属学会・所属協会: 国際プロテアーゼ学会
日本生化学会
日本ミトコンドリア学会
病態と治療におけるプロテアーゼとインヒビター学会
日本植物学会
日本分析化学会
委員歴・役員歴: 研究者総覧に該当データはありませんでした。
受賞: 最優秀学術賞 (社団法人日本植物学会)
Asian Mitochondrial Young Investigator Awards (アジアミトコンドリア研究医学会)
東北大学大学院学科長賞 (理学研究科)
研究奨励賞 (病態と治療におけるプロテアーゼとインヒビター学会)
活動: 研究者総覧に該当データはありませんでした。

リサーチマップで最新データを確認するＪグローバルで最新データを確認する

2024年5月12日更新

2024年5月18日更新

Ｊグローバル

Jグローバル最終確認日: 2024/5/18 01:25
氏名（漢字）: 千田淳司
氏名（フリガナ）: チダジュンジ
氏名（英字）: Chida Junji
所属機関: 徳島大学

リサーチマップ

researchmap最終確認日: 2024/5/12 01:43
氏名（漢字）: 千田淳司
氏名（フリガナ）: チダジュンジ
氏名（英字）: Chida Junji
プロフィール: リサーチマップAPIで取得できませんでした。
登録日時: 2018/11/19 17:12
更新日時: 2024/2/1 23:59
アバター画像URI: https://researchmap.jp/rmjc/avatar.jpg
ハンドル: リサーチマップAPIで取得できませんでした。
eメール: リサーチマップAPIで取得できませんでした。
eメール（その他）: リサーチマップAPIで取得できませんでした。
携帯メール: リサーチマップAPIで取得できませんでした。
性別: リサーチマップAPIで取得できませんでした。
没年月日: リサーチマップAPIで取得できませんでした。
所属ID: 0344000000
所属: 徳島大学
部署: 次世代酵素学研究領域神経変性病態学分野
職名: リサーチマップAPIで取得できませんでした。
学位: リサーチマップAPIで取得できませんでした。
学位授与機関: リサーチマップAPIで取得できませんでした。
URL: リサーチマップAPIで取得できませんでした。
科研費研究者番号: リサーチマップAPIで取得できませんでした。
Google Analytics ID: リサーチマップAPIで取得できませんでした。
ORCID ID: リサーチマップAPIで取得できませんでした。
その他の所属ID: リサーチマップAPIで取得できませんでした。
その他の所属名: リサーチマップAPIで取得できませんでした。
その他の所属部署: リサーチマップAPIで取得できませんでした。
その他の所属職名: リサーチマップAPIで取得できませんでした。
最近のエントリー: リサーチマップAPIで取得できませんでした。
Read会員ID: リサーチマップAPIで取得できませんでした。
経歴
受賞
Misc
論文
講演・口頭発表等: リサーチマップAPIで取得できませんでした。
書籍等出版物: リサーチマップAPIで取得できませんでした。
研究キーワード
研究分野
所属学協会
担当経験のある科目: リサーチマップAPIで取得できませんでした。
その他: リサーチマップAPIで取得できませんでした。
Works: リサーチマップAPIで取得できませんでした。
特許
学歴
委員歴: リサーチマップAPIで取得できませんでした。
社会貢献活動: リサーチマップAPIで取得できませんでした。

ＫＡＫＥＮで最新データを確認する

2024年5月18日更新

研究者番号: 20437651

所属（現在）: 2024/4/1 : 徳島大学, 先端酵素学研究所, 講師

所属（過去の研究課題 情報に基づく）*注記: 2022/4/1 – 2023/4/1 : 徳島大学, 先端酵素学研究所, 講師
2021/4/1 : 徳島大学, 先端酵素学研究所, 助教
2016/4/1 – 2020/4/1 : 徳島大学, 先端酵素学研究所(次世代), 助教
2008/4/1 – 2017/4/1 : 徳島大学, 疾患酵素学研究センター, 助教
2016/4/1 : 徳島大学, 先端酵素学研究所, 助教
2007/4/1 : 徳島大学, 疾患酵素学研究センター, 科学技術振興研究員

審査区分/研究分野

研究代表者

生物系 / 医歯薬学 / 内科系臨床医学 / 小児科学
小区分54030:感染症内科学関連

研究代表者以外

生物系 / 医歯薬学 / 内科系臨床医学 / 感染症内科学
生物系 / 医歯薬学 / 外科系臨床医学 / 救急医学
生物系 / 医歯薬学 / 内科系臨床医学 / 神経内科学
生物系 / 医歯薬学 / 薬学 / 天然資源系薬学
小区分51030:病態神経科学関連

キーワード

研究代表者

インフルエンザ / 脳症 / 多臓器不全 / ミトコンドリア / 脂肪酸代謝不全 / ATP / MOF(多臓器不全) / ATP(アデノシン三リン酸) / サイトカイン / 分子生物学 / インフルエンザ脳症(IAE) / 多臓器不全(MOF) / アデノシン三リン酸(ATP) / 脂肪酸代謝 / 脂肪酸代謝障害 / 多臓器不全 (MOF) / アデノシン三リン酸 (ATP) / アデノシン三リン酸 / プリオン蛋白質 / 抗プリオン抗体 / プリオン / 抗PrP抗体 / インフルエンザウイルス / インフルエンザ脳症 / SFKs / 重症化 / エネルギー代謝 / インフルエンザAウイルス / 換気障害 / 浮腫 / 活性酸素 / 抗酸化酵素 / 銅イオン / Src family kinase / SFK蛋白質 / マクロファージ / SFKタンパク質 / 炎症性サイトカイン / Src / Src蛋白質 / 抗体療法 / 新興感染症

研究代表者以外

高病原性鳥インフルエンザ / プロセシングプロテアーゼ / 多臓器不全 / サイトカインストーム / トリプシン / MMP-9 / ミトコンドリア膜電位 / ATP産生 / MMP-97 / 高病原も生鳥インフルエンザ / インフルエンザ脳症 / エイズ脳症 / プロテアーゼ / ストレス蛋白質 / 集中治療室 / ATP / 乳酸 / 重症度 / リアルタイム・バイオマーカー / 予後判定 / エネルギー代謝 / 代謝障害 / 予后判定 / プリオン / プリオン病 / ソーチリン / 蛋白質輸送 / 蛋白質分解 / ノックアウトマウス / 神経変性疾患 / プリオン蛋白質 / トランスジェニックマウス / アトラクチン / インスリン受容体 / ポストゴルジ小胞輸送 / 神経変性 / 小胞輸送 / 細胞膜蛋白質 / Tgマウス / ポストゴルジ輸送 / ガン抑制因子 / 細胞性粘菌 / ガン抑制遺伝子 / 微生物由来ガン抑制因子 / エタノールアミン / インフルエンザウイルス / 神経細胞死

研究課題研究成果共同研究者

「研究課題をさがす」で表示
テキスト（CSV）で出力

テキスト（CSV）で出力

注目研究はありません。

研究者を探す

千田 淳司

Ｊグローバル

リサーチマップ

研究代表者

研究代表者以外

研究代表者

研究代表者以外

千田淳司