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International Journal of Oral Science 2024年第3期16卷 499-514页

作者： Tokuju Okano Hiroshi Ashida Noriko Komatsu Masayuki Tsukasaki Tamako Iida Marie Iwasawa Yuto Takahashi Yasuo Takeuchi Takanori Iwata Miwa Sasai Masahiro Yamamoto Hiroshi takayanagi Toshihiko Suzuki Department of Bacterial Pathogenesis Infection and Host ResponseGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoTokyoJapan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoTokyoJapan Department of Lifetime Oral Health Care Science Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Periodontology Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan Department of Immunoparasitology Research Institute for Microbial DiseasesOsaka UniversityOsakaJapan

Clinical studies have shown that Aggregatibacter actinomycetemcomitans(***)is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis(RA).However,the mechanism is poorly ***,we show that systemic infection with *** triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis(CAIA)model following IL-1βsecretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in *** administration of polymyxin B(PMB),chloroquine,and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice,suggesting that the recognition of lipopolysaccharide(LPS)in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in *** data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with *** work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with ***.

关键词： CD11b inflam infection

The neutrophil–osteogenic cell axis promotes bone destruction in periodontitis

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International Journal of Oral Science 2024年第1期16卷 154-162页

作者： Yutaro Ando Masayuki Tsukasaki Nam Cong-Nhat Huynh Shizao Zang Minglu Yan Ryunosuke Muro Kazutaka Nakamura Masatsugu Komagamine Noriko Komatsu Kazuo Okamoto Kenta Nakano Tadashi Okamura Akira Yamaguchi Kazuyuki Ishihara Hiroshi takayanagi Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of Tokyo7-3-1HongoBunkyo-kuTokyoJapan Department of Microbiology Tokyo Dental College2-1-14 Kanda-Misaki-choChiyoda-kuTokyoJapan Oral Health Science Center Tokyo Dental College2-9-18Kanda-Misaki-choChiyodakuTokyoJapan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of Tokyo7-3-1HongoBunkyo-kuTokyoJapan Unit of Prosthodontics Laboratory of Oral-Maxillofacial Biology Faculty of Odonto-StomatologyUniversity of Medicine and Pharmacy at Ho Chi Minh CityHo Chi Minh CityVietnam Department of Oral and Maxillofacial Surgery Department of Sensory and Motor System MedicineGraduate School of MedicineThe University of TokyoTokyoJapan Division of Rheumatology Department of Internal MedicineKeio University School of MedicineTokyoJapan Department of Laboratory Animal Medicine Research InstituteNational Center for Global Health and MedicineTokyoJapan

The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune–bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNAsequencing analysis on mouse periodontal lesions and showed that neutrophil–osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.

关键词： period neutrophil destruction

SOME COLLISION PROCESSES IN PLASMAS WITH HIGHER TEMPERATURE AND DENSITY

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原子与分子物理学报 1990年第4期7卷 1561-1564页

作者： Kazuo takayanagi

Some collision processes important in hot and dense plasmas are *** calculation of secondary electron velocity distribution in ionizing collision between an electron and a multiply-charged ion is reported.

关键词：等离子体高温高密度碰撞过程

Influence of oxygen exposure on instabilities of perfluoropentacene transistor characteristics with different gate insulators

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Progress in Natural Science:Materials International 2011年第1期21卷 12-16页

作者： Hideharu UEKI Hiroaki YANO Hirokuni OHUCHI Yutaro takayanagi Yasushiro NISHIOKA Department of Precision Machinery College of Science and TechnologyNihon UniversityChiba 274-8501Japan

Pentacene for p-channel organic field effect transistors（OTFTs） and perfluoropentacene for n-channel OTFTs have attracted strong attentions to be used as CMOS type organic semiconductor materials for flexible organic displays.n-channel OTFTs with different gate insulators of polyimide（PI） and SiO2and perfluoropentacene as a semiconductor layer were fabricated,and their instability of the transistor characteristics measured in air,vacuum and oxygen was *** results show that both of the transistors exhibit a significant increase of mobility when measured in ***,the mobility of the transistors is significantly reduced when measured in pure oxygen,and the threshold voltages continuously *** phenomena may be related to water diffusion into the perfluoropentacene/gate insulator interface in air and oxidation of perfluoropentacene in oxygen.

关键词： oxygen exposure OTFT perfluoropentacene gate insulator polyimide SiO2

Lysophosphatidic acid induced nuclear translocation of nuclear factor-κB in Panc-1 cells by mobilizing cytosolic free calcium

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World Journal of Gastroenterology 2008年第28期14卷 4473-4479页

作者： Yoshiyuki Arita Tetsuhide Ito Takamasa Oono Ken Kawabe Terumasa Hisano Ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical SciencesKyushu UniversityFukuoka 812-8582Japan

AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-κB (NF-κB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout the study. The expression of LPA receptors was confirmed by reverse-transcript polymerase chain reaction (RT-PCR). Cytosolic free calcium was measured by fluorescent calcium indicator fura-2, and the localization of NF-κB was visualized by immunofluorescent method with or without various agents, which effect cell signaling. RESULTS: Panc-1 expressed LPA receptors, LPA1, LPA2 and LPA3. LPA caused the elevation of cytosolic free calcium dose-dependently. LPA also caused the nuclear translocation of NF-κB. Cytosolic free calcium was attenuated by pertussis toxin (PTX) and U73122, an inhibitor of phospholipase C. The translocation of NF-κB was similarly attenuated by PTX and U73122, but phorbol ester, an activator of protein kinase C, alone did not translocate NF-κB. Furthermore, the translocation of NF-κB was completely blocked by Ca2+ chelator BAPTA-AM. Thapsigargin, an endoplasmic- reticulum Ca2+-ATPase pump inhibitor, also promoted the translocation of NF-κB. Staurosporine, a proteinkinase C inhibitor, attenuated translocation of NF-κB induced by LPA. CONCLUSION: These findings suggest that protein kinase C is activated endogenously in Panc-1, and protein kinase C is essential for activating NF-κB with cytosolic calcium and that LPA induces the nuclear translocation of NF-κB in Panc-1 by mobilizing cytosolic free calcium.

关键词： Lysophosphatidic acid Nuclear translocation Nuclear factor-κB Cytosolic free calcium Panc-1

Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1αsignaling

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Bone Research 2022年第4期10卷 770-783页

作者： Takehito Ono Ryosuke Denda Yuta Tsukahara Takashi Nakamura Kazuo Okamoto Hiroshi takayanagi Tomoki Nakashima Department of Cell Signaling Graduate School of Medical and Dental SciencesTokyo Medical and Dental University(TMDU)Yushima 1-5-45Bunkyo-kuTokyo 113-8549Japan Department of Orthopaedic Surgery The Jikei University School of Medicine3-25-8 Nishi-ShimbashiMinato-kuTokyo 105-8461Japan School of Dentistry Tokyo Medical and Dental University(TMDU)Yushima 1-5-45Bunkyo-kuTokyo 113-8549Japan Department of Biochemistry Tokyo Dental CollegeKandamisakicho 2-9-18Chiyoda-kuTokyo 101-0061Japan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyo 113-0033Japan Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyo 113-0033Japan

Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming *** exercise at times can be an effective remedy for frailty,but exercise therapy cannot be applied in all clinical *** is safer than exercise,but there are no drugs that reinforce both muscle and bone when administered *** medications increase the risk of adverse events;thus,there is a need for individual drugs targeting both *** this end,we established a novel sequential drug screening system and identified an aminoindazole derivative,locamidazole(LAMZ),which promotes both myogenesis and osteoblastogenesis while suppressing *** of this drug enhanced locomotor function,with muscle and bone significantly ***,LAMZ induced Mef2c and PGC-1αin a calcium signaling–dependent *** this signaling is activated upon physical exercise,LAMZ mimics physical ***,LAMZ is a promising therapeutic drug for locomotor diseases,including sarcopenia and osteoporosis.

关键词： drugs clinical diseases

Chemoradiotherapy with twice-weekly administration of low-dose gemcitabine for locally advanced pancreatic cancer

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World Journal of Gastroenterology 2008年第34期14卷 5311-5315页

作者： Hisato Igarashi Tetsuhide Ito Ken Kawabe Terumasa Hisano Yoshiyuki Arita Toyoma Kaku Ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical ScienceKyushu University

AIM:To evaluate the chemoradiotherapy for locally advanced pancreatic cancer utilizing low dose gemcitabine as a radiation sensitizer administered twice weekly. METHODS: We performed a retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2. After that, maintenance systemic chemotherapy with gemcitabine, at a dose of 1000 mg/m2, was administered weekly for 3 wk with 1-wk rest until disease progression or unacceptable toxicity developed. RESULTS: Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled. Three of those patients could not continue with the therapy; one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis during an early stage of the therapy. The median survival was 15.0 mo and the overall 1-year survival rate was 60%, while the median progression-free survival was 8.0 mo. The subgroup which showed the reduction of tumor development, more than 50% showed a tendency for a better prognosis; however, other parameters including age, gender and performance status did not correlate with survival. The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 mo and 27.7 mo, ***: Chemoradiotherapy with low-dose gemcitabine administered twice weekly could be effective to patients with locally advanced pancreatic cancer; however, patients developing liver metastases had a worse prognosis. Another chemoradiotherapy strategy might be needed for those patients, such as administrating one or two cycles of chemotherapy initially, followed by chemoradiotherapy for the cases with no distant metastases.

关键词： Advanced pancreatic cancer Chemoradio-therapy Gemcitabine Radiosensitizer Tumor marker

Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans

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World Journal of Gastroenterology 2008年第42期14卷 6488-6495页

作者： Mikihiko Yasuda Tetsuhide Ito Takamasa Oono Ken Kawabe Toyoma Kaku Hisato Igarashi Taichi Nakamura Ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Fukuoka 812-8582 Japan

MM： To clarify whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of chronic pancreatitis （CP）. This study aimed at clarifying whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of CR METHODS： Serum monocyte chemoattractant protein-1 （MCP-1）, transforming growth factor beta-1 （TGF-βI）, and soluble type fractalkine （s-fractalkine） concentrations were examined in patients with CP （n = 109） and healthy controls （n = 116）. Severity of disease was classified in patients with CP by a staging system. Relationships between stage-specific various clinical factors and serum MCP-1, TGF-β1, and s-fractalkine levels were investigated. Furthermore, 57 patients with non-alcoholic CP were similarly evaluated in order to exclude influence of alcohol intake. RESULTS： Patients with CP showed significant higher levels of serum TGF-β1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-β1 in the severe stage and s-fractalkine in the mild and thesevere stage of CP significantly increased compared to those of controls. However, it was observed that both TGF-β1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-β1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed significant increase in the early stage of CP. CONCLUSION： It is suggested that the measurement of serum F-fractalkine is useful to diagnose early- stage CP. Moreover, the combined determination of both, s-fractalkine and TGF-β1, in human sera may be helpful in evaluating the severity status of CP.

关键词： Chronic pancreatitis Transforming growth factor beta-l Soluble fractalkine Monocyte chemoattractant protein-1

Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

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Bone Research 2019年第1期7卷 66-75页

作者： Yuta Nakai Kazuo Okamoto Asuka Terashima Shogo Ehata Jun Nishida Takeshi Imamura Takashi Ono Hiroshi takayanagi Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Orthodontic Science Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityYushima 1-5-45Bunkyo-kuTokyoJapan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Molecular Pathology Graduate School of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Molecular Medicine for Pathogenesis Ehime University Graduate School of MedicineShitsukawaToonEhimeJapan

Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant *** cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand(RANKL),which promotes osteoclast differentiation and ***-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth,causing bone pain and ***,RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor,*** inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis,and a human monoclonal anti-RANKL antibody,denosumab,has been used in the ***,orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to *** we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse *** administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced ***2676293 suppressed RANKLmediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10,which is known not to trigger osteoclast *** on the results from this study,RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.

关键词： Bone tumours metastasis