記述言語：日本語   出版者・発行元：日本エネルギー環境教育学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS INC  

In the NLR family, pyrin domain containing 3 (NLRP3) is an intracellular pattern recognition receptor that activates pro-caspase-1, leading to IL-1 beta and IL-18 processing and activation in a large complex called the NLRP3 inflammasome. Since various pathogens or endogenous metabolites have been reported to stimulate NLRP3 inflammasome, the interaction between NLRP3 and ASC induced by these stimulants may be an attractive drug target for NLRP3-related diseases, called inflammasomopathies. However, the endogenous ligand that directly interacts with NLRP3, leading to binding to ASC, remains unclear. Therefore, we developed a cell-free system consisting of NLRP3, ASC, and pro-caspase-1 or ASC and NLRP3 with an amplified luminescent proximity homogeneous assay (ALPHA). ALPHA signals of the interaction between NLRP3 and ASC were not enhanced following an incubation without any ligand, whereas strong ALPHA signals for the interaction between NLRP3 and ASC and between NLRP3 and pro-caspase-1 with the adaptor ASC were observed upon an incubation with poly (I:C) and hyaluronic acid (HA). Poly (I:C) and HA both directly interacted with NLRP3 within a specific concentration. These results suggest that NLRP3 directly interacts with intrinsic RNA and HA, which is followed by the activation of NLRP3 inflammasome, and the cell-free system consisting of NLRP3 and ASC, or NLRP3, ASC, and pro-caspase-1 may be a useful tool for elucidating the pathogenesis of inflammasomopathies and developing target therapeutics.

DOI： 10.1177/1721727X17711047

Web of Science

Scopus

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

This study examined the pathogenesis of early-onset sarcoidosis (EOS) in a patient with a rare NOD2 mutation and surveyed the literature to identify the hallmark features for early diagnosis. An infant girl suffering from prolonged fever and skin rash of multiple pinkish papules and subsequent erythema nodosum was referred to our institution. Skin biopsy and DNA sequencing were performed along with cytokine profiling of the patient's serum and stimulated mononuclear cells. NF-κB activation was analyzed using transfected cells. Multiple non-caseating granuloma inclusions were recognized in biopsy specimens obtained from the patient's rash. DNA sequencing revealed a very rare heterozygous Met513Thr (M513T) mutation in NOD2. Mononuclear cells produced a low amount of IL-1β upon stimulation as compared with normal control cells. Mutated NOD2 transfection enhanced NF-κB activation. We suspected that the M513T mutation in NOD2 decreased IL-1β production and enhanced NF-κB activation, which was likely responsible for the patient's granuloma involvement. A comprehensive review of the literature on 30 cases of sporadic type of EOS revealed that all patients had cutaneous manifestations, with all but one displaying granulation. A majority of EOS patients have R334W/Q. But about half of sporadic EOS had NOD2 mutations other than R334W/Q, as in the present case. Accordingly, skin rash with granuloma formation and specific NOD2 mutations may represent early diagnostic hallmarks of EOS in infants with persistent inflammation.

DOI： 10.1007/s10067-017-3544-6

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The inflammasome, typically consisting of a Nod-like receptor, apoptosis-associated speck-like protein, and pro-caspase-1, has recently been identified as a huge intracellular complex, which plays a crucial role in interleukin-1 maturation or specific physiological functions. Two Nod-like receptors, such as nucleotide-binding oligomerization domains-containing protein (Nod)1 and Nod2, interact with the receptor-interacting protein serine-threonine kinase (RIPK)2 accompanied by Iκ-B kinase (IKK) complexes to construct the nodosome, leading to nuclear factor (NF)-κB activation. The aberrant activation of inflammasomes or nodosomes causes autoinflammatory diseases. Therefore, inflammasomes may be attractive targets to treat autoinflammatory diseases. Our aim is to develop reconstituted inflammasomes in a cell-free system to discover specific molecular-target drugs and elucidate the molecular pathogenesis of autoinflammatory diseases. In this review, we describe reconstituted inflammasomes in a cell-free system.

DOI： 10.1186/s41232-017-0040-y

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA). Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.

DOI： 10.1155/2016/2597376

PubMed

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

The microphase separation of lipid molecules on a vesicle membrane can be induced, depending on the difference in the geometric structures of their headgroups. Through cryo-transmission-electron-microscopy analysis, a lens-like vesicle was prepared by mixing 50 wt% Span 40 (sorbitan monopalmitate) and 50 wt% Tween 40 [polyoxyethylene (20) sorbitan monopalmitate]. Considering the molecular structures of Span 40 and Tween 40, the high-curvature region was mainly formed by Tween 40. As determined by Fourier-transform infrared spectroscopy, dielectric-dispersion analysis, and differential scanning calorimetry, a hydration layer was likely formed because polyoxyethylene conjugates with the headgroups of Tween 40. These investigations of the obtained self-assembled aggregates of nonionic surfactants with heterogeneous surfaces could contribute to the development of new types of biomaterials.

DOI： 10.1016/j.colsurfb.2015.07.071

Web of Science

PubMed

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

Absent in melanoma 2 (AIM2) is an intracellular pattern-recognition receptor, which is a member of the PYHIN protein family, consisting of a PYD domain and an IFN-inducible nuclear localization (HIN) domain. AIM2 is reported to oligomerize with adaptor protein ASC upon sensing bacterial and viral cytosolic DNA in order to form the AIM2 inflammasome, which activates caspase-1 leading to IL-1β secretion. Dysregulation of AIM2 inflammasome is supposed to result in autoinflammatory and autoimmune diseases. Thus, the development of new targeted drugs against AIM2 inflammasome would be important for the treatment of these diseases. However, since AIM2 inflammasome is an intracellular receptor, enforced internalization of both ligands and candidate molecules is necessary for the screening of AIM2-inflammasome-targeted molecules. We developed a reconstituted AIM2 inflammasome in a cell-free system with amplified luminescent proximity homogeneous assay (Alpha). Strong Alpha signal was detected upon incubation with poly-deoxyadenylic-deoxythymidylic acid, poly(dA:dT), whereas no Alpha signal was detected upon incubation with muramyl dipeptide, one of the NLR ligands of Nod2 ligand. The interaction between AIM2 and ASC was disrupted by an anti-human ASC monoclonal antibody, CRID3, a class of diarylsulfonylurea-containing compounds, and glycyrrhizin, a substance found in liquorice root. Thus, the reconstituted AIM2 inflammasome in a cell-free system is useful for screening AIM2-inflammasome-targeted therapeutic molecules.

DOI： 10.1016/j.jim.2015.08.004

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

In recent years, chemotherapy with caffeine has manifested potently high efficacy against osteosarcoma, although adverse effects have been observed. Recently, we developed a novel drug delivery system (DDS) with nonionic vesicles prepared from Span 80 which have promising physicochemical properties as an attractive possible alternative to commonly used liposomes. Herein, we demonstrated that tumor-specific caffeine-potentiated chemotherapy for murine osteosarcoma administered by a novel DDS with Span 80 nano-vesicles showed significant antitumor effects as well as limited adverse effects. The osteosarcoma cell line, LM8, was transplanted into C3H/HeJ mice which then were administered therapeutic agents. Ifosfamide (IFO) was employed as well as caffeine as an enhancer. Span 80 vesicles containing IFO and/or caffeine were freshly prepared. On days 0, 2 and 4, different combinations of the agents were administered to mice: IFO alone (direct i.v.), IFO vesicles (IV), IV+caffeine, IV+caffeine vesicles (CV), PBS alone vesicles (PV), and PBS alone as negative control (PBS i.v.). Then, the mice were sacrificed on day 7. Antitumor effects of the reagents were also analyzed in vitro. Moreover, fertility examination was performed. In vitro, a combination of IV+CV showed significant induction of apoptosis in the early phase. Tumor volumes in the IV+CV group were significantly reduced compared with the other groups. Histological analyses showed that the IV and IV+CV groups had significantly lower viable tumor areas. The IFO direct i.v. group showed a certain grade of renal injury as well as marked suppression of spermatogenesis, while the IV or IV+CV group showed no marked changes. The fertility test revealed that the male mice with IV+CV administration had normal fertility, and no malformations were detected in their progeny. This DDS model is of potential importance for clinical application in the therapy of metastatic osteosarcoma.

DOI： 10.3892/or.2015.3761

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BENTHAM SCIENCE PUBL LTD  

Inflammation is a protective response to eliminate cytotoxic agents and pathogens. Various factors are thought to be involved in the pathological changes in tissues caused by inflammation. Interleukin 1, an inflammatory cytokine, is thought to have diverse physiological functions and to play an important role in inflammatory disease. In this review, we discuss interleukin-1 as a target of inflammatory disease.

DOI： 10.2174/1871530315666150316123657

Web of Science

PubMed

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(公社)日本生化学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：日本DDS学会  

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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記述言語：日本語   出版者・発行元：日本DDS学会  

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記述言語：日本語   出版者・発行元：公益社団法人 化学工学会  

DOI： 10.11491/scej.2009.0.724.0

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開催年月日： 2022年3月

会議種別：ポスター発表  

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開催年月日： 2021年9月

会議種別：ポスター発表  

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開催年月日： 2021年6月

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開催年月日： 2021年3月

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開催年月日： 2020年12月

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開催年月日： 2020年9月

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開催年月日： 2020年6月

会議種別：ポスター発表  

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開催年月日： 2019年10月

会議種別：ポスター発表  

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開催地：大阪  

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開催地：金沢  

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開催地：広島  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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開催地：岡山  

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開催地：神奈川  

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記述言語：日本語   会議種別：口頭発表（一般）  

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会議種別：ポスター発表  

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