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Isolation and characterization ofβ-transducin repeat-containing protein ligands screened using a high-throughput screening system

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Oncology Research 2023年第5期31卷 645-654页

作者： XINTONG LIU EMIKO SANADA JIANG LI XIAOMENG LI hiroyuki osada NOBUMOTO WATANABE Chemical Resource Development Research Unit RIKEN CSRSWakoSaitama351-0198Japan Department of RIKEN Molecular and Chemical Somatology Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityBunkyokuTokyo113-8510Japan Bioprobe Application Research Unit RIKEN CSRSWakoSaitama351-0198Japan Chemical Biology Research Group RIKEN CSRSWakoSaitama351-0198Japan Guangdong Engineering Research Center of Oral Restoration and Reconstruction Affiliated Stomatology Hospital of Guangzhou Medical UniversityGuangzhou510180China KingMed School of Laboratory Medicine Guangzhou Medical UniversityGuangzhou510182China Department of Pharmaceutical Sciences University of ShizuokaSuruga-kuShizuoka422-8526Japan

β-transducin repeat-containing protein(β-TrCP)is an F-box protein subunit of the E3 Skp1-Cullin-F box(SCF)type ubiquitin-ligase complex,and provides the substrate specificity for the *** find potent ligands ofβ-TrCP useful for the proteolysis targeting chimera(PROTAC)system usingβ-TrCP in the future,we developed a high-throughput screening system for small moleculeβ-TrCP *** screened the chemical library utilizing the system and obtained several hit *** effects of the hit compounds on in vitro ubiquitination activity of SCFβ-TrCP1 and on downstream signaling pathways were *** compounds NPD5943,NPL62020-01,and NPL42040-01 inhibited the TNFα-induced degradation of IκBαand its phosphorylated ***,they inhibited the activation of the transcription activity of NF-κB,indicating the effective inhibition ofβ-TrCP by the hit compounds in ***,we performed an in silico analysis of the hit compounds to determine the important moieties of the hit *** groups of NPL62020-01 and NPL42040-01 and hydroxyl groups of NPD5943 created hydrogen bonds withβ-TrCP similar to those created by intrinsic target phosphopeptides ofβ-*** findings enhance our knowledge of useful small molecule ligands ofβ-TrCP and the importance of residues that can be ligands ofβ-TrCP.

关键词： Ubiquitin F-box protein Chemical biology

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Identification of microbial metabolites that accelerate the ubiquitindependent degradation of c-Myc

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Oncology Research 2023年第5期31卷 655-666页

作者： ZIYU LIU AKIKO OKANO EMIKO SANADA YUSHI FUTAMURA TOSHIHIKO NOGAWA KOSUKE ISHIKAWA KENTARO SEMBA JIANG LI XIAOMENG LI hiroyuki osada NOBUMOTO WATANABE Bioprobe Application Research Unit RIKEN CSRSSaitama351-0198Japan Graduate School of Medical and Dental Sciences Tokyo Medical and Dental UniversityTokyo113-8510Japan Chemical Biology Research Group RIKEN CSRSSaitama351-0198Japan Chemical Resource Development Research Unit RIKEN CSRSSaitama351-0198Japan Molecular Structure Characterization Unit RIKEN CSRSSaitama351-0198Japan Japan Biological Informatics Consortium(JBIC) Tokyo135-8073Japan Department of Life Science and Medical Bioscience School of Advanced Science and EngineeringWaseda UniversityTokyo162-8480Japan Medical-Industrial Translational Research Center Fukushima Medical UniversityFukushima960-1295Japan Guangdong Engineering Research Center of Oral Restoration and Reconstruction Affiliated Stomatology Hospital of Guangzhou Medical UniversityGuangzhouChina KingMed School of Laboratory Medicine Guangzhou Medical UniversityGuangzhouChina Department of Pharmaceutical Sciences University of ShizuokaShizuoka422-8526Japan

Myc belongs to a family of proto-oncogenes that encode transcription *** overexpression of c-Myc causes many types of ***,we established a system for screening c-Myc inhibitors and identified antimycin A by screening the RIKEN NPDepo chemical *** specific mechanism of promoting tumor cell metastasis by high c-Myc expression remains to be *** this study,we screened approximately 5,600 microbial extracts using this system and identified a broth prepared from Streptomyces ***19-A0402 strongly inhibits c-Myc transcriptional *** purification of the hit broth,we identified compounds closely related to the aglycone of cytovaricin and had a structure similar to that of oligomycin *** to oligomycin A,the hit compounds inhibited mitochondrial complex *** mitochondria dysfunction caused by the compounds induced the production of reactive oxygen species(ROS),and the ROS activated GSK3α/βthat phosphorylated c-Myc for *** study provides a successful screening strategy for identifying natural products as potential c-Myc inhibitors as potential anticancer agents.

关键词： High-throughput screening Phosphorylation Reactive oxygen species

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Identification of a dihydroorotate dehydrogenase inhibitor thatinhibits cancer cell growth by proteomic profiling

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Oncology Research 2023年第6期31卷 833-844页

作者： MAKOTO KAWATANI HARUMI AONO SAYOKO HIRANUMA TAKESHI SHIMIZU MAKOTO MUROI TOSHIHIKO NOGAWA TOMOKAZU OHISHI SHUN-ICHI OHBA MANABU KAWADA KANAMI YAMAZAKI SHINGO DAN NAOSHI DOHMAE hiroyuki osada Biomolecular Characterization Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Chemical Resource Development Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Chemical Biology Research Group RIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Molecular Structure Characterization Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Institute of Microbial Chemistry(BIKAKEN) NumazuMicrobial Chemistry Research FoundationShizuoka410-0301Japan Division of Molecular Pharmacology Cancer Chemotherapy CenterJapan Foundation for Cancer ResearchTokyo135-8550Japan Department of Pharmaceutical Sciences University of ShizuokaShizuoka422-8526Japan

Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune *** study presents the identification of a potent DHODH inhibitor by proteomic ***-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer *** profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic ***,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic *** results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell ***,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.

关键词： Anticancer agents Differentiating agents Drug target identification

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SYNTHETIC HYDROGELS AS SCAFFOLDS FOR MANIPULATING ENDOTHELIUM CELL BEHAVIORS

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Chinese Journal of Polymer Science 2011年第1期29卷 23-41页

作者：陈咏梅 Yoshihito osada MOE Key Laboratory for Non-equilibrium Condensed Matter and Quantum Engineering Biomedical Engineering and Biomechanics CenterDepartment of ChemistrySchool of ScienceXi'an Jiaotong University Faculty of Advanced Life Science Hokkaido University RIKEN 2-1 HirosawaWakoSaitama 351-0198Japan

Synthetic hydrogels can be used as scaffolds that not only favor endothelial cells （ECs） proliferation but also manipulate the behaviors and functions of the ECs. In this review paper, the effect of chemical structure, Young＇s modulus （E） and zeta potential （ζ） of synthetic hydrogel scaffolds on static cell behaviors, including cell morphology, proliferation, cytoskeleton structure and focal adhesion, and on dynamic cell behaviors, including migration velocity and morphology oscillation, as well as on EC function such as anti-platelet adhesion, are reported. It was found that negatively charged hydrogels, poly（2-acrylamido-2-methylpropanesulfonic sodium）（PNaAMPS） and poly（sodium p-styrene sulphonate）（PNaSS）, can directly promote cell proliferation, with no need of surface modifcation by any cell-adhesive proteins or peptides at the environment of serum-containing medium. In addition, the Young＇s modulus （E） and zeta potential （ζ） of hydrogel scaffolds are quantitatively tuned by copolymer hydrogels, poly（NaAMPS-co-DMAAm） and poly（NaSS-co-DMAAm）, in which the two kinds of negatively charged monomers NaAMPS and NaSS are copolymerized with neutral monomer, N,N-dimethylacrylamide （DMAAm）. It was found that the critical zeta potential of hydrogels manipulating EC morphology, proliferation, and motility is ζcritical= -20.83 mV and ζcritical = -14.0 mV for poly（NaAMPS-co-DMAAm） and poly（NaSS-co-DMAAm）, respectively. The above mentioned EC behaviors well correlate with the adsorption of fibronectin, a kind of cell-adhesive protein, on the hydrogel surfaces. Furthermore, adhered platelets on the EC monolayers cultured on the hydrogel scaffolds obviously decreases with an increase of the Young＇s modulus （E） of the hydrogels, especially when E 〉 60 kPa. Glycocalyx assay and gene expression of ECs demonstrate that the anti-platelet adhesion well correlates with the EC-specific glycocalyx. The above investigation suggests that understanding the relationship between physic-chem

关键词： Synthetic hydrogel Scaffold Endothelial cell Cell behavior.

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Methane, Nitrous Oxide and Ammonia generation in full-scale swine wastewater purification facilities

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Frontiers of Environmental Science & Engineering 2017年第3期11卷 115-122页

作者： Takashi osada Makoto Shiraishi Teruaki Hasegawa Hirofumi Kawahara National Agriculture and Food Research Organization Tsukuba Ibaraki 305-0005 Japan Okayama Prefectural Center for Animal Husbandry Research Misaki Okayama 709-3401 Japan Chiba Prefectural Livestock Research Center Yachimata Chiba 289-1113 Japan Saga Prefectural Higashimastuura Agricultural Development and Extension Center Karatsu Saga 847-0861 Japan

The activated sludge process to remove nitrogen and biochemical oxygen demand （BOD） is reportedly cost-effective for swine wastewater treatment, and it use has thus increased in pig farming. Nitrous oxide （N20） is generated on farms as an intermediate product in nitrification and denitrification, and methane （CH4） is also generated from organic degradation under anaerobic conditions by microorganisms in manure or wastewater. This study was carried out at five activated sludge treatment facilities across Japan between August 2014 and January 2015. Measurements were conducted over several weeks at wastewater purification facilities for swine farms： two in Chiba prefecture （East Japan）, two in Okayama prefecture （West Japan）, and one in Saga （Southern Japan）. Taking several environmental fluctuations into account, we collected measurement data continuously day and night, during both high-temperature and low-temperature periods. The results indicated that CH4 and N20 emission factors were 0.91% （kgCHa·kg volatile solids^-1） and 2.87% （g N2O-N·kg total N^-1）, respectively. Ammonia emissions were negligible in all of the measurements from the wastewater facilities. The N20 emission factor calculated under this experiment was low compared to our previous finding （5.0%; g N2O-N·kg N^-1） in a laboratory experiment. In contrast, the CH4 emission factor calculated herein was rather high compared to the laboratory measurements. There was great variation in daily GHG emission factors measured in the actual wastewater treatment facilities. In particular, the N2O emission rate was affected by several environmental conditions at each facility location, as well as by the management of the wastewater treatment.

关键词： Manure Greenhouse gas Denitrification BOD/NNitrous oxide Methane

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Scaling relation of domain competition on(2+1)-dimensional ballistic deposition model with surface diffusion

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Journal of Semiconductors 2016年第9期37卷 12-17页

作者： Kenyu osada Hiroyasu Katsuno Toshiharu Irisawa Yukio Saito Department of Physics Gakushuin University Computer Centre Gakushuin University Department of Physical Science Ritsumeikan University Department of Physics Keio University

During heteroepitaxial overlayer growth multiple crystal domains nucleated on a substrate surface compete with each other in such a manner that a domain covered by neighboring ones stops *** number density of active domains ρ decreases as the height h increases.A simple scaling argument leads to a scaling law of ρ~ h^（-γ） with a coarsening exponent γ=d/z,where d is the dimension of the substrate surface and z the dynamic exponent of a growth *** scaling relation is confirmed by performing kinetic Monte Carlo simulations of the ballistic deposition model on a two-dimensional（d=2） surface,even when an isolated deposited particle diffuses on a crystal surface.

关键词： domain competition ballistic deposition model Kardar-Parisi-Zhang universality class surface diffusion

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SURFACE DYNAMIC FRICTION OF POLYMER GELS

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Chinese Journal of Polymer Science 2000年第3期18卷 271-275页

作者： J.P.Gong G.KagatavY.Iwasaki Y.osada Graduate School of Science Hokkaido University Sapporo 060-0810 JapanGraduate School of Science Hokkaido University Sapporo 060-0810 JapanGraduate School of Science Hokkaido University Sapporo 060-0810 Japan

The sliding friction of various kinds of hydrogels has been studied and it was found that the frictional behaviors ofthe hydrogels do not conform to Amonton's law F=μW which well describes the friction of solids. The frictional force andits dependence on the load are quite different depending on the chemical structures of the gels, surface properties of theopposing substrates, and the measurement condition. The gel friction is explained in terms of interracial interaction, eitherattractive or repulsive, between the polymer chain and the solid surface. According to this model, the friction is ascribed tothe viscous flow of solvent at the interface in the repulsive case. In the attractive case, the force to detach the adsorbing chainfrom the substrate appears as friction. The surface adhesion between glass particles and gels measured by AFM showed agood correlation with the friction, which supported the repulsion-adsorption model proposed by the authors.

关键词： Polymer gels Surface dynamic friction Repulsion-adsorption model

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SUPER TOUGH GELS WITH A DOUBLE NETWORK STRUCTURE

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Chinese Journal of Polymer Science 2009年第1期27卷 1-9页

作者： Tasuku Nakajima Takayuki Kurokawa Hidemitsu Furukawa Yoshimi Tanaka Yoshihito osada 龚剑萍 Department of Biological Sciences Graduate School of ScienceHokkaido University

Living tissues work with fantastic functions in soft and wet gel-like ***,hydrogels have attracted much attention as excellent soft and wet materials,suitable tot making artificial organs for medical ***, conventional hydrogels are mechanically too weak for practical *** have created double network (DN) hydrogels with extremely high mechanical strength in order to overcome this *** gels are interpenetrating network (IPN) hydrogels consisting of rigid polyelectrolyte and soft...

关键词： Hydrogel Toughness Fracture Necking phenomenon

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Asian international grid connection and potentiality of DC superconducting power transmission

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Global Energy Interconnection 2018年第1期1卷 11-19页

作者： Satarou Yamaguchi Takashi Iitsuka Masashi osada Ryuichi Yokoyama Chubu University Matsumoto-cho 1200Kasugai487-8500AichiJapan JGC Corporation Minato Mirai 2-3-1Nishi-kuYokohama 220-6001Japan ABB K.K. Ohsaki 2-1-1Shinagawa-ku141-6022 TokyoJapan Energy and Environment Technology Research Institute 1-22-2 Nishiwaseda Shinjuku169-0051 TokyoJapan

In 2011, a large scale earthquake and tsunami hit the northeastern coast of Japan, and nuclear plants were damaged to a large extent. Before the Tsunami, 54 nuclear plants were operated, however presently, only three nuclear plants are in operation. Therefore, Japan is suffering from high price of electricity and low supply reliability. In generation mix, nuclear plants generate only one percent and 87 percent of electricity is generated by fossil energy. This is not preferable for Japan from the viewpoints of energy security and stable electricity supply. Therefore, it is mandatory to increase sustainable energy and to decrease consumption of fossil fuel. International grid connection and the Global Energy Interconnection will be one of countermeasures against these problems existing in Japan. In this paper, international grid connection initiatives proposed in Asia are described and features and issues of electric power grids in Japan are discussed to implement the international grid connection. As the key technology for implementing the international grid connection, the present status of DC superconducting power transmission lines and power converters for long-distance power transmission lines are presented. In conclusion, conditions and legal frameworks for realizing the international grid connection are described.

关键词： International grid connection Global Energy Interconnection Sustainable energy DC superconducting Power converter

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Aberrant Light-Induced Depression is Associated with Impaired Sensorimotor Gating in Mice

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World Journal of Neuroscience 2018年第1期8卷 1-9页

作者： Toshiaki Haga Junichi Toei Kenichi Mitsui Mareki Ohtsuji Yo Kodera Kenichi osada hiroyuki Nishimura Department of Biomedical Engineering Toin University of Yokohama Yokohama Japan Department of Neuropsychiatry St. Marianna University School of Medicin Kawasaki Japan

Mice subjected to an irregular light-dark cycle are known to lose their capacity to synchronize their behavioral rhythm to environmental light, and to show endophenotypes related to depressive disorders. Here we observed that a susceptible strain of mice (C3H/HeJ) subjected to an irregular 3.5 hr:3.5 hr light-dark cycle showed an enhanced acoustic startle reflex and deficits in prepulse inhibition. As impaired sensorimotor gating is associated with the onset of a variety of mental disorders such as schizophrenia and major depressive disorder, irregular environmental light without circadian photo-entrainment may cause stress that has the potential to be involved in humans’ susceptibility to neuropsychiatric abnormalities.

关键词： Depression Sensorimotor Gating C3H/HeJ Prepulse Inhibition Circadian Rhythm

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