start-ver=1.4 cd-journal=joma no-vol=96 cd-vols= no-issue= article-no= start-page=129536 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2023 dt-pub=20231115 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Direct evaluation of polarity of the ligand binding pocket in retinoid X receptor using a fluorescent solvatochromic agonist en-subtitle= kn-subtitle= en-abstract= kn-abstract=High selectivity of small-molecule drug candidates for their target molecule is important to minimize potential side effects. One factor that contributes to the selectivity is the internal polarity of the ligand-binding pocket (LBP) in the target molecule, but this is difficult to measure. Here, we first confirmed that the retinoid X receptor (RXR) agonist 6-(ethyl(1-isobutyl-2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)amino)nicotinic acid (NEt-iFQ, 1) exhibits fluorescence solvatochromism, i.e., its Stokes shift depends on the polarity of the solvent, and then we utilized this property to directly measure the internal polarity of the RXRα-LBP. The Stokes shift of 1 when bound to the RXRα-LBP corresponded to that of 1 in chloroform solution. This finding is expected to be helpful for designing RXR-selective ligands. A similar approach should be appliable to evaluate the internal polarity of the LBPs of other receptors. en-copyright= kn-copyright= en-aut-name=MiuraKizuku en-aut-sei=Miura en-aut-mei=Kizuku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujiharaMichiko en-aut-sei=Fujihara en-aut-mei=Michiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeMasaki en-aut-sei=Watanabe en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawasakiMayu en-aut-sei=Kawasaki en-aut-mei=Mayu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakanoShogo en-aut-sei=Nakano en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka kn-affil= affil-num=6 en-affil=Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=RXR kn-keyword=RXR en-keyword=Fluorescence kn-keyword=Fluorescence en-keyword=Solvatochromism kn-keyword=Solvatochromism en-keyword=Binding assay kn-keyword=Binding assay END start-ver=1.4 cd-journal=joma no-vol=65 cd-vols= no-issue=8 article-no= start-page=6039 end-page=6055 dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220411 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo en-subtitle= kn-subtitle= en-abstract= kn-abstract=Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize. en-copyright= kn-copyright= en-aut-name=KhazanNegar en-aut-sei=Khazan en-aut-mei=Negar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KimKyu Kwang en-aut-sei=Kim en-aut-mei=Kyu Kwang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HansenJeanne N. en-aut-sei=Hansen en-aut-mei=Jeanne N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SinghNiloy A. en-aut-sei=Singh en-aut-mei=Niloy A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MooreTaylor en-aut-sei=Moore en-aut-mei=Taylor kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SnyderCameron W. A. en-aut-sei=Snyder en-aut-mei=Cameron W. A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=PanditaRavina en-aut-sei=Pandita en-aut-mei=Ravina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=StrawdermanMyla en-aut-sei=Strawderman en-aut-mei=Myla kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiharaMichiko en-aut-sei=Fujihara en-aut-mei=Michiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=JianYe en-aut-sei=Jian en-aut-mei=Ye kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=BattagliaNicholas en-aut-sei=Battaglia en-aut-mei=Nicholas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YanoNaohiro en-aut-sei=Yano en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TeramotoYuki en-aut-sei=Teramoto en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ArnoldLeggy A. en-aut-sei=Arnold en-aut-mei=Leggy A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=HopsonRussell en-aut-sei=Hopson en-aut-mei=Russell kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KishorKeshav en-aut-sei=Kishor en-aut-mei=Keshav kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NayakSneha en-aut-sei=Nayak en-aut-mei=Sneha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=OjhaDebasmita en-aut-sei=Ojha en-aut-mei=Debasmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=SharonAshoke en-aut-sei=Sharon en-aut-mei=Ashoke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=AshtonJohn M. en-aut-sei=Ashton en-aut-mei=John M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=WangJian en-aut-sei=Wang en-aut-mei=Jian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=MilanoMichael T. en-aut-sei=Milano en-aut-mei=Michael T. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=MiyamotoHiroshi en-aut-sei=Miyamoto en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=LinehanDavid C. en-aut-sei=Linehan en-aut-mei=David C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=GerberScott A. en-aut-sei=Gerber en-aut-mei=Scott A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=KawarNada en-aut-sei=Kawar en-aut-mei=Nada kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=SinghAjay P. en-aut-sei=Singh en-aut-mei=Ajay P. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=TabdanovErdem D. en-aut-sei=Tabdanov en-aut-mei=Erdem D. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=DokholyanNikolay V. en-aut-sei=Dokholyan en-aut-mei=Nikolay V. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=JurutkaPeter W. en-aut-sei=Jurutka en-aut-mei=Peter W. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= en-aut-name=SchorNina F. en-aut-sei=Schor en-aut-mei=Nina F. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=33 ORCID= en-aut-name=Rowswell-TurnerRachael B. en-aut-sei=Rowswell-Turner en-aut-mei=Rachael B. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=34 ORCID= en-aut-name=SinghRakesh K. en-aut-sei=Singh en-aut-mei=Rakesh K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=35 ORCID= en-aut-name=MooreRichard G. en-aut-sei=Moore en-aut-mei=Richard G. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=36 ORCID= affil-num=1 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=2 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=3 en-affil=Department of Pediatrics, University of Rochester Medical Center kn-affil= affil-num=4 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=5 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=6 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=7 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=8 en-affil=Department of Biostatistics and Computational Biology, University of Rochester Medical Center kn-affil= affil-num=9 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Division of Surgery and of Microbiology and Immunology, University of Rochester Medical Center kn-affil= affil-num=12 en-affil=Division of Surgery and of Microbiology and Immunology, University of Rochester Medical Center kn-affil= affil-num=13 en-affil=Department of Surgery, Division of Surgical Research, Rhode Island Hospital, Alpert Medical School of Brown University kn-affil= affil-num=14 en-affil=Department of Pathology and Laboratory Medicine, University of Rochester Medical Center kn-affil= affil-num=15 en-affil=Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee kn-affil= affil-num=16 en-affil=Department of Chemistry, Brown University kn-affil= affil-num=17 en-affil=Department of Chemistry, Birla Institute of Technology kn-affil= affil-num=18 en-affil=Department of Chemistry, Birla Institute of Technology kn-affil= affil-num=19 en-affil=Department of Chemistry, Birla Institute of Technology kn-affil= affil-num=20 en-affil=Department of Chemistry, Birla Institute of Technology kn-affil= affil-num=21 en-affil=Genomics Core Facility, Wilmot Cancer Center, University of Rochester Medical Center kn-affil= affil-num=22 en-affil=Department of Pharmacology and Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State University kn-affil= affil-num=23 en-affil=Department of Radiation Oncology, University of Rochester Medical Center kn-affil= affil-num=24 en-affil=Department of Pathology and Laboratory Medicine, University of Rochester Medical Center kn-affil= affil-num=25 en-affil=Division of Surgery and of Microbiology and Immunology, University of Rochester Medical Center kn-affil= affil-num=26 en-affil=Division of Surgery and of Microbiology and Immunology, University of Rochester Medical Center kn-affil= affil-num=27 en-affil=Center for Breast Health and Gynecologic Oncology, Mercy Medical Center kn-affil= affil-num=28 en-affil=Rutgers, The State University of New Jersey kn-affil= affil-num=29 en-affil=CytoMechanobiology Laboratory, Department of Pharmacology, Penn State College of Medicine, Pennsylvania State University kn-affil= affil-num=30 en-affil=Department of Pharmacology and Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State University kn-affil= affil-num=31 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=32 en-affil=School of Mathematical and Natural Sciences, Arizona State University, Health Futures Center kn-affil= affil-num=33 en-affil=Departments of Pediatrics, Neurology, and Neuroscience, University of Rochester Medical Center kn-affil= affil-num=34 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=35 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= affil-num=36 en-affil=Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center kn-affil= END start-ver=1.4 cd-journal=joma no-vol=70 cd-vols= no-issue=2 article-no= start-page=146 end-page=154 dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals en-subtitle= kn-subtitle= en-abstract= kn-abstract=Abstract Small-molecular drugs, which are generally inexpensive compared with biopharmaceuticals and can often be taken orally, may contribute to the Sustainable Development Goals (SDGs) adopted by the United Nations. We previously reported the retinoid X receptor (RXR) agonist 4-(ethyl(3-isobutoxy-4-isopropylphenyl)amino)benzoic acid (NEt-3IB, 1) as a small-molecular drug candidate to replace biopharmaceuticals for the treatment of inflammatory bowel disease. The previous synthetic method to 1 required a large amount of organic solvent and extensive purification. In line with the SDGs, we aimed to develop an environmentally friendly, inexpensive method for the large-scale synthesis of 1. The developed method requires only a hydrophobic ether and EtOH as reaction and extraction solvents. The product was purified by recrystallization twice to afford 99% pure 1 at 100?mmol scale in about 30% yield. The optimized process showed a 35-fold improvement of the E-factor (an index of environmental impact) compared to the original method. This work, which changes the solvent used to environmentally preferable ones based on the existing synthetic method for 1, illustrates how synthetic methods for small-molecular drugs can be adapted and improved to contribute to the SDGs. en-copyright= kn-copyright= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MorishitaKen-ichi en-aut-sei=Morishita en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KikuzawaShota en-aut-sei=Kikuzawa en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasaki en-aut-sei=Watanabe en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=715752 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210812 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RB(high)CD4(+) T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-gamma-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs. en-copyright= kn-copyright= en-aut-name=MatsumotoRyohtaroh en-aut-sei=Matsumoto en-aut-mei=Ryohtaroh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakahashiDaisuke en-aut-sei=Takahashi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeMasaki en-aut-sei=Watanabe en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakataniShunsuke en-aut-sei=Nakatani en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KurosakiYuji en-aut-sei=Kurosaki en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaseKoji en-aut-sei=Hase en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= affil-num=2 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= en-keyword=RXR kn-keyword=RXR en-keyword=NEt-3IB kn-keyword=NEt-3IB en-keyword=inflammatory bowel disease kn-keyword=inflammatory bowel disease en-keyword=colitis kn-keyword=colitis en-keyword=Th1 cells kn-keyword=Th1 cells END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=6 article-no= start-page=1360 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200526 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Combination therapy, which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC(50)values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 mu M, respectively, IC(50)of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 mu M sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 mu M of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 mu M sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects. en-copyright= kn-copyright= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AtallahMarwa N. en-aut-sei=Atallah en-aut-mei=Marwa N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MansourHager en-aut-sei=Mansour en-aut-mei=Hager kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AlamMd Jahangir en-aut-sei=Alam en-aut-mei=Md Jahangir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OsmanAmira en-aut-sei=Osman en-aut-mei=Amira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HamadaHiroki en-aut-sei=Hamada en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name=妹尾彬正 kn-aut-sei=妹尾 kn-aut-mei=彬正 aut-affil-num=12 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name=妹尾昌治 kn-aut-sei=妹尾 kn-aut-mei=昌治 aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Vertebrates Embryology and Comparative Anatomy, Zoology Department, Faculty of Science, Menoufia University kn-affil= affil-num=6 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=10 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= affil-num=12 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=13 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=combination therapy kn-keyword=combination therapy en-keyword=paclitaxel kn-keyword=paclitaxel en-keyword=sorafenib kn-keyword=sorafenib END start-ver=1.4 cd-journal=joma no-vol=139 cd-vols= no-issue=6 article-no= start-page=873 end-page=874 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Towards Further Sharing of Knowledge and Activities on Standards of Quality Assurance (QA) across Industry, Academia and Government to Promote Research Integrity and Accelerate Drug Discovery kn-title=研究公正化，医薬品開発のスピードアップのための「信頼性確保の知識・方法論」の産学官での共有を目指して en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name=加来田博貴 kn-aut-sei=加来田 kn-aut-mei=博貴 aut-affil-num=1 ORCID= en-aut-name=SudoHirokazu en-aut-sei=Sudo en-aut-mei=Hirokazu kn-aut-name=須藤宏和 kn-aut-sei=須藤 kn-aut-mei=宏和 aut-affil-num=2 ORCID= affil-num=1 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil=岡山大学大学院医歯薬学総合研究科 affil-num=2 en-affil= kn-affil=中外製薬 END start-ver=1.4 cd-journal=joma no-vol=139 cd-vols= no-issue=6 article-no= start-page=887 end-page=890 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Problems with Laboratory Notebooks in Academia and How to Resolve Them kn-title=アカデミアにおける実験記録の悩み それを解決するには en-subtitle= kn-subtitle= en-abstract= kn-abstract= There is currently a major effort to promote drug discovery in academia as a way to seed new drug development in the pharmaceutical industry. However, there are concerns in industry about the quality of drug candidates generated in academic institutions. These concerns encompass culture and perceptions with respect to intellectual property management, the process of product development, and the reliability of scientific data. Questions about data reliability underscore the particularly serious problem of mistrust in academic research. Therefore, the author became interested in the topic of industry standards for quality assurance (QA) and arranged training workshops at Okayama University on the appropriate methods for recording experimental notes by lecturers involved in QA. The outcomes are presented here. en-copyright= kn-copyright= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name=加来田博貴 kn-aut-sei=加来田 kn-aut-mei=博貴 aut-affil-num=1 ORCID= affil-num=1 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil=岡山大学大学院医歯薬学総合研究科 en-keyword=research record kn-keyword=research record en-keyword=laboratory notebook kn-keyword=laboratory notebook en-keyword=good practice standard kn-keyword=good practice standard en-keyword=attributable kn-keyword=attributable en-keyword=legible kn-keyword=legible en-keyword=contemporaneous kn-keyword=contemporaneous en-keyword=original kn-keyword=original en-keyword=and accurate (ALCOA) and complete kn-keyword=and accurate (ALCOA) and complete en-keyword=consistent kn-keyword=consistent en-keyword=enduring kn-keyword=enduring en-keyword=and available (CCEA) standards kn-keyword=and available (CCEA) standards en-keyword=data integrity kn-keyword=data integrity END start-ver=1.4 cd-journal=joma no-vol=62 cd-vols= no-issue=19 article-no= start-page=8809 end-page=8818 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190904 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening en-subtitle= kn-subtitle= en-abstract= kn-abstract= Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration. en-copyright= kn-copyright= en-aut-name=YamadaShoya en-aut-sei=Yamada en-aut-mei=Shoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawasakiMayu en-aut-sei=Kawasaki en-aut-mei=Mayu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujiharaMichiko en-aut-sei=Fujihara en-aut-mei=Michiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasaki en-aut-sei=Watanabe en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakiokuMaho en-aut-sei=Takioku en-aut-mei=Maho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishiokaHiromi en-aut-sei=Nishioka en-aut-mei=Hiromi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakeuchiYasuo en-aut-sei=Takeuchi en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MakishimaMakoto en-aut-sei=Makishima en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MotoyamaTomoharu en-aut-sei=Motoyama en-aut-mei=Tomoharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ItoSohei en-aut-sei=Ito en-aut-mei=Sohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TokiwaHiroaki en-aut-sei=Tokiwa en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NakanoShogo en-aut-sei=Nakano en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil= kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine kn-affil= affil-num=10 en-affil=Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka kn-affil= affil-num=11 en-affil=Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka kn-affil= affil-num=12 en-affil=Department of Chemistry and Research Center of Smart Molecules, Rikkyo University kn-affil= affil-num=13 en-affil=Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka kn-affil= affil-num=14 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END