Nature PortfolioActa Medica Okayama2041-17231412023Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis621ENKosakuOkudaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKengoNakaharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityAkihiroItoChemical Genomics Research Group, RIKEN Center for Sustainable Resource ScienceYutaIijimaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityRyosukeNomuraDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityAshutoshKumarLaboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKENKanaFujikawaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKazuyaAdachiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityYukiShimadaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversitySatoshiFujioDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityReinaYamamotoDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityNobumasaTakasugiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKunishigeOnumaDivision of Experimental Pathology, Faculty of Medicine, Tottori UniversityMitsuhikoOsakiDivision of Experimental Pathology, Faculty of Medicine, Tottori UniversityFutoshiOkadaDivision of Experimental Pathology, Faculty of Medicine, Tottori UniversityTaichiUkegawaDepartment of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityYasuoTakeuchiDepartment of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityNorihisaYasuiLaboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityAtsukoYamashitaLaboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityHiroyukiMarusawaDepartment of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto UniversityYosukeMatsushitaDivision of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima UniversityToyomasaKatagiriDivision of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima UniversityTakahiroShibataGraduate School of Bioagricultural Sciences, Nagoya UniversityKojiUchidaLaboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of TokyoSheng-YongNiuBroad Institute of MIT and HarvardNhi B.LangNeurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research InstituteTomohiroNakamuraNeurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research InstituteKam Y. J.ZhangLaboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKENStuart A.LiptonNeurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research InstituteTakashiUeharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityDNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 <= 100nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.No potential conflict of interest relevant to this article was reported.Frontiers Media SAActa Medica Okayama2296-889X82021Exploring the Retinal Binding Cavity of Archaerhodopsin-3 by Replacing the Retinal Chromophore With a Dimethyl Phenylated Derivative794948ENTaichiTsuneishiLaboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasatakaTakahashiLaboratory of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasakiTsujimuraDepartment of Applied Chemistry, The University of TokyoKeiichiKojimaLaboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroshiIshikitaDepartment of Applied Chemistry, The University of TokyoYasuoTakeuchiLaboratory of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiSudoLaboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRhodopsins act as photoreceptors with their chromophore retinal (vitamin-A aldehyde) and they regulate light-dependent biological functions. Archaerhodopsin-3 (AR3) is an outward proton pump that has been widely utilized as a tool for optogenetics, a method for controlling cellular activity by light. To characterize the retinal binding cavity of AR3, we synthesized a dimethyl phenylated retinal derivative, (2E,4E,6E,8E)-9-(2,6-Dimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenal (DMP-retinal). QM/MM calculations suggested that DMP-retinal can be incorporated into the opsin of AR3 (archaeopsin-3, AO3). Thus, we introduced DMP-retinal into AO3 to obtain the non-natural holoprotein (AO3-DMP) and compared some molecular properties with those of AO3 with the natural A1-retinal (AO3-A1) or AR3. Light-induced pH change measurements revealed that AO3-DMP maintained slow outward proton pumping. Noteworthy, AO3-DMP had several significant changes in its molecular properties compared with AO3-A1 as follows; 1) spectroscopic measurements revealed that the absorption maximum was shifted from 556 to 508 nm and QM/MM calculations showed that the blue-shift was due to the significant increase in the HOMO-LUMO energy gap of the chromophore with the contribution of some residues around the chromophore, 2) time-resolved spectroscopic measurements revealed the photocycling rate was significantly decreased, and 3) kinetical spectroscopic measurements revealed the sensitivity of the chromophore binding Schiff base to attack by hydroxylamine was significantly increased. The QM/MM calculations show that a cavity space is present at the aromatic ring moiety in the AO3-DMP structure whereas it is absent at the corresponding beta-ionone ring moiety in the AO3-A1 structure. We discuss these alterations of the difference in interaction between the natural A1-retinal and the DMP-retinal with binding cavity residues.No potential conflict of interest relevant to this article was reported.American Chemical SocietyActa Medica Okayama0022262362192019Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening88098818ENShoyaYamadaDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMayuKawasakiMichikoFujiharaDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasakiWatanabeDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYutaTakamuraDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMahoTakiokuDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiromiNishiokaDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuoTakeuchiDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMakotoMakishimaDivision of Biochemistry, Department of Biomedical Sciences, Nihon University School of MedicineTomoharuMotoyamaGraduate School of Integrated Pharmaceutical and Nutritional Sciences, University of ShizuokaSoheiItoGraduate School of Integrated Pharmaceutical and Nutritional Sciences, University of ShizuokaHiroakiTokiwaDepartment of Chemistry and Research Center of Smart Molecules, Rikkyo UniversityShogoNakanoGraduate School of Integrated Pharmaceutical and Nutritional Sciences, University of ShizuokaHirokiKakutaDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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.No potential conflict of interest relevant to this article was reported.American Chemical SocietyActa Medica Okayama152050022952017Real-Time, in Situ Monitoring of the Oxidation of Graphite: Lessons Learned21502156ENNaokiMorimotoGraduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, Okayama UniversityHideyukiSuzukiResearch Core for Interdisciplinary Sciences, Okayama UniversityYasuoTakeuchiGraduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, Okayama UniversitShogoKawaguchiJapan Synchrotron Radiation Research Institute (JASRI), SPring-8MasahiroKunisuToray Research Center, Inc., Surface Science LaboratoriesChristopher W.BielawskiCenter for Multidimensional Carbon Materials (CMCM), Institute for Basic Science (IBS)YutaNishinaResearch Core for Interdisciplinary Sciences, Okayama University Graphite oxide (GO) and its constituent layers (i.e., graphene oxide) display a broad range of functional groups and, as such, have attracted significant attention for use in numerous applications. GO is commonly prepared using the “Hummers method” or a variant thereof in which graphite is treated with KMnO4 and various additives in H2SO4. Despite its omnipresence, the underlying chemistry of such oxidation reactions is not well understood and typically affords results that are irreproducible and, in some cases, unsafe. To overcome these limitations, the oxidation of graphite under Hummers-type conditions was monitored over time using in situ X-ray diffraction and in situ X-ray absorption near edge structure analyses with synchrotron radiation. In conjunction with other atomic absorption spectroscopy, UV–vis spectroscopy and elemental analysis measurements, the underlying mechanism of the oxidation reaction was elucidated, and the reaction conditions were optimized. Ultimately, the methodology for reproducibly preparing GO on large scales using only graphite, H2SO4, and KMnO4 was developed and successfully adapted for use in continuous flow systems.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama45112004Enantioselective construction of biaryl part in the synthesis of stegane related compounds23272329ENHitoshiAbeShigemitsuTakedaTakuroFujitaKeisukeNishiokaYasuoTakeuchiTakashiHarayama<p>A Pd-mediated intramolecular aryl-aryl coupling reaction of phenyl benzoate derivatives were examined to form benzo[c]chromen-6-ones, and then enantioselective lactone-opening reaction with a borane-oxazaborolidine combination was carried out. The resulting biphenyl was transformed into a key intermediate for the stegane related compounds. The absolute configuration of the biphenyl is also discussed.
Stegane and related compounds are important because of their interesting biological activities such as antileukemic properties.1 One of the most outstanding features of their chemical structures is an unsymmetrical 2,2’-disubstituted biphenyl moiety with an axial chirality (Figure 1). For the formation of such a biphenyl part in the syntheses of the stegane families, several approaches have been attempted such as photocyclization,2 Suzuki coupling,3 oxidative biaryl coupling,4 the SNAr reaction,5 Ullmann coupling,6 and the [2+2+2] three-component cyclization reaction.7</p>
No potential conflict of interest relevant to this article was reported.Acta Medica Okayama46182005Synthesis of graphislactones A-D through a palladium-mediated biaryl coupling 31973200ENHitoshiAbeKeisukeNishiokaShigemitsuTakedaMasatsuguAraiYasuoTakeuchiTakashiHarayama<p>The chemical synthesis of graphislactones A-D was achieved through the Pd-mediated intramolecular biaryl coupling reaction of phenyl benzoate derivatives.</p>
No potential conflict of interest relevant to this article was reported.岡山大学環境管理センターActa Medica Okayama71985有機廃液の貯蔵について20ENYasuoTakeuchiNo potential conflict of interest relevant to this article was reported.