MDPI Acta Medica Okayama 2309-608X 9 3 2023 The Fungal Metabolite (+)-Terrein Abrogates Inflammatory Bone Resorption via the Suppression of TNF-α Production in a Ligature-Induced Periodontitis Mouse Model 314 EN Hidefumi Sako Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital Kazuhiro Omori Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masaaki Nakayama Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroki Mandai Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science Hidetaka Ideguchi Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Saki Yoshimura-Nakagawa Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital Kyosuke Sakaida Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital Chiaki Nagata-Kamei Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroya Kobayashi Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Satoki Ishii Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Mitsuaki Ono Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral and Maxillofacial Surgery and Biopathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tadashi Yamamoto Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Shogo Takashiba Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis. No potential conflict of interest relevant to this article was reported.

Frontiers Media SA Acta Medica Okayama 1663-9812 12 2021 The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-kappa B Ligand-Induced Osteoclastogenesis by Suppressing Protein Kinase-C alpha/beta II Phosphorylation 674366 EN Kyosuke Sakaida Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiro Omori Department of Periodontics and Endodontics, Okayama University Hospital Masaaki Nakayama Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroki Mandai Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science Saki Nakagawa Department of Periodontics and Endodontics, Okayama University Hospital Hidefumi Sako Department of Periodontics and Endodontics, Okayama University Hospital Chiaki Kamei Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Satoshi Yamamoto Department of Periodontics and Endodontics, Okayama University Hospital Hiroya Kobayashi Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Satoki Ishii Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Mitsuaki Ono Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Ibaragi Department of Oral Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Yamashiro Department of Periodontics and Endodontics, Okayama University Hospital, Okayama, Japan, 3Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tadashi Yamamoto Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Shogo Takashiba Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKC alpha/beta II, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis. No potential conflict of interest relevant to this article was reported.

Thieme Gruppe Acta Medica Okayama 0936-5214 31 19 2020 Integrated Synthesis of Thienyl Thioethers and Thieno[3,2-b]thiophenes via 1-Benzothiophen-3(2H)-ones 1947 1952 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Nanae Habara Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Yoshiak Kobashi Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Yuji Kurimoto Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University A one-pot procedure for the synthesis of thienyl thioethers is described. Several thienyl thioethers were synthesized by a TfOH-promoted Friedel–Crafts-type cyclization, a subsequent nucleophilic attack by an arenethiol, and dehydration. This protocol was successfully applied to the synthesis of thienoacene derivatives by using a Pd-catalyzed dehydrogenative cyclization. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1433-7851 59 20 2020 Electrochemical Synthesis of Thienoacene Derivatives: Transition‐Metal‐Free Dehydrogenative C－S Coupling Promoted by a Halogen Mediator 7803 7807 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Ren Matsuo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Toki Yonezawa Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Haruka Inoue Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Department of Medical Technology, Gifu University of Medical Science Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University The first electrochemical dehydrogenative C－S bond formation leading to thienoacene derivatives is described. Several thienoacene derivatives were synthesized by dehydrogenative C－H/S－H coupling. The addition of nBu4NBr, which catalytically promoted the reaction as a halogen mediator, was essential. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 1567-5769 83 2020 The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1 106429 EN Saki Nakagawa Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Omori Department of Periodontics and Endodontics, Okayama University Hospital Masaaki Nakayama Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroki Mandai Department of Medical Technology, School of Health Science, Gifu University of Medical Science Satoshi Yamamoto Department of Periodontics and Endodontics, Okayama University Hospital Hiroya Kobayashi Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama Universit Hidefumi Sako Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyosuke Sakaida Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroshi Yoshimura ivision of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Satoki Ishii Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Soichiro Ibaragi Department of Oral Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kimito Hirai Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Yamashiro Department of Periodontics and Endodontics, Okayama University Hospital Tadashi Yamamoto Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University Shogo Takashiba Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease. No potential conflict of interest relevant to this article was reported.

American Chemical Society Acta Medica Okayama 15237060 20 22 2018 Synthesis and Properties of Dithieno-Fused 1,4-Azaborine Derivatives. 7336 7340 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Keisuke Shigemori Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Atsushi Wakamiya Institute for Chemical Research, Kyoto University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University The first synthesis of dithieno[3,2- b:2',3'- e][1,4]azaborinine (DTAB) derivatives has been achieved by Buchwald-Hartwig coupling and subsequent Friedel-Crafts-type C-H borylation. A facile method for further π-extension of DTAB was also developed via stannylation and subsequent Kosugi-Migita-Stille cross-coupling reaction. The fundamental properties of DTAB derivatives were also investigated. No potential conflict of interest relevant to this article was reported.

American Chemical Society Acta Medica Okayama 15237060 19 11 2017 Synthesis of 3-Benzo[b]thienyl 3-Thienyl Ether via an Addition-Elimination Reaction and Its Transformation to an Oxygen-Fused Dithiophene Skeleton: Synthesis and Properties of Benzodithienofuran and Its π-Extended Derivatives 2821 2824 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Yuji Kurimoto Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University The synthesis of 3-benzo[b]thienyl 3-thienyl ether and its dehydrogenative cyclization leading to benzodithienofuran (BDTF; [1]benzothieno[3,2-b]thieno[2,3-d]furan) are described for the first time. Further transformation of BDTF to more π-extended BDTF derivatives and their fundamental physical properties are also studied. No potential conflict of interest relevant to this article was reported.

Chemical Society of Japan Acta Medica Okayama 03667022 47 8 2018 Cu/Fe/O=PPh3-Catalyzed Etherification for the Synthesis of Aryl 3-Benzo[b]thienyl Ethers 1044 1047 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Takuya Asada Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Tomohiro Inada Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Yuji Kurimoto Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Cu/Fe-cocatalyzed cross-coupling reactions between 3-bromobenzo[b]thiophene and hydroxyaryls are described herein. The combination of Cu and Fe catalysts is important for the progress of the reactions, and the use of triphenylphosphine oxide as a ligand suppresses the dehalogenation of 3-bromobenzo[b]thiophene, and promptly facilitates the reaction. The obtained aryl benzo[b]thienyl ethers can be converted to pextended thienobenzofuran derivatives via Pd-catalyzed dehydrogenative cyclizations. No potential conflict of interest relevant to this article was reported.

GEORG THIEME Acta Medica Okayama 09365214 30 10 2019 1,10-Phenanthroline- or Electron-Promoted Cyanation of Aryl Iodides 1209 1214 EN Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Kazuki Yoshioka Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Takayuki Hirata Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Hiroki Mandai Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Koji Midorikawa Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University A 1,10-phenanthroline-promoted cyanation of aryl iodides has been developed. 1,10-Phenanthroline worked as an organocatalyst for the reaction of aryl iodides with tetraalkylammonium cyanide to afford aryl cyanides. A similar reaction occurred through an electroreductive process. No potential conflict of interest relevant to this article was reported.

American Chemical Society Acta Medica Okayama 15237060 21 7 2019 Iodide-Mediated or Iodide-Catalyzed Demethylation and Friedel-Crafts C-H Borylative Cyclization Leading to Thiophene-Fused 1,2-Oxaborine Derivatives 2171 2175 EN Keisuke Shigemori Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Momoka Watanabe Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Julie Kong Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Koichi Mitsudo Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Atsushi Wakamiya Institute for Chemical Research, Kyoto University Hiroki Mandai Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Seiji Suga Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University The first synthesis of dithieno-1,2-oxaborine derivatives was achieved via iodide-mediated or iodide-catalyzed demethylation of 3-methoxy-2,2'-bithiophene and subsequent C-H borylation. A wide variety of thiophene-fused oxaborines could be synthesized by the procedure. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1420-3049 16 10 2011 Studies on the Synthesis of DMAP Derivatives by Diastereoselective Ugi Reactions 8815 8832 EN Hiroki Mandai Shunsuke Irie Koichi Mitsudo Seiji Suga Diastereoselective Ugi reactions of DMAP-based aldehydes with α-amino acids and tert-butyl isocyanide were examined. The reactions of 4-(dimethylamino)-2-pyridine-carboxaldehyde with various α-amino acids afforded 2-substituted DMAP derivatives with low diastereoselectivity. On the contrary, reactions with 4-(dimethylamino)-3-pyridine-carboxaldehyde delivered 3-substituted DMAP derivatives with moderate to high diastereoselectivity. The combination of α-amino acid and DMAP-based aldehyde is thus important to achieve high diastereoselectivity. Kinetic resolution of a secondary alcohol using a chiral DMAP derivative obtained through these reactions was also examined. No potential conflict of interest relevant to this article was reported.