Papers - OMORI Kazuhiro

Establishment of a rapid and quantitative method for detecting the range of infection exposure in preclinical dental education. International journal

Ayaka Ueda, Yuki Shinoda-Ito, Kazu Takeuchi-Hatanaka, Takashi Ito, Shintaro Ono, Kimito Hirai, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

BMC oral health   25 ( 1 )   199 - 199   2025.2

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BACKGROUNDS: Safe dental treatments that prevent nosocomial and cross-infections are essential for patients and dental workers. However, dental students sometimes pay inadequate attention to infection control, especially in preclinical practice, because of too much focus on technical training, such as the use of equipment, etc. The spread of infections such as SARS-CoV-2, antibiotic-resistant bacteria, and oral bacteria are sometimes lethal for medically compromised patients. Thus, the rapid and inexpensive detection system to detect and measure dental practice-related infection spread during preclinical treatment is highly desired for dental education. This study aimed to establish a method to quantify and visualize infected areas using dental phantoms for safe and effective preclinical dental practices. METHODS: At first, we developed artificial saliva as an in vitro study, including food-derived bacteria and fluorescence dye, which is safe for application to preclinical practice education. In vitro study, the correlation between adenosine triphosphate (ATP) levels and Lactobacillus colony numbers in yogurt was examined using the ATP fluorescent method, with colony counting on yogurt only and a mixture of yogurt and ultraviolet (UV)-sensitive hand lotion. The mixed liquid of yogurt and hand lotion was used as artificial saliva. Second, we used this artificial saliva in preclinical education. The degree of contamination of personal protective equipment and dental chairs in preclinical practice using this artificial saliva was determined using the ATP fluorescent method and measuring the luminescence areas among 10 dentists, 10 dental residents, and 10 fifth-grade dental students. RESULTS: ATP levels and Lactobacillus colony numbers in yogurt were positively correlated with yogurt alone and a mixture of yogurt and UV-sensitive hand lotions (correlation coefficient ≒ 1). Preclinical education using a mixture of artificial saliva successfully quantified and visualized infectious areas and droplets, which revealed significant differences in ATP amounts in personal protective equipment among groups according to years of experience as dental practitioners (p < 0.05). CONCLUSIONS: An education system for infection control constructed using artificial saliva containing Lactobacillus and a UV-sensitive fluorescent hand lotion quantified the infectious areas and degrees. Thus, this method is effective in preclinical practice using dental phantoms.

DOI： 10.1186/s12903-025-05584-4

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Effectiveness of oral health care intervention for stroke patients following the introduction of Oral Health Assessment Tool. Reviewed

Kazuyuki Matsunaga, Ayaka Yoshida-Tsuboi, Ken Inohara, Yasuko Yoshida, Kanako Nakahama, Kazuki Sasaki, Fumie Souda, Yuka Terasawa, Yutaka Shimoe, Kazu Takeuchi-Hatanaka, Tadashi Yamamoto, Kazuhiro Omori, Tatsuo Kohriyama, Shogo Takashiba

Geriatrics & gerontology international   2024.12

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AIM: This study aimed to evaluate the effectiveness of oral health assessment tools in facilitating oral health care interventions by dental care providers for acute stroke patients within 48 h of admission, following a reform of the nursing system. METHODS: Data were gathered from a retrospective cohort study conducted at a stroke center, comparing 10 months before and after the implementation of the reformed system, with a 2-month interval. Parameters assessed included stroke type, severity measured using the National Institutes of Health Stroke Scale, stroke history, stroke-related factors, number of teeth, hospitalization cost and duration, occurrence of fever and pneumonia, stroke treatment, days from admission to dental intervention, and intervention frequency. RESULTS: Implementation of the new system significantly reduced the time before dental intervention (P < 0.001), increased the frequency of interventions (P < 0.001), and allowed for the management of more severe cases (P = 0.007). However, there was a slight increase in the occurrence of fevers and the days of fever (P = 0.039 and P = 0.015, respectively). Multiple regression analysis showed that fever days were positively correlated with stroke severity and the number of days from admission to dental intervention (P < 0.001 and P = 0.013, respectively). Even after propensity score matching adjusting for stroke severity, these associations persisted. Additional multiple regression analysis was performed after this, but fever days were positively correlated with stroke severity and sex (P < 0.001 and P = 0.008, respectively), as well as with the presence of other factors affecting the occurrence of fever. CONCLUSIONS: Although the frequency and duration of fevers increased slightly, this approach, incorporating oral health assessment tools, made it possible to provide early dental intervention, particularly for patients with severe strokes. Geriatr Gerontol Int 2024; ••: ••-••.

DOI： 10.1111/ggi.15035

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Resolvin D2-induced reparative dentin and pulp stem cells after pulpotomy in a rat model Reviewed

Mitsuhiro Yoneda, Hidetaka Ideguchi, Shin Nakamura, Zulema Arias, Mitsuaki Ono, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

Heliyon   10 ( 13 )   e34206 - e34206   2024.7

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2024.e34206

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歯周病を取り巻く最新の話題と医科歯科連携 超高齢社会における糖尿病医科歯科連携医療の実践

大森 一弘

糖尿病合併症   38 ( 2 )   203 - 206   2024.7

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Bacterial DNA and serum IgG antibody titer assays for assessing infection of human-pathogenic and dog-pathogenic Porphyromonas species in dogs Reviewed

Masako Tai-Tokuzen, Takashi Ito, Kazuya Tamura, Haruko Hirayama, Hirohito Ogawa, Shin Nakamura, Keisuke Okubo, Kazuhiro Omori, Tadashi Yamamoto, Katsumi Mominoki, Shogo Takashiba

Heliyon   10 ( 11 )   e31872 - e31872   2024.6

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2024.e31872

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Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells. Reviewed International journal

Taira Hirose, Yuki Kunisada, Koichi Kadoya, Hiroki Mandai, Yumi Sakamoto, Kyoichi Obata, Kisho Ono, Hiroaki Takakura, Kazuhiro Omori, Shogo Takashiba, Seiji Suga, Soichiro Ibaragi

Cancer genomics & proteomics   21 ( 5 )   464 - 473   2024

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BACKGROUND/AIM: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. MATERIALS AND METHODS: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. RESULTS: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. CONCLUSION: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.

DOI： 10.21873/cgp.20464

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Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report. Reviewed International journal

Yuki Shinoda-Ito, Anna Hirai, Kazuhiro Omori, Hidetaka Ideguchi, Hideki Yamamoto, Fumino Kato, Kyoichi Obata, Tatsuo Ogawa, Keisuke Nakano, Takato Nakadoi, Eri Katsuyama, Soichiro Ibaragi, Tadashi Yamamoto, Hitoshi Nagatsuka, Akira Hirasawa, Shogo Takashiba

BMC oral health   23 ( 1 )   843 - 843   2023.11

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BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

DOI： 10.1186/s12903-023-03586-8

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Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans. Invited Reviewed International journal

Yuki Shinoda-Ito, Kazuhiro Omori, Takashi Ito, Masaaki Nakayama, Atsushi Ikeda, Masahiro Ito, Toshiaki Ohara, Shogo Takashiba

Antibiotics (Basel, Switzerland)   12 ( 11 )   2023.10

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

DOI： 10.3390/antibiotics12111562

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急激なHbA1c値の悪化に重度歯周炎症の関与を疑った一症例 Reviewed

石田 房子, 大森 一弘, 佐々木 知津, 平松 恭子, 中川 眞奈美, 松原 ゆかり, 井手口 英隆, 徳善 真砂子, 滝川 雅之

日本歯周病学会会誌   65 ( 2 )   69 - 79   2023.6

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

重度の歯周炎症が糖尿病の病態に悪影響を及ぼすことは知られている。今回,急激な血糖値(HbA1c)悪化の背景に,重度歯周炎症の関与を疑った症例を報告する。患者は78歳,男性。2021年3月,血糖値の急激な悪化(HbA1c=13.8%)をかかりつけ内科で指摘され,大学病院糖尿病内科に教育入院した。同科で歯周病検査の必要性を指摘され,同院歯科(歯周科部門)へ紹介された。同歯科での検査において,重度の歯周炎の進行を指摘され,専門的な歯周治療介入が早期に必要と判断された。歯周病専門医のいる当院での加療を希望し,2021年5月に受診した。歯周組織検査において,4mm以上のPPDの割合は76%,BOP陽性率は81%,PCRは100%,PISAは3,217mm2であった。エックス線検査所見では,全顎的に中等度の水平性骨吸収の進行を確認し,37,47には根尖におよぶ骨吸収像が存在した。診断は,広汎型重度慢性歯周炎(ステージIV,グレードC)とした。糖尿病の病態への影響を考慮しながら,局所抗菌薬併用SRPを主体とした歯周基本治療を行った。歯周治療に対する反応性は非常に良く,歯周炎症の改善(再評価時のPISA:605mm2)とともに,HbA1c値は6.5%に改善した(2022年1月)。緊密な医科歯科連携によって,早期に専門的歯周治療介入を行えたことが良好な血糖値の改善につながったと考える。(著者抄録)

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歯内治療が原因で菌血症となった単心室症患者の一症例 Reviewed

大森 一弘, 杜 徳尚, 井手口 英隆, 岡本 憲太郎, 佐光 秀文, 児玉 加奈子, 山本 直史, 赤木 禎治, 笠原 真悟, 伊藤 浩, 高柴 正悟

日本成人先天性心疾患学会雑誌   12 ( 2 )   30 - 36   2023.5

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本成人先天性心疾患学会  

歯科治療は,観血的処置にはみえなくても菌血症を起こすリスクが高い.今回,感染性心内膜炎(IE)高リスクに分類されるフォンタン手術後の患者が歯科治療に起因すると考えられる感染症を起こし,緊急入院に至る症例を経験した.患者は20歳の男性.多脾症候群,右室型単心室に対して,両側両方向性グレン手術とフォンタン手術の手術歴がある.2021年6月,近医で下顎左側第二大臼歯(#37)の慢性根尖性歯周炎の診断のもと,予防的抗菌薬の投与なく歯内治療を開始した.2021年7月,治療中の#37部の自発痛,悪寒,戦慄,発熱を自覚し,当院循環器内科を緊急受診した.履歴から歯性感染が疑われたため,当院歯周科へ緊急紹介され,#37急性根尖性歯周炎と診断した.IE高リスク患者のため緊急入院となり,経験的抗菌療法を開始した.入院5日目,抗菌薬持続投与下で#37の歯内治療を再開,入院12日目に歯内治療を終了,入院13日目に退院した.今回の症例を教訓に,患者自身が歯科治療に先立ち予防的抗菌薬投与の必要性を簡便に提示できる患者カードを作成した.本カードが適切に運用され,歯科治療由来のIE発症リスクが軽減されることを期待する.(著者抄録)

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Recent Advances in Apical Periodontitis Treatment: A Narrative Review Reviewed

Zulema Arias, Mohammed Zahedul Islam Nizami, Xiaoting Chen, Xinyi Chai, Bin Xu, Canyan Kuang, Kazuhiro Omori, Shogo Takashiba

Bioengineering   10 ( 4 )   488 - 488   2023.4

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Apical periodontitis is an inflammatory response caused by pulp infection. It induces bone resorption in the apical and periapical regions of the tooth. The most conservative approach to treat this condition is nonsurgical endodontic treatment. However, clinical failure has been reported with this approach; thus, alternative procedures are required. This review highlights recent literature regarding advanced approaches for the treatment of apical periodontitis. Various therapies, including biological medications, antioxidants, specialized pro-resolving lipid mediators, and stem cell therapy, have been tested to increase the success rate of treatment for apical periodontitis. Some of these approaches remain in the in vivo phase of research, while others have just entered the translational research phase to validate clinical application. However, a detailed understanding of the molecular mechanisms that occur during development of the immunoinflammatory reaction in apical periodontitis remains unclear. The aim of this review was to summarize advanced approaches for the treatment of apical periodontitis. Further research can confirm the potential of these alternative nonsurgical endodontic treatment approaches.

DOI： 10.3390/bioengineering10040488

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The Fungal Metabolite (+)-Terrein Abrogates Inflammatory Bone Resorption via the Suppression of TNF-α Production in a Ligature-Induced Periodontitis Mouse Model Reviewed

Hidefumi Sako, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Hidetaka Ideguchi, Saki Yoshimura-Nakagawa, Kyosuke Sakaida, Chiaki Nagata-Kamei, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

Journal of Fungi   9 ( 3 )   314 - 314   2023.3

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

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 &lt; 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 &lt; 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.

DOI： 10.3390/jof9030314

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Autophagy as a potential mechanism underlying the biological effect of 1,25-Dihydroxyvitamin D3 on periodontitis: a narrative review. Reviewed International journal

Xiaoting Chen, Zulema Arias, Kazuhiro Omori, Tadashi Yamamoto, Yuki Shinoda-Ito, Shogo Takashiba

BMC oral health   23 ( 1 )   90 - 90   2023.2

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Language：English   Publishing type：Research paper (scientific journal)  

The major active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is known for its wide bioactivity in periodontal tissues. Although the exact mechanisms underlying its protective action against periodontitis remain unclear, recent studies have shown that 1,25D3 regulates autophagy. Autophagy is vital for intracellular pathogen invasion control, inflammation regulation, and bone metabolic balance in periodontal tissue homeostasis, and its regulation could be an interesting pathway for future periodontal studies. Since vitamin D deficiency is a worldwide health problem, its role as a potential regulator of autophagy provides new insights into periodontal diseases. Based on this premise, this narrative literature review aimed to investigate the possible connection between 1,25D3 and autophagy in periodontitis. A comprehensive literature search was conducted on PubMed using the following keywords (e.g., vitamin D, autophagy, periodontitis, pathogens, epithelial cells, immunity, inflammation, and bone loss). In this review, the latest studies on the protective action of 1,25D3 against periodontitis and the regulation of autophagy by 1,25D3 are summarized, and the potential role of 1,25D3-activated autophagy in the pathogenesis of periodontitis is analyzed. 1,25D3 can exert a protective effect against periodontitis through different signaling pathways in the pathogenesis of periodontitis, and at least part of this regulatory effect is achieved through the activation of the autophagic response. This review will help clarify the relationship between 1,25D3 and autophagy in the homeostasis of periodontal tissues and provide perspectives for researchers to optimize prevention and treatment strategies in the future.

DOI： 10.1186/s12903-023-02802-9

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A case report of bacteremia caused by dental endodontic treatment in a patient with single ventricle Reviewed

Kazuhiro Omori, Norihisa Toh, Hidetaka Ideguchi, Kentaro Okamoto, Hidefumi Sako, Kanako Kodam, Tadashi Yamamoto, Teiji Akagi, Shingo Kasahara, Hiroshi Ito, Shogo Takashib

12 ( 2 )   1 - 8   2023.2

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DOI： 10.34376/jsachd.C-2022-0002

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Reattachment of Fractured Tooth Fragment by Multidisciplinary Treatment Approach Reviewed

Zulema Arias, Heber Falú Hinojosa Ledezma, Claudia Patricia Osorio Terán, Kazuhiro Omori, Tadashi Yamamoto, Mohammed Zahedul Islam Nizami, Shogo Takashiba

The Bulletin of Tokyo Dental College   2023

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Publishing type：Research paper (scientific journal)   Publisher：Tokyo Dental College  

DOI： 10.2209/tdcpublication.2022-0019

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Analysis of subgingival microbiota in monozygotic twins with different severity and progression risk of periodontitis. Reviewed International journal

Tadashi Yamamoto, Makoto Taniguchi, Kazuyuki Matsunaga, Yusuke Kawata, Mari Kawamura, Keisuke Okubo, Keisuke Yamashiro, Kazuhiro Omori, Shogo Takashiba

Clinical Case Reports   10 ( 4 )   e05725   2022.4

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The study aims to reveal the composition of subgingival bacteria in monozygotic twins with discordant in severity and progression risk of periodontitis. Microbiome analysis indicated that most bacteria were heritable but differed in their abundance and immune response. The dysbiotic bacteria can be considered as risk markers for periodontitis progression.

DOI： 10.1002/ccr3.5725

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Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E2 Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades. Reviewed International journal

Masaaki Nakayama, Mariko Naito, Kazuhiro Omori, Shintaro Ono, Koji Nakayama, Naoya Ohara

Journal of Immunology (Baltimore, Md. : 1950)   208 ( 5 )   1146 - 1154   2022.3

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Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.

DOI： 10.4049/jimmunol.2100866

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The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation Reviewed

Kyosuke Sakaida, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Saki Nakagawa, Hidefumi Sako, Chiaki Kamei, Satoshi Yamamoto, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

Frontiers in Pharmacology   12   2021.6

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

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 <italic>Aspergillus terreus</italic>, has shown receptor activator of nuclear factor-κB 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). <italic>In vivo</italic> administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (<italic>p</italic> &amp;lt; 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (<italic>p</italic> &amp;lt; 0.01). In an <italic>in vitro</italic> study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (<italic>p</italic> &amp;lt; 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 <italic>Ocstamp</italic>, <italic>Dcstamp</italic>, <italic>Calcr</italic>, <italic>Atp6v0d2</italic>, <italic>Oscar</italic>, and <italic>Itgb3</italic> (<italic>p</italic> &amp;lt; 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

DOI： 10.3389/fphar.2021.674366

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歯周組織の炎症と不妊の関連性を示唆する、ある侵襲性歯周炎患者の病態生理 Reviewed

大森 一弘, 河野 隆幸, 小林 寛也, 新井 英雄, 山本 直史, 高柴 正悟

日本歯科保存学雑誌   63 ( 5 )   451 - 460   2020.10

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Authorship：Lead author   Language：Japanese   Publisher：(NPO)日本歯科保存学会  

緒言:歯周病原細菌の感染と歯周組織の炎症が,妊娠に影響を与える可能性が報告されている.今回,不妊治療の経過が思わしくない侵襲性歯周炎患者に感染源除去の観点から専門的歯周治療を行い,自然妊娠から正常出産にいたった症例の経過をふまえ病態を考察する.症例:33歳,女性,既婚(不妊治療中).2016年9月,26の動揺および同部の自発痛を自覚し,かかりつけ歯科医院を受診した.同院でエックス線検査を受けて,重度の歯槽骨吸収があると説明された.早期の専門的歯周治療を勧められ,当科を紹介された.既往歴の特記事項はなく,不妊検査においても患者本人および夫ともに異常所見はなかった.歯周組織検査において,probing pocket depthが4mm以上の部位の割合は49.5%,bleeding on probingは47.9%,plaque control recordは3.1%,歯周炎症表面積(PISA)は2,392mm2であった.エックス線検査所見では,主訴部の26部を中心に根尖に及ぶ骨吸収像が多数存在した.歯周病原細菌に対する血清抗体価検査および歯周ポケット内細菌DNA検査ともに,Porphyromonas gingivalisの感染が強く疑われた.診断は広汎型侵襲性歯周炎(ステージIV,グレードC),二次性咬合性外傷とした.治療方針として,患者の妊娠希望に配慮して,できるかぎり早期(1年以内)の歯周環境の改善を目指すこととした.また,歯周外科治療が終了するまでの不妊治療を含めた妊娠活動を控える必要性について説明し,同意を得た.治療計画は,(1)歯周基本治療(患者教育,抜歯,局所抗菌療法を併用したスケーリング・ルートプレーニング,暫間固定),(2)歯周組織再生療法,(3)口腔機能回復治療,(4)歯周病安定期治療(SPT)とした.治療経過として,歯周治療に対する宿主反応性は非常に良く,炎症改善と歯槽骨の再生を確認した(歯周外科治療後PISA:43mm2).口腔機能回復治療中に自然妊娠し,35歳時に男児を正常出産(経腟分娩,3,240g,出産週数:38週+5日)した.考察および結論:重度のP. gingivalis感染および歯周炎症を伴う侵襲性歯周炎の罹患が,妊娠成立に影響を及ぼす可能性が示唆された.本症例のように不妊治療の経過が思わしくない場合には,歯周組織を含めた口腔状態を一度精査することが望まれる.(著者抄録)

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The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1. Reviewed International journal

Saki Nakagawa, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Satoshi Yamamoto, Hiroya Kobayashi, Hidefumi Sako, Kyosuke Sakaida, Hiroshi Yoshimura, Satoki Ishii, Soichiro Ibaragi, Kimito Hirai, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

International Immunopharmacology   83   106429 - 106429   2020.3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.intimp.2020.106429

PubMed

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