研究活動情報

• 2020年05月 国立大学臨床検査学系博士後期課程優秀賞

• Sushi, von Willebrand Factor Type A, EGF and Pentraxin Domain-Containing Protein 1: A Novel Fibroblast-Derived Circulating Biomarker Reflecting Cardiac Fibrosis.

  Naoya Kuwahara, Manabu Nagao, Yu Izawa, Kenta Kaneshiro, Hiromi Hashimura, Takeshi Yoshida, Takuo Emoto, Takayoshi Toba, Hidekazu Tanaka, Tatsuro Ishida, Masakazu Shinohara, Hiromasa Otake

  BACKGROUND: Cardiac fibrosis is a hallmark of heart failure and can be quantified by the extracellular volume fraction (ECV) derived from diagnostic imaging. However, noninvasive assessment is limited by the lack of specific circulating biomarkers. Recent large plasma proteome analyses have identified SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1) as candidate molecules reflecting cardiac fibrosis. This study aimed to evaluate SVEP1 as a biomarker for cardiac fibrosis. METHODS: In 72 patients with heart failure due to aortic stenosis, computed tomography-based ECV, serum SVEP1, and BNP (brain natriuretic peptide) levels were assessed. Multivariable regression was used to determine independent predictors of ECV. Publicly available single-nucleus RNA sequencing of human hearts revealed the cellular origin of SVEP1. SVEP1 secretion was assessed in human cardiac fibroblasts after TGF-β (transforming growth factor-β) stimulation or small interfering RNA knockdown. Plasma Svep1 and cardiac hydroxyproline levels were measured in mice with angiotensin II- and phenylephrine-induced cardiac fibrosis. RESULTS: Serum SVEP1 correlated with ECV and outperformed BNP in detecting fibrosis. Multivariable analysis revealed SVEP1 as an independent predictor of ECV. In addition, snRNA-seq revealed fibroblast-specific expression, expanded in failing hearts consistent with activated fibroblast emergence. Furthermore, TGF-β increased SVEP1 secretion in human cardiac fibroblasts, whereas its knockdown reduced SVEP1 secretion. Plasma Svep1 and cardiac hydroxyproline levels were elevated and positively correlated in mice. CONCLUSIONS: Compared with BNP, SVEP1, derived from cardiac fibroblasts, is more strongly associated with ECV-defined fibrosis and may serve as a novel fibrosis-specific circulating biomarker in heart failure.

  2026年04月, Journal of the American Heart Association, e047119, 英語, 国際誌

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation

  Naoya Kuwahara, Manabu Nagao, Masakazu Shinohara, Kenta Kaneshiro, Takuo Emoto, Takeshi Yoshida, Terunobu Fukuda, Makoto Nishimori, Seimi Satomi-Kobayashi, Hiromasa Otake, Ken-Ichi Hirata, Tatsuro Ishida, Ryuji Toh

  BACKGROUND: ATP citrate lyase (ACLY) is a key enzyme in de novo lipogenesis that generates acetyl-CoA from citrate. Although fatty acids are required for energy production and biomass synthesis in the heart, the regulatory mechanisms of ACLY-mediated de novo lipogenesis in pathological cardiac fibroblasts remain unknown. The aim of this study was to investigate the biological role of ACLY in cardiac remodeling. METHODS: Adeno-associated virus serotype 9-mediated shRNA targeting Acly was intravenously injected into C57BL/6J male mice. The mice were subsequently continuously infused with a mixture of angiotensin II and phenylephrine. Cardiac phenotypes were evaluated via histological staining. Cell proliferation assays, stable isotope tracing with 13C-labeled glucose, and chromatin immunoprecipitation assays were performed using human cardiac fibroblasts. RESULTS: ACLY expression was upregulated in the heart sections of mice treated with angiotensin II/phenylephrine, in particular in fibrotic areas. Masson trichrome staining revealed that Acly gene silencing significantly reduced cardiac fibrosis in these mice. Both siRNA-mediated ACLY knockdown and pharmacological ACLY inhibition suppressed the proliferation and expression of fibrous proteins in cultured human cardiac fibroblasts stimulated with transforming growth factor-β. Mechanistically, ACLY inhibition reduced de novo lipogenesis, limiting the fatty acid supply essential for cellular growth and proliferation. It also decreased H3K9 and H3K27 acetylation, in addition to the presence of acetylated H3K9 and H3K27 at the promoter regions of fibrotic genes. CONCLUSIONS: Our findings demonstrate that ACLY plays an important role in maladaptive cardiac fibrosis. ACLY could be a novel therapeutic target to prevent the development of heart failure.

  Ovid Technologies (Wolters Kluwer Health), 2025年03月, Hypertension

  [査読有り]

  研究論文（学術雑誌）


• The clock gene Bmal1 controls inflammatory mediators in rheumatoid arthritis fibroblast-like synoviocytes

  Kenta Kaneshiro, Kanako Nakagawa, Hikari Tsukamoto, Genta Matsuoka, Seitaro Okuno, Koji Tateishi, Yasuhiro Terashima, Nao Shibanuma, Kohsuke Yoshida, Akira Hashiramoto

  Elsevier BV, 2024年01月, Biochemical and Biophysical Research Communications, 691, 149315 - 149315

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Tocilizumab suppresses NF-kappa B activation via toll-like receptor 9 signaling by reducing cell-free DNA in rheumatoid arthritis

  Teppei Hashimoto, Kohsuke Yoshida, Yuichi Yokoyama, Naonori Hashimoto, Kenta Kaneshiro, Takahiro Yoshikawa, Koji Tateishi, Yasuhiro Terashima, Kiyoshi Matsui, Akira Hashiramoto

  Abstract Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA.

  Oxford University Press (OUP), 2023年06月, Clinical and Experimental Immunology, 213(2) (2), 209 - 220

  [査読有り]

  研究論文（学術雑誌）


• IL-6はミトコンドリア内因性経路を介して関節リウマチ滑膜細胞に細胞死抵抗性をもたらす

  桶谷 優斗, 内田 京, 鈴木 行人, 金城 健太, 森井 寛太, 八重倉 愛里沙, 奥村 郁美, 吉田 幸祐, 川崎 善子, 立石 耕司, 寺島 康浩, 柴沼 均, 酒井 良忠, 柱本 照

  (一社)日本リウマチ学会, 2020年08月, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64回, 705 - 705, 日本語


• Chronotherapy targeting cytokine secretion attenuates collagen-induced arthritis in mice

  Arisa Yaekura, Kohsuke Yoshida, Kanta Morii, Yuto Oketani, Ikumi Okumura, Kenta Kaneshiro, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  Elsevier BV, 2020年07月, International Immunopharmacology, 84, 106549 - 106549

  [査読有り]

  研究論文（学術雑誌）


• Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators and proliferate rheumatoid arthritis fibroblast-like synovial cells

  K Kaneshiro, Y Sakai, K Suzuki, K Uchida, K Tateishi, Y Terashima, Y Kawasaki, N Shibanuma, K Yoshida, A Hashiramoto

  Informa UK Limited, 2019年08月, Scandinavian Journal of Rheumatology, 48(5) (5), 353 - 361

  [査読有り]

  研究論文（学術雑誌）


• Expressions of circadian clock genes represent disease activities of RA patients treated with biological DMARDs

  Kenta Kaneshiro, Kohsuke Yoshida, Kanta Morii, Yuto Oketani, Koto Uchida, Arisa Yaekura, Ikumi Okumura, Teppei Hashimoto, Yoshiko Kawasaki, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  Oxford University Press (OUP), 2019年05月, Modern Rheumatology, 30(2) (2), 293 - 300

  [査読有り]

  研究論文（学術雑誌）


• Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on rheumatoid arthritis synovial fibroblasts

  Kohjin Suzuki, Kohsuke Yoshida, Takeshi Ueha, Kenta Kaneshiro, Ayako Nakai, Naonori Hashimoto, Koto Uchida, Teppei Hashimoto, Yoshiko Kawasaki, Nao Shibanuma, Natsuko Nakagawa, Yoshitada Sakai, Akira Hashiramoto

  Springer Science and Business Media LLC, 2018年03月, Arthritis Research & Therapy, 20(1) (1)

  [査読有り]

  研究論文（学術雑誌）


• TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells

  Kohsuke Yoshida, Ayako Nakai, Kenta Kaneshiro, Naonori Hashimoto, Kohjin Suzuki, Koto Uchida, Teppei Hashimoto, Yoshiko Kawasaki, Koji Tateishi, Natsuko Nakagawa, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  Elsevier BV, 2018年01月, Biochemical and Biophysical Research Communications, 495(2) (2), 1675 - 1680

  [査読有り]

  研究論文（学術雑誌）


• Circulating cell free DNA: a marker to predict the therapeutic response for biological DMARDs in rheumatoid arthritis

  Teppei Hashimoto, Kohsuke Yoshida, Naonori Hashimoto, Ayako Nakai, Kenta Kaneshiro, Kohjin Suzuki, Yoshiko Kawasaki, Nao Shibanuma, Akira Hashiramoto

  Wiley, 2016年12月, International Journal of Rheumatic Diseases, 20(6) (6), 722 - 730

  [査読有り]

  研究論文（学術雑誌）


• 関節リウマチ患者における血清遊離DNAと疾患活動性の検討

  橋本 哲平, 吉田 幸佑, 橋本 尚憲, 金城 健太, 中井 綾子, 鈴木 行人, 松浦 香里, 川崎 善子, 柴沼 均, 立石 博臣, 柱本 照

  (一社)日本臨床免疫学会, 2015年09月, 日本臨床免疫学会会誌, 38(4) (4), 361 - 361, 日本語

• 冠動脈リスク評価のためのHDL結合型ビリルビンを測定する蛍光UnaGベースアッセイの開発

  FUJIOKA Tomoo, 飯野琢也, 飯野琢也, 杜隆嗣, 原田周, 金城健太, 長尾学, 篠原正和, 篠原正和, 篠原正和, 篠原正和, 篠原正和, 久保田美咲, 戸崎麻子, 石田達郎, 石田達郎, 石田達郎, 宮脇敦史, 大竹寛雅

  2025年, 日本動脈硬化学会総会・学術集会プログラム・抄録集(Web), 57th


• IL-6はBikを介して関節リウマチ滑膜細胞の内因性経路による細胞死に抵抗する

  芦田千歩, 塚本光里, 金城健太, 吉田幸祐, 立石耕司, 寺島康浩, 柴沼均, 酒井良忠, 柱本照, 柱本照

  2025年, 日本リウマチ学会総会・学術集会プログラム・抄録集, 69th


• 関節リウマチ治療反応性を予測する循環細胞外遊離DNA検出システムの開発

  吉田幸祐, 金城健太, 芦田千歩, 戸田朱音, 塚本光里, 立石耕司, 寺島康浩, 橋本哲平, 柴沼均, 酒井良忠, 柱本照, 柱本照

  2025年, 日本リウマチ学会総会・学術集会プログラム・抄録集, 69th


• Clock Gene Bmal1 Contributes to Inflammation via Phosphorylation of NF-κB/p65 in RA-FLS

  Hikari Tsukamoto, Kenta Kaneshiro, Kohsuke Yoshida, Koji Tateishi, Yasuhiro Terashima, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  2024年09月, ARTHRITIS & RHEUMATOLOGY, 76, 5265 - 5266, 英語

  研究発表ペーパー・要旨（国際会議）


• IL-6 and TNF-a Cooperate to Modulate the Cell Cycle of RA-Fibroblast-like Synoviocytes Via Cyclin Dependent Kinase Inhibitors

  Kenta Kaneshiro, Kohsuke Yoshida, Ayako Nakai, Kohjin Suzuki, Koto Uchida, Teppei Hashimoto, Yoshiko Kawasaki, Natsuko Nakagawa, Koji Tateishi, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  2017年10月, ARTHRITIS & RHEUMATOLOGY, 69, 英語

  研究発表ペーパー・要旨（国際会議）


• A NOVEL PHARMACOLOGICAL ACTION OF MTX THROUGH CIRCADIAN CLOCK GENES IN RA FIBROBLAST-LIKE SYNOVIAL CELLS

  K. Suzuki, K. Yoshida, T. Hashimoto, K. Kaneshiro, A. Nakai, N. Hashimoto, Y. Kawasaki, N. Shibanuma, N. Nakagawa, Y. Sakai, A. Hashiramoto

  2017年06月, ANNALS OF THE RHEUMATIC DISEASES, 76, 499 - 499, 英語

  研究発表ペーパー・要旨（国際会議）


• A Novel Pharmacological Action of MTX on RA Fibroblast-like Synoviocytes Via Circadian Clock Genes

  Kohjin Suzuki, Kohsuke Yoshida, Teppei Hashimoto, Kenta Kaneshiro, Ayako Nakai, Naonori Hashimoto, Yoshiko Kawasaki, Nao Shibanuma, Natsuko Nakagawa, Yoshitada Sakai, Akira Hashiramoto

  2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語

  研究発表ペーパー・要旨（国際会議）


• TCZ Modulates the Production of Ccfdna Derived from RA Synovial Cells

  Naonori Hashimoto, Kohsuke Yoshida, Teppei Hashimoto, Ayako Nakai, Kenta Kaneshiro, Kohjin Suzuki, Yoshiko Kawasaki, Nao Shibanuma, Natsuko Nakagawa, Yoshitada Sakai, Akira Hashiramoto

  2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語

  研究発表ペーパー・要旨（国際会議）


• IL-6 and TNF-alpha Modulate Expressions of Cell Cycle Regulators of Rheumatoid Arthritis Fibroblast-like Synoviocytes

  Kenta Kaneshiro, Teppei Hashimoto, Kohsuke Yoshida, Ayako Nakai, Naonori Hashimoto, Kohjin Suzuki, Koto Uchida, Yoshiko Kawasaki, Natsuko Nakagawa, Nao Shibanuma, Yoshitada Sakai, Akira Hashiramoto

  2016年10月, ARTHRITIS & RHEUMATOLOGY, 68, 英語

  研究発表ペーパー・要旨（国際会議）


• TNF-a Modulates the Expression of Circadian Clock Genes Via Calcium Signaling in Rheumatoid Synovial Cells

  Kohsuke Yoshida, Nao Shibanuma, Teppei Hashimoto, Yoshiko Kawasaki, Naonori Hashimoto, Ayako Nakai, Kenta Kaneshiro, Koji Tateishi, Natsuko Nakagawa, Akira Hashiramoto

  2014年10月, ARTHRITIS & RHEUMATOLOGY, 66, S457 - S458, 英語

  研究発表ペーパー・要旨（国際会議）

• 日本循環器学会

  2025年 - 現在


• 日本リウマチ学会

  2015年 - 現在

• 時計遺伝子を標的とした心不全の新規検査法、治療法の開拓

  金城 健太

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2025年04月 - 2028年03月


• 難治性関節リウマチに挑む：時計遺伝子BMAL1を標的とした創薬戦略

  公益財団法人 ひょうご科学技術協会 令和5年度学術研究助成, 2026年04月 - 2027年03月, 研究代表者


• 関節リウマチの新規治療薬「抗circulating cell-free DNA抗体」とコンパニオン診断薬の開発

  2024年度 神戸大学GAPファンドプログラム（うりぼーファンド）, 2024年07月 - 2025年03月, 研究代表者


• 関節リウマチ滑膜細胞の時計遺伝子Bmal1がNF-κBの転写活性に与える影響

  金城 健太

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2023年04月 - 2025年03月


• 時計遺伝子を介した滑膜細胞の炎症性メディエーター産生とオートクライン機構の研究

  金城 健太

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2021年04月 - 2023年03月

  TNF-α、IL-1β刺激下において、RA-FLSのBmal1が各種炎症性メディエーター(MMP-3/9, IL-6, CCL2)産生を制御していることがリアルタイムPCR、蛍光免疫染色によって明らかとなった。この研究成果は、骨軟骨破壊、細胞遊走に関わる炎症性メディエーター発現、関節破壊がBmal1によって広範囲に制御されることを示唆するものである。 以上を踏まえて、Bmal1が制御する炎症性メディエーター発現機構をNF-κB転写活性の観点から明らかにする発展的な研究課題を新たに立案することができた。