研究者詳細 - 細田　隆介

論文 - 細田　隆介

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Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes.

Atsushi Kuno, Ryusuke Hosoda, Yukika Saga, Naotoshi Iwahara, Yuki Tatekoshi, Ryo Numazawa, Yoshiyuki Horio

Journal of Pharmacological Sciences ( Elsevier BV ) 2024年11月

Administration of Nicotinamide Mononucleotide, a Precursor of NAD+, Attenuates Doxorubicin-induced Cardiotoxicity and Renal Tubular Injury in Mice(タイトル和訳中)

齊藤圭司, 細田隆介, 嵯峨幸夏, 舘越勇輝, 久野篤史

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 ) 88回 PJ114 - 4 2024年03月

Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy

Ryuta Nakashima, Ryusuke Hosoda, Yuki Tatekoshi, Naotoshi Iwahara, Yukika Saga, Atsushi Kuno

Scientific Reports 14, ( 1365 ) 2024年01月 [査読有り]

DOI

Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice.

Ryusuke Hosoda, Ryuta Nakashima, Masaki Yano, Naotoshi Iwahara, Seidai Asakura, Iyori Nojima, Yukika Saga, Risa Kunimoto, Yoshiyuki Horio, Atsushi Kuno

Journal of Pharmacological Sciences ( Elsevier BV ) 2023年04月 [査読有り]

担当区分：筆頭著者

DOI

No sex differences in the acute effects of caffeine on mental calculation and pulse rate in healthy college students.

Nobuyuki Kurokawa, Rumi Niwa, Kouhei Tada, Ryusuke Hosoda, Naotoshi Iwahara, Yoshiyuki Horio, Atsushi Kuno

Clinical Nutrition Open Science ( Elsevier BV ) 2023年02月 [査読有り]

DOI

Activation of SIRT1 promotes membrane resealing via cortactin

Naotoshi Iwahara, Kuya Azekami, Ryusuke Hosoda, Iyori Nojima, Shin Hisahara, Atsushi Kuno

Scientific Reports ( Springer Science and Business Media LLC ) 12 ( 1 ) 15328 - 15328 2022年09月 [査読有り] [国際誌]

Abstract Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis.

DOI PubMed

Downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts

Iyori Nojima, Ryusuke Hosoda, Yuki Toda, Yoshiki Saito, Naohiro Ueda, Kouhei Horimoto, Naotoshi Iwahara, Yoshiyuki Horio, Atsushi Kuno

Aging ( Impact Journals, LLC ) 14 ( 7 ) 2966 - 2988 2022年04月 [査読有り] [国際誌]

Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in replicative senescence in embryonic mouse fibroblasts (MEFs). During passages according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) based on cell growth arrest, an increase in the number of cells positive for senescence-associated β-galactosidase (SA-β-GAL) staining, and upregulation of p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the number of SA-β-GAL-positive cells, upregulated p16 and p19, and inhibited cell growth. Incubation of MEFs with IGFBP5 during serial passage increased the cumulative population doubling and decreased SA-β-GAL positivity compared with those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, blocked the increase in the number of SA-β-GAL-positive cells in IGFBP5-knockdown cells. The reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest that downregulation of IGFBP5 during serial passage contributes to replicative senescence via ERK2 in MEFs.

DOI PubMed

SIRT1 in the cardiomyocyte counteracts doxorubicin-induced cardiotoxicity via regulating histone H2AX

Atsushi Kuno, Ryusuke Hosoda, Miki Tsukamoto, Tatsuya Sato, Hiromi Sakuragi, Nami Ajima, Yukika Saga, Kouhei Tada, Yoshiki Taniguchi, Naotoshi Iwahara, Yoshiyuki Horio

Cardiovascular Research ( Oxford University Press (OUP) ) 2022年03月 [査読有り] [国際誌]

Abstract Aims Cardiotoxicity by doxorubicin predicts worse prognosis of patients. Accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. SIRT1, an NAD+-dependent histone/protein deacetylase, protects cells by deacetylating target proteins. We investigated whether SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating Ser139 phosphorylation of histone H2AX, a critical signal of the DNA damage response. Methods and results Doxorubicin (5 mg/kg per week, x4) was administered to mice with intact SIRT1 (Sirt1f/f) and mice that lack SIRT1 activity in cardiomyocytes (Sirt1f/f;MHCcre/+). Reductions in left ventricular fractional shortening and ejection fraction by doxorubicin treatment were more severe in Sirt1f/f;MHCcre/+ than in Sirt1f/f. Myocardial expression level of type-B natriuretic peptide was 2.5-fold higher in Sirt1f/f;MHCcre/+ than in Sirt1f/f after doxorubicin treatment. Sirt1f/f;MHCcre/+ showed larger fibrotic areas and higher nitrotyrosine levels in the heart after doxorubicin treatment. Although doxorubicin-induced DNA damage evaluated by TUNEL staining was enhanced in Sirt1f/f;MHCcre/+, the myocardium from Sirt1f/f;MHCcre/+ showed blunted Ser139 phosphorylation of H2AX by doxorubicin treatment. In H9c2 cardiomyocytes, SIRT1 knockdown attenuated Ser139 phosphorylation of H2AX, increased DNA damage, and enhanced caspase-3 activation under doxorubicin treatment. Immunostaining revealed that acetylation level of H2AX at Lys5 was higher in hearts from Sirt1f/f;MHCcre/+. In H9c2 cells, acetyl-Lys5-H2AX level was increased by SIRT1 knockdown and reduced by SIRT1 overexpression. Ser139 phosphorylation in response to doxorubicin treatment was blunted in a mutant H2AX with substitution of Lys5 to Gln (K5Q) that mimics acetylated lysine compared with that in wild-type H2AX. Expression of K5Q-H2AX as well as S139A-H2AX, which cannot be phosphorylated at Ser139, augmented doxorubicin-induced caspase-3 activation. Treatment of mice with resveratrol, a SIRT1 activator, attenuated doxorubicin-induced cardiac dysfunction, which was associated with a reduction in acetyl-Lys5-H2AX level and a preserved phospho-Ser139-H2AX level. Conclusion These findings suggest that SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating H2AX phosphorylation through its deacetylation in cardiomyocytes.

DOI PubMed

SIRT1は脱アセチル化を介してヒストンH2AXのリン酸化を媒介しドキソルビシン誘発性心毒性を弱める(SIRT1 Mediates Histone H2AX Phosphorylation via Its Deacetylation and Counteracts Doxorubicin-induced Cardiotoxicity)

久野篤史, 細田隆介

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 ) 86回 PJ21 - 1 2022年03月

Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress

Takashi Hayashi, Takashi Matsushita, Shin Hisahara, Naotoshi Iwahara, Atsushi Kuno, Risa Kunimoto, Ryusuke Hosoda, Masaya Tanno, Shun Shimohama, Yoshiyuki Horio

The Journal of Biochemistry ( Oxford University Press (OUP) ) 171 ( 2 ) 201 - 213 2022年02月 [査読有り]

Abstract SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-β (Aβ), and overexpression of SIRT3ct suppressed the toxic function of Aβ in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.

DOI

Aging-associated inflammation and fibrosis in arachnoid membrane

Hime Suzuki, Takeshi Mikami, Naotoshi Iwahara, Yukinori Akiyama, Masahiko Wanibuchi, Katsuya Komatsu, Rintaro Yokoyama, Tsukasa Hirano, Ryusuke Hosoda, Yoshiyuki Horio, Atsushi Kuno, Nobuhiro Mikuni

BMC Neurology ( Springer Science and Business Media LLC ) 21 ( 1 ) 169 - 169 2021年12月 [査読有り] [国際誌]

Abstract Background The physiological and pathological significance of the arachnoid membrane (AM) is still unknown. In this study, we investigated various characteristics of the AM, focusing on the influence of inflammation and fibrosis. Methods Small pieces of AM sample were obtained during neurosurgical procedures from 74 cases. The clinical and pathological characteristics of the hyperplastic AM group (≥ 50 μm) and the non-hyperplastic AM group (< 50 μm) were compared. Then, potential correlations between AM thickness and clinical characteristics were analyzed. Moreover, VEGFα, TGFβ, and TGFα levels were quantitated by real time PCR. Then, the potential correlations between AM thickness and these inflammatory or anti-inflammatory markers, and the influence of the original disease were calculated. Results The median age of the patients in hyperplastic AM group was significantly older than that of the non-hyperplastic AM group. Moreover, the number of fibroblasts, CD68⁺ cells, CD86⁺ cells, and CD206⁺ cells in the hyperplastic AM group was significantly higher than that in the non-hyperplastic AM group. The AM thickness was significantly correlated to age and number of fibroblasts, CD68⁺ cells, CD86⁺ cells, and CD206⁺ cells. The thickness of the AM was significantly correlated to the messenger RNA expression levels of VEGFα (ρ = 0.337), and the VEGFα expression levels were significantly correlated with TGFβ and TNFα. Conclusions The AM hyperplasia was influenced by aging and could be a result of inflammation and fibrosis through cytokine secretion from the inflammatory cells and fibroblasts in the AM.

DOI PubMed

Different Antioxidative and Antiapoptotic Effects of Piceatannol and Resveratrol

Ryusuke Hosoda, Hiroki Hamada, Daisuke Uesugi, Naotoshi Iwahara, Iyori Nojima, Yoshiyuki Horio, Atsushi Kuno

Journal of Pharmacology and Experimental Therapeutics ( American Society for Pharmacology & Experimental Therapeutics (ASPET) ) 376 ( 3 ) 385 - 396 2021年03月 [査読有り] [国際誌]

担当区分：筆頭著者

Resveratrol affords protection against reactive oxygen species (ROS)-related diseases via activation of SIRT1, an NAD+-dependent deacetylase. However, the low bioavailability of resveratrol limits its therapeutic applications. Since piceatannol is a hydroxyl analog of resveratrol with higher bioavailability, it could be an alternative to resveratrol. In this study, we compared the cytotoxicity, antioxidative activity, and mechanisms of cytoprotection of piceatannol with those of resveratrol. In C2C12 cells incubated with piceatannol, electrospray ionization mass spectrometry analysis showed that piceatannol was present in the intracellular fraction. A high concentration (50 μM) of piceatannol, but not resveratrol, induced mitochondrial depolarization and apoptosis. However, piceatannol at 10 μM inhibited the increase in mitochondrial ROS level induced by antimycin A, and this ROS reduction was greater than that by resveratrol. The reduction in hydrogen peroxide-induced ROS by piceatannol was also greater than that by resveratrol or vitamin C. Piceatannol reduced antimycin A-induced apoptosis more than did resveratrol. SIRT1 knockdown abolished the antiapoptotic activity of resveratrol, whereas it blocked only half of the antiapoptotic activity of piceatannol. Piceatannol, but not resveratrol, induced heme oxygenase-1 (HO1) expression, which was blocked by knockdown of the transcription factor NRF2, but not by SIRT1 knockdown. HO1 knockdown partially blocked the reduction of ROS by piceatannol. Furthermore, the antiapoptotic action of piceatannol was abolished by HO1 knockdown. Our results suggest that the therapeutic dose of piceatannol protects cells against mitochondrial ROS more than does resveratrol via SIRT1- and NRF2/HO1-dependent mechanisms. The activation of NRF2/HO1 could be an advantage of piceatannol compared with resveratrol for cytoprotection. SIGNIFICANCE STATEMENT: This study showed that piceatannol and resveratrol were different in cytotoxicity, oxidant-scavenging activities, and mechanisms of cytoprotection. Protection by piceatannol against apoptosis induced by reactive oxygen species was superior to that by resveratrol. In addition to the sirtuin 1-dependent pathway, piceatannol exerted nuclear factor erythroid 2-related factor 2/heme oxygenase-1-mediated antioxidative and antiapoptotic effects, which could be an advantage of piceatannol compared with resveratrol.

DOI PubMed

SIRT1 deficiency interferes with membrane resealing after cell membrane injury

Daisuke Fujiwara, Naotoshi Iwahara, Rio Sebori, Ryusuke Hosoda, Shun Shimohama, Atsushi Kuno, Yoshiyuki Horio

PLOS ONE ( Public Library of Science (PLoS) ) 14 ( 6 ) e0218329 - e0218329 2019年06月 [査読有り]

DOI

Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice

Atsushi Kuno, Ryusuke Hosoda, Rio Sebori, Takashi Hayashi, Hiromi Sakuragi, Mika Tanabe, Yoshiyuki Horio

Scientific Reports ( Springer Science and Business Media LLC ) 8 ( 1 ) 2018年12月 [査読有り]

DOI

Resveratrol Decreases Oxidative Stress by Restoring Mitophagy and Improves the Pathophysiology of Dystrophin-Deficient <i>mdx</i> Mice

Rio Sebori, Atsushi Kuno, Ryusuke Hosoda, Takashi Hayashi, Yoshiyuki Horio

Oxidative Medicine and Cellular Longevity ( Hindawi Limited ) 2018 1 - 13 2018年10月 [査読有り]

We previously showed that treatment with resveratrol (3,5,4-trihydroxy-trans-stilbene), an activator of the NAD⁺-dependent deacetylase SIRT1 at 4 g/kg food for 32 weeks, significantly decreased the muscular reactive oxygen species (ROS) levels and ameliorated the pathology of mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Here, we treated mdx mice with various doses of resveratrol (0.04, 0.4, and 4 g/kg food) for 56 weeks and examined the effects on serum creatine kinase levels and physical activities. Because resveratrol promotes autophagy, we also investigated whether autophagy including mitochondrial autophagy (mitophagy) is involved in resveratrol’s effects. Autophagy/mitophagy-related genes and autophagic flux were downregulated in the muscle of mdx mice, and these phenomena were reversed by resveratrol with significant ROS reduction. Resveratrol at 4 g/kg food reduced the number of immature myofibers containing central nuclei and fine fibers < 400 μm² and increased that of thicker myofibers in the quadriceps, suggesting that resveratrol decreased myofiber wasting and promoted muscular maturation. Accordingly, resveratrol at 0.4 g/kg food reduced the creatine kinase levels to one-third of those in untreated mdx mice and significantly increased the animals’ physical activities. In C2C12 myoblast cells, resveratrol promoted mitophagy and eliminated mitochondria containing high superoxide levels. The clearance of damaged mitochondria and ROS reduction by resveratrol was completely suppressed by an autophagy inhibitor (chloroquine) and by knocking down Atg5 or Pink1, essential genes for autophagy and mitophagy, respectively. Thus, resveratrol is a potential therapeutic agent for DMD, and the clearance of damaged mitochondria probably contributes to its action.

DOI

Pterostilbene and Its Glucoside Induce Type XVII Collagen Expression

Hiroki Hamada, Kei Shimoda, Yoshiyuki Horio, Tsubasa Ono, Ryusuke Hosoda, Noriyuki Nakayama, Koichi Urano

NATURAL PRODUCT COMMUNICATIONS ( NATURAL PRODUCTS INC ) 12 ( 1 ) 85 - 86 2017年01月 [査読有り]

ピセアタンノールとレスベラトロールの酸化ストレスに対する細胞保護効果の比較

細田隆介, 久野篤史, 瀬堀理生, 濱田博喜, 堀尾嘉幸

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 ( (公社)日本生化学会 ) 88回・38回 [3P0135] - [3P0135] 2015年12月

Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells

Yusuke S. Hori*, Ryusuke Hosoda*, Yukinori Akiyama, Rio Sebori, Masahiro Wanibuchi, Takeshi Mikami, Toshiya Sugino, Kengo Suzuki, Mitsuhisa Maruyama, Miki Tsukamoto, Nobuhiro Mikuni, Yoshiyuki Horio, Atsushi Kuno.*=equal contribution

JOURNAL OF NEURO-ONCOLOGY ( SPRINGER ) 122 ( 1 ) 11 - 20 2015年03月 [査読有り]

担当区分：筆頭著者

Mitochondrial autophagy eliminates damaged mitochondria and decreases reactive oxygen species (ROS). The autophagy inhibitor chloroquine (CQ) potentiates temozolomide (TMZ) cytotoxicity in glioma cells, but it is not known whether CQ does this by inhibiting mitochondrial autophagy. The effects of CQ and TMZ on MitoSOX Red fluorescence, a mitochondrial ROS indicator, and cell death were examined in rat C6 glioma cells. Mitochondrial autophagy was monitored by the colocalization of MitoTracker Red fluorescence and EGFP-LC3 dots. Mitochondrial content was measured by MitoTracker Green fluorescence and immunoblotting for a mitochondrial protein. Finally, CQ's effects on tumor cells derived from a glioblastoma patient and human U87-MG glioblastoma cells were assessed. TMZ (100-1,000 mu M) alone did not affect mitochondrial ROS or cell death in C6 cells, but when administered with CQ (10 mu M), it increased mitochondrial ROS and cell death. Antioxidants significantly suppressed the CQ-augmented cell death in TMZ-treated cells, indicating that mitochondrial ROS were involved in this cell death. TMZ treatment reduced MitoTracker Green fluorescence and mitochondrial protein levels, and these effects were inhibited by CQ. TMZ also increased the colocalization of EGFP-LC3 dots with mitochondria, and CQ enhanced this effect. CQ potentiated TMZ-induced cytotoxicity in patient-derived glioblastoma cells as well as human U87-MG glioblastoma cells. These results suggest that CQ increases cellular ROS and augments TMZ cytotoxicity in glioma cells by inhibiting mitochondrial autophagy.

DOI

Regulation of FOXOs and p53 by SIRT1 Modulators under Oxidative Stress

Yusuke S. Hori*, Atsushi Kuno*, Ryusuke Hosoda*, Yoshiyuki Horio.*=equal contribution

PLoS ONE ( Public Library of Science (PLoS) ) 8 ( 9 ) e73875 - e73875 2013年09月 [査読有り]

担当区分：筆頭著者

DOI

Regioselective Hydroxylation and Glucosylation of Flavanones with Cultured Plant Cells of Eucalyptus perriniana

Ryusuke Hosoda, Yoshiyuki Horio, Kei Shimoda, Manabu Hamada, Hatsuyuki Hamada, Hiroki Hamada

NATURAL PRODUCT COMMUNICATIONS ( NATURAL PRODUCTS INC ) 8 ( 7 ) 905 - 906 2013年07月 [査読有り]

担当区分：筆頭著者

Cultured plant cells of Eucalyptus perriniana catalyzed reduction, regioselective hydroxylation, and regioselective glycosylation of flavanones. (2S)-Flavanone was converted into (2S)-flavan-4-ol, (2S)-flavan-4,7-diol, (2S)-flavan-7-ol, (2S)-flavan-7-yl glucoside, and (2S)-flavan-7-yl gentiobioside. The cells glucosylated (25)-flavan-6-ol to (25)-flavan-6-yl glucoside. (2S)-Flavan-2-ol was transformed to (2S)-flavan-2,4-diol, (2S)-flavan-2,7-diol, (2S)-flavan-2'-yl glucoside. In addition, (25)-flavan-4'-ol was transformed to (25)-flavan-4,4'-diol, (2S)-flavan-4',7-diol, (28)-flavan-4'-yl glucoside.

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