755 results on '"To, Yoko"'
Search Results
2. Simple methods for measuring milk exosomes using fluorescent compound GIF-2250/2276
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Furukawa, Saho, Kawaguchi, Kyoka, Chikama, Kotomi, Yamada, Ryohei, Kamatari, Yuji O., Lim, Lee Wah, Koyama, Hiroko, Inoshima, Yasuo, Ikemoto, Mitsushi J., Yoshida, Saishi, Hirata, Yoko, Furuta, Kyoji, and Takemori, Hiroshi
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- 2024
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3. RSK4 confers paclitaxel resistance to ovarian cancer cells, which is resensitized by its inhibitor BI-D1870
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Nagumo, Yoko, Villareal, Myra O., Isoda, Hiroko, and Usui, Takeo
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- 2023
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4. Overexpression of Slc22a18 facilitates fat accumulation in mice
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Yamamoto, Takashi, primary, Iizuka, Yoko, additional, Izumi-Yamamoto, Kozue, additional, Shirota, Midori, additional, Mori, Nobuko, additional, Tahara, Yoshikazu, additional, Fujita, Toshiro, additional, and Gotoda, Takanari, additional
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- 2024
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5. Pathological analysis of Prader-Willi syndrome using adipocytes
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Kishimura, Urara, primary, Soeda, Shuhei, additional, Ito, Daiki, additional, Ueta, Yoko, additional, Harada, Maki, additional, Tanaka, Mai, additional, and Taniura, Hideo, additional
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- 2024
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6. A role of Achaete-scute complex homolog 2 in T follicular regulatory cell development
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Kazuma Iida, Kensuke Suga, Kotaro Suzuki, Shunjiro Kurihara, Yoko Yabe, Takahiro Kageyama, Kazuyuki Meguro, Shigeru Tanaka, Arifumi Iwata, Akira Suto, and Hiroshi Nakajima
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
7. HTLV-1 bZIP factor impairs DNA mismatch repair system
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Maki Sakurada-Aono, Takashi Sakamoto, Masayuki Kobayashi, Yoko Takiuchi, Fumie Iwai, Kohei Tada, Hiroyuki Sasanuma, Shigeki Hirabayashi, Yasuhiro Murakawa, Kotaro Shirakawa, Chihiro Sakamoto, Keisuke Shindo, Jun-ichirou Yasunaga, Masao Matsuoka, Yves Pommier, Shunichi Takeda, and Akifumi Takaori-Kondo
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
8. Inhibition of protein phosphatase 2A by okadaic acid induces translocation of nucleocytoplasmic O-GlcNAc transferase
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Heriati Sitosari, Ikkei Morimoto, Yao Weng, Yilin Zheng, Yoko Fukuhara, Mika Ikegame, and Hirohiko Okamura
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
9. Deubiquitinating enzymes UBP12 and UBP13 regulate carbon/nitrogen-nutrient stress responses by interacting with the membrane-localized ubiquitin ligase ATL31 in Arabidopsis
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Yongming Luo, Shigetaka Yasuda, Junpei Takagi, Yoko Hasegawa, Yukako Chiba, Junji Yamaguchi, and Takeo Sato
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Deubiquitinating Enzymes ,Arabidopsis Proteins ,Nitrogen ,Ubiquitin ,Ubiquitin-Protein Ligases ,Arabidopsis ,Ubiquitination ,Biophysics ,Nutrients ,Cell Biology ,Plants, Genetically Modified ,Biochemistry ,Carbon ,Gene Expression Regulation, Plant ,Endopeptidases ,Molecular Biology - Abstract
Ubiquitination is an important post-translational modification that regulates multiple cellular activities in plants including environmental stress responses. In addition to activity of ubiquitin ligases, the activity of deubiquitinating enzymes (DUBs) is critical for modulating the optimal ubiquitination status of target proteins in response to environmental stimuli. However, while several ubiquitin ligases have been isolated to date, little is known about the DUBs involved in plant stress responses. Here, we report that two DUBs, UBP12 and UBP13, function in response to disrupted carbon (C)/nitrogen (N)-nutrient stress conditions in Arabidopsis. Knockdown of UBP12 and UBP13 expression resulted in hypersensitivity to high C/low N-nutrient stress conditions, whereas overexpression of UBP13 reduced the sensitivity. Additionally, UBP13 physically interacted with and deubiquitinated the ubiquitin ligase ATL31, a key regulator of plant resistance to high C/low N-nutrient stress conditions. Genetic analysis showed that the loss of ATL31 and its homolog ATL6 suppressed the high C/low N-hyposensitivity of UBP13-overexpressing plants, suggesting that ATL31 is epistatic to UBP12 and UBP13. Taken together, our results suggest that the DUBs UBP12 and UBP13 function together with the ubiquitin ligase ATL31 to mediate C/N-nutrient stress responses in plants.
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- 2022
10. Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells
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Tomoyuki Uchida, Tetsuro Oda, Takeshi Yamamoto, Masako Inamitsu, Chihiro Sakai, Hitoshi Uchinoumi, Takeshi Suetomi, Yoshihide Nakamura, Yoko Okamoto, Satomi Tateda, Shohei Fujii, Shinji Tanaka, Junya Nawata, Takayuki Okamura, Shigeki Kobayashi, and Masafumi Yano
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Tunicamycin ,Biophysics ,Ryanodine Receptor Calcium Release Channel ,Suramin ,Cell Biology ,Atherosclerosis ,Endoplasmic Reticulum Stress ,Biochemistry ,Dantrolene ,Muscle, Smooth, Vascular ,Mice ,Calmodulin ,Animals ,Molecular Biology - Abstract
Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER CaTunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER CaWe observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.
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- 2022
11. A role of Achaete-scute complex homolog 2 in T follicular regulatory cell development
- Author
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Iida, Kazuma, primary, Suga, Kensuke, additional, Suzuki, Kotaro, additional, Kurihara, Shunjiro, additional, Yabe, Yoko, additional, Kageyama, Takahiro, additional, Meguro, Kazuyuki, additional, Tanaka, Shigeru, additional, Iwata, Arifumi, additional, Suto, Akira, additional, and Nakajima, Hiroshi, additional
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- 2023
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12. Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model
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Akiko, Toyota, Megumi, Goto, Masaya, Miyamoto, Yoko, Nagashima, Shiho, Iwasaki, Takahiro, Komatsu, Takayuki, Momose, Keisuke, Yoshida, Tomoharu, Tsukada, Tetsuyoshi, Matsufuji, Ami, Ohno, Makoto, Suzuki, Osamu, Ubukata, and Yasuyuki, Kaneta
- Subjects
Gene Expression Regulation, Neoplastic ,Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,Young Adult ,Carcinoma, Hepatocellular ,Catalytic Domain ,Liver Neoplasms ,Biophysics ,Humans ,Cell Biology ,HSP40 Heat-Shock Proteins ,Protein Kinase Inhibitors ,Molecular Biology ,Biochemistry - Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.
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- 2022
13. HTLV-1 bZIP factor impairs DNA mismatch repair system
- Author
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Sakurada-Aono, Maki, primary, Sakamoto, Takashi, additional, Kobayashi, Masayuki, additional, Takiuchi, Yoko, additional, Iwai, Fumie, additional, Tada, Kohei, additional, Sasanuma, Hiroyuki, additional, Hirabayashi, Shigeki, additional, Murakawa, Yasuhiro, additional, Shirakawa, Kotaro, additional, Sakamoto, Chihiro, additional, Shindo, Keisuke, additional, Yasunaga, Jun-ichirou, additional, Matsuoka, Masao, additional, Pommier, Yves, additional, Takeda, Shunichi, additional, and Takaori-Kondo, Akifumi, additional
- Published
- 2023
- Full Text
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14. Inhibition of protein phosphatase 2A by okadaic acid induces translocation of nucleocytoplasmic O-GlcNAc transferase
- Author
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Sitosari, Heriati, primary, Morimoto, Ikkei, additional, Weng, Yao, additional, Zheng, Yilin, additional, Fukuhara, Yoko, additional, Ikegame, Mika, additional, and Okamura, Hirohiko, additional
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- 2023
- Full Text
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15. Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model
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Atsushi Kimura, Kenya Kamimura, Marina Ohkoshi-Yamada, Yoko Shinagawa-Kobayashi, Ryo Goto, Takashi Owaki, Chiyumi Oda, Osamu Shibata, Shinichi Morita, Norihiro Sakai, Hiroyuki Abe, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, and Shuji Terai
- Subjects
Benzoxazoles ,Reverse Transcriptase Polymerase Chain Reaction ,Oryzias ,Biophysics ,Cell Biology ,Diet, High-Fat ,Biochemistry ,Animals, Genetically Modified ,Butyrates ,Disease Models, Animal ,Gene Ontology ,Glucosides ,Liver ,Non-alcoholic Fatty Liver Disease ,Exome Sequencing ,Animal Fins ,Quinolines ,Animals ,PPAR alpha ,Benzhydryl Compounds ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Transcriptome ,Sodium-Glucose Transporter 2 Inhibitors ,Molecular Biology - Abstract
Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model.To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples.Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs.The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.
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- 2022
16. Neuron-derived neurotrophic factor protects against dexamethasone-induced skeletal muscle atrophy
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Yuta Ozaki, Koji Ohashi, Naoya Otaka, Hayato Ogawa, Hiroshi Kawanishi, Tomonobu Takikawa, Lixin Fang, Minako Tatsumi, Mikito Takefuji, Takashi Enomoto, Mohamed Darwish, Yoko Iijima, Takatoshi Iijima, Toyoaki Murohara, and Noriyuki Ouchi
- Subjects
Mice, Knockout ,Neurons ,Anti-Inflammatory Agents ,Biophysics ,Cell Biology ,Protective Agents ,Biochemistry ,Dexamethasone ,Mice, Inbred C57BL ,Mice ,Muscular Atrophy ,Gene Expression Regulation ,Animals ,Female ,Nerve Growth Factors ,Phosphorylation ,Muscle, Skeletal ,Molecular Biology - Abstract
Skeletal muscle atrophy caused by various conditions including aging, nerve damage, and steroid administration, is a serious health problem worldwide. We recently reported that neuron-derived neurotrophic factor (NDNF) functions as a muscle-derived secreted factor, also known as myokine, which exerts protective actions on endothelial cell and cardiomyocyte function. Here, we investigated whether NDNF regulates skeletal muscle atrophy induced by steroid administration and sciatic denervation. NDNF-knockout (KO) mice and age-matched wild-type (WT) mice were subjected to continuous dexamethasone (DEX) treatment or sciatic denervation. NDNF-KO mice exhibited decreased gastrocnemius muscle weight and reduced cross sectional area of myocyte fiber after DEX treatment or sciatic denervation compared with WT mice. Administration of an adenoviral vector expressing NDNF (Ad-NDNF) or recombinant NDNF protein to gastrocnemius muscle of WT mice increased gastrocnemius muscle weight after DEX treatment. NDNF-KO mice showed increased expression of ubiquitin E3-ligases, including atrogin-1 and MuRF-1, in gastrocnemius muscle after DEX treatment, whereas Ad-NDNF reduced expression of atrogin-1 and MuRF-1 in gastrocnemius muscle of WT mice after DEX treatment. Pretreatment of cultured C2C12 myocytes with NDNF protein reversed reduced myotube diameter and increased expression of atrogin-1 and MuRF-1 after DEX stimulation. Treatment of C2C12 myocytes increased Akt phosphorylation. Pretreatment of C2C12 myotubes with the PI3-kinase/Akt inhibitor reversed NDNF-induced increase in myotube fiber diameter after DEX treatment. In conclusion, our findings indicated that NDNF prevents skeletal muscle atrophy in vivo and in vitro through reduction of ubiquitin E3-ligases expression, suggesting that NDNF could be a novel therapeutic target of muscle atrophy.
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- 2022
17. Valproic acid promotes differentiation of adipose tissue-derived stem cells to neuronal cells selectively expressing functional N-type voltage-gated Ca2+ channels
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Azusa Satoh, Shinri Fujimoto, Tomohiko Irie, Takehito Suzuki, Yoko Miyazaki, Kazuaki Tanaka, Makoto Usami, and Tatsuya Takizawa
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2022
18. Deubiquitinating enzymes UBP12 and UBP13 regulate carbon/nitrogen-nutrient stress responses by interacting with the membrane-localized ubiquitin ligase ATL31 in Arabidopsis
- Author
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Luo, Yongming, primary, Yasuda, Shigetaka, additional, Takagi, Junpei, additional, Hasegawa, Yoko, additional, Chiba, Yukako, additional, Yamaguchi, Junji, additional, and Sato, Takeo, additional
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- 2022
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19. Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells
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Uchida, Tomoyuki, primary, Oda, Tetsuro, additional, Yamamoto, Takeshi, additional, Inamitsu, Masako, additional, Sakai, Chihiro, additional, Uchinoumi, Hitoshi, additional, Suetomi, Takeshi, additional, Nakamura, Yoshihide, additional, Okamoto, Yoko, additional, Tateda, Satomi, additional, Fujii, Shohei, additional, Tanaka, Shinji, additional, Nawata, Junya, additional, Okamura, Takayuki, additional, Kobayashi, Shigeki, additional, and Yano, Masafumi, additional
- Published
- 2022
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20. Natto extract, a Japanese fermented soybean food, directly inhibits viral infections including SARS-CoV-2 in vitro
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Akatsuki Saito, Yutaka Nibu, Koji Nishifuji, Tetsuya Mizutani, Tamaki Okabayashi, Tomoko Yokota, Hitoshi Wake, Wen Rongduo, Junko Yasuoka, Mami Oba, and Yoko Sato
- Subjects
viruses ,medicine.medical_treatment ,Proteolysis ,Biophysics ,Bacillus subtilis ,Biochemistry ,Article ,Microbiology ,law.invention ,Antiviral effect ,Viral Proteins ,Western blot ,law ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Molecular Biology ,Cells, Cultured ,Herpesvirus 1, Bovine ,Serine protease ,Protease ,medicine.diagnostic_test ,biology ,SARS-CoV-2 ,Plant Extracts ,COVID-19 ,Soy Foods ,virus diseases ,Glycoprotein D ,Herpesviridae Infections ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,In vitro ,Bovine herpesvirus 1 ,COVID-19 Drug Treatment ,biology.protein ,Recombinant DNA ,BHV-1 ,Cattle ,Soybeans ,Receptor binding domain - Abstract
Natto, a traditional Japanese fermented soybean food, is well known to be nutritious and beneficial for health. In this study, we examined whether natto impairs infection by viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as bovine herpesvirus 1 (BHV-1). Interestingly, our results show that both SARS-CoV-2 and BHV-1 treated with a natto extract were fully inhibited infection to the cells. We also found that the glycoprotein D of BHV-1 was shown to be degraded by Western blot analysis and that a recombinant SARS-CoV-2 receptor-binding domain (RBD) was proteolytically degraded when incubated with the natto extract. In addition, RBD protein carrying a point mutation (UK variant N501Y) was also degraded by the natto extract. When the natto extract was heated at 100 °C for 10 min, the ability of both SARS-CoV-2 and BHV-1 to infect to the cells was restored. Consistent with the results of the heat inactivation, a serine protease inhibitor inhibited anti-BHV-1 activity caused by the natto extract. Thus, our findings provide the first evidence that the natto extract contains a protease(s) that inhibits viral infection through the proteolysis of the viral proteins.
- Published
- 2021
21. CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2
- Author
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Hiroaki Suzuki, Hitoshi Shimano, Motohiro Sekiya, Yuki Murayama, Kenji Saito, Takafumi Miyamoto, Yoshinori Takeuchi, Yoko Sugano, Hitoshi Iwasaki, Ryo Takano, Naoya Yahagi, Takehito Sugasawa, Yoshimi Nakagawa, Kenta Kainoh, Yang Ma, Yoshinori Osaki, and Takashi Matsuzaka
- Subjects
0301 basic medicine ,Transcription, Genetic ,NF-E2-Related Factor 2 ,NF-E2-Related Factor 1 ,Biophysics ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,Biochemistry ,Antioxidants ,03 medical and health sciences ,0302 clinical medicine ,Transcriptional regulation ,medicine ,Humans ,Amino Acid Sequence ,NRF1 ,Molecular Biology ,Transcription factor ,Gene ,Obligate ,Binding protein ,Cell Biology ,Cell biology ,Alcohol Oxidoreductases ,Oxidative Stress ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Co-Repressor Proteins ,Oxidative stress ,Protein Binding - Abstract
While molecular oxygen is essential for aerobic organisms, its utilization is inseparably connected with generation of oxidative insults. To cope with the detrimental aspects, cells evolved antioxidative defense systems, and insufficient management of the oxidative insults underlies the pathogenesis of a wide range of diseases. A battery of genes for this antioxidative defense are regulated by the transcription factors nuclear factor-erythroid 2-like 1 and 2 (NRF1 and NRF2). While the regulatory steps for the activation of NRFs have been investigated with particular emphasis on nuclear translocation and proteosomal degradation, unknown redundancy may exist considering the indispensable nature of these defense systems. Here we unraveled that C-terminal binding protein 2 (CtBP2), a transcriptional cofactor with redox-sensing capability, is an obligate partner of NRFs. CtBP2 forms transcriptional complexes with NRF1 and NRF2 that is required to promote the expression of antioxidant genes in response to oxidative insults. Our findings illustrate a basis for understanding the transcriptional regulation of antioxidative defense systems that may be exploited therapeutically.
- Published
- 2021
22. Abnormal cleavage is involved in the self-correction of bovine preimplantation embryos
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Hiroki Nagai, Hiroaki Okae, Ryosuke Suzuki, Yoko Nagai, Yoshiyuki Sakuraba, Mai Okada, and Satoshi Sugimura
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0301 basic medicine ,Blastomeres ,DNA Copy Number Variations ,Cleavage Stage, Ovum ,Biophysics ,Aneuploidy ,Biology ,Cleavage (embryo) ,Morula ,Time-Lapse Imaging ,Biochemistry ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Chromosome instability ,medicine ,Animals ,Zona pellucida ,Molecular Biology ,Zygote ,Embryo ,Cell Biology ,Blastomere ,medicine.disease ,Blastocyst ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,embryonic structures ,Cattle ,Ploidy - Abstract
Chromosome instability leading to aneuploidy during early cleavage is well known in humans and cattle. Partial compaction (PC), which occurs only in some blastomeres, is suggested as a self-correction mechanism through which human embryos avoid aneuploid mosaicism. Partially compacted embryos show abnormal cleavages more frequently during early development; however, the mechanism by which blastomeres are excluded has not been elucidated. Here, we confirmed PC in approximately half of the tested bovine embryos, similar to that in human embryos. DNA sequencing of single-cell and intact embryos revealed that the morulae that excluded some blastomeres had euploidy, but many of the excluded blastomeres had aneuploidy. Time-lapse imaging of zygotes without the zona pellucida revealed that the excluded blastomeres underwent reverse and direct cleavages, which are abnormal cleavages, more frequently than the blastomeres involved in compaction. These results suggest the potential role of abnormal cleavage in the self-correction mechanism during the development of mammalian preimplantation embryos.
- Published
- 2021
23. Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model
- Author
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Toyota, Akiko, primary, Goto, Megumi, additional, Miyamoto, Masaya, additional, Nagashima, Yoko, additional, Iwasaki, Shiho, additional, Komatsu, Takahiro, additional, Momose, Takayuki, additional, Yoshida, Keisuke, additional, Tsukada, Tomoharu, additional, Matsufuji, Tetsuyoshi, additional, Ohno, Ami, additional, Suzuki, Makoto, additional, Ubukata, Osamu, additional, and Kaneta, Yasuyuki, additional
- Published
- 2022
- Full Text
- View/download PDF
24. Trehalose liposomes induce apoptosis of breast tumor cells in vitro and in vivo
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Keiji Kuwabara, Hideaki Ichihara, and Yoko Matsumoto
- Subjects
0301 basic medicine ,Biophysics ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Membrane fluidity ,Animals ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Mice, Inbred BALB C ,Liposome ,TUNEL assay ,Chemistry ,Cell Membrane ,Trehalose ,Cancer ,Cell Biology ,medicine.disease ,Molecular biology ,In vitro ,030104 developmental biology ,030220 oncology & carcinogenesis ,Liposomes ,Female ,Signal Transduction - Abstract
The inhibitory effects of trehalose liposomes (TL) comprising l -α-dimyristoylphosphatidylcholine (DMPC) and α-D-glucopyranosyl-α-D-glucopyranoside monomyritate (TreC14) were investigated on breast cancer MDA-MB-453 cells in vitro and in vivo. The IC50 values of TL for MDA-MB-453 cells were remarkably lower than those of DMPC liposomes. The inhibitory effects of TL on the proliferation of MDA-MB-453 cells mediated via apoptosis induction were observed following their accumulation on MDA-MB-453 cell membranes. The membrane fluidity of MDA-MB-453 cells increased after TL treatment, as evident from a fluorescence depolarization assay. TL induced the apoptosis of MDA-MB-453 cells through caspase activation and mitochondrial membrane potential reduction, and suppressed the nuclear factor kappa B activity. A remarkable reduction in tumor volume was observed in a human breast cancer mouse model topically treated with TL. Induction of apoptosis was evident in TL-treated breast cancer tumors of mice using the TUNEL assay.
- Published
- 2020
25. Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model
- Author
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Kimura, Atsushi, primary, Kamimura, Kenya, additional, Ohkoshi-Yamada, Marina, additional, Shinagawa-Kobayashi, Yoko, additional, Goto, Ryo, additional, Owaki, Takashi, additional, Oda, Chiyumi, additional, Shibata, Osamu, additional, Morita, Shinichi, additional, Sakai, Norihiro, additional, Abe, Hiroyuki, additional, Yokoo, Takeshi, additional, Sakamaki, Akira, additional, Kamimura, Hiroteru, additional, and Terai, Shuji, additional
- Published
- 2022
- Full Text
- View/download PDF
26. Neuron-derived neurotrophic factor protects against dexamethasone-induced skeletal muscle atrophy
- Author
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Ozaki, Yuta, primary, Ohashi, Koji, additional, Otaka, Naoya, additional, Ogawa, Hayato, additional, Kawanishi, Hiroshi, additional, Takikawa, Tomonobu, additional, Fang, Lixin, additional, Tatsumi, Minako, additional, Takefuji, Mikito, additional, Enomoto, Takashi, additional, Darwish, Mohamed, additional, Iijima, Yoko, additional, Iijima, Takatoshi, additional, Murohara, Toyoaki, additional, and Ouchi, Noriyuki, additional
- Published
- 2022
- Full Text
- View/download PDF
27. Valproic acid promotes differentiation of adipose tissue-derived stem cells to neuronal cells selectively expressing functional N-type voltage-gated Ca2+ channels
- Author
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Satoh, Azusa, primary, Fujimoto, Shinri, additional, Irie, Tomohiko, additional, Suzuki, Takehito, additional, Miyazaki, Yoko, additional, Tanaka, Kazuaki, additional, Usami, Makoto, additional, and Takizawa, Tatsuya, additional
- Published
- 2022
- Full Text
- View/download PDF
28. An aspherical microlens assembly for deep brain fluorescence microendoscopy
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Yoko Kudo, Masaaki Sato, Sano Shotaro, Junichi Nakai, and Watanabe Hiroki
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0301 basic medicine ,Materials science ,Biophysics ,Biochemistry ,Fluorescence ,law.invention ,Radius of curvature (optics) ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Optics ,law ,Chromatic aberration ,Animals ,Molecular Biology ,Brain Chemistry ,Endoscopes ,Microlens ,business.industry ,Optical Imaging ,Brain ,Endoscopy ,Equipment Design ,Cell Biology ,Optical axis ,Lens (optics) ,030104 developmental biology ,030220 oncology & carcinogenesis ,Calcium ,Gradient-index optics ,Monochromatic color ,business ,Refractive index - Abstract
Fluorescence microendoscopy is becoming a standard technique in neuroscience for visualizing neuronal activity in the deep brain. Gradient refractive index (GRIN) lenses are increasingly used for fluorescence microendoscopy; however, they inherently suffer from strong aberrations and distortion. Aspherical lenses change their radius of curvature with distance from the optical axis and can effectively eliminate spherical aberrations. The use of these lenses has not been fully explored in deep brain fluorescence microendoscopy due to technical difficulties in manufacturing miniature aspherical lenses. In this study, we fabricated a novel microendoscope lens assembly comprised two nested pairs of aspherical microlenses made by precision glass molding. This assembly, which was 0.6 mm in diameter and 7.06 mm in length, was assembled in a stainless steel tube of 0.7 mm outer diameter. This assembly exhibited marked improvements in monochromatic and chromatic aberrations compared with a conventional GRIN lens, and is useful for deep brain fluorescence microendoscopy, as demonstrated by two-photon microendoscopic calcium imaging of R-CaMP1.07-labeled mouse hippocampal CA1 neurons. Our aspherical-lens-based approach offers a non-GRIN-lens alternative for fabrication of microendoscopic lenses.
- Published
- 2020
29. Stabilizing cardiac ryanodine receptor prevents the development of cardiac dysfunction and lethal arrhythmia in Ca2+/calmodulin-dependent protein kinase IIδc transgenic mice
- Author
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Tetsuro Oda, Shinichi Okuda, Masafumi Yano, Takayoshi Kato, Yoko Sufu-Shimizu, Takeshi Yamamoto, Hitoshi Uchinoumi, Shigehiko Nishimura, and Shigeki Kobayashi
- Subjects
0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Calmodulin ,Biophysics ,Biochemistry ,Ryanodine receptor 2 ,Dantrolene ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ca2+/calmodulin-dependent protein kinase ,medicine ,Protein kinase A ,Molecular Biology ,biology ,Chemistry ,Ryanodine receptor ,Cell Biology ,musculoskeletal system ,medicine.disease ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Heart failure ,cardiovascular system ,biology.protein ,tissues ,medicine.drug - Abstract
Aims Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca2+ release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca2+ release, cardiac function, and lethal arrhythmia in CaMKIIδc transgenic (TG) mice. Methods and results The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca2+ transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. Conclusions Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.
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- 2020
30. Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, lead to noncompaction cardiomyopathy in mice
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Mayuko Kosugi, Kohei Sakai, Tohru Kimura, Yoko Itakura, Mai Otani, Toshiaki Ito, Yurika Kikkawa, Yoichi Sekita, and Masashi Toyoda
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0301 basic medicine ,Genetics ,Noncompaction cardiomyopathy ,Autosome ,biology ,Biophysics ,Cell Biology ,Human Males ,Y chromosome ,medicine.disease ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,Demethylase ,Molecular Biology ,Gene ,Functional divergence - Abstract
Mammalian X and Y chromosomes evolved from a pair of autosomes. Although most ancestral genes have been lost from the Y chromosome, a small number of ancestral X-Y gene pairs are still present on the sex chromosomes. The KDM5C and KDM5D genes, which encode H3K4 histone demethylases, are a surviving ancestral gene pair located on the X and Y chromosomes, respectively. Mutations in KDM5C cause X-linked intellectual disability in human males, suggesting functional divergence between KDM5C and KDM5D in the nervous system. In this study, to explore the functional conservation and divergence between these two genes in other organs, we generated female mice lacking Kdm5c (homozygous X5c- X5c- females) and male mice lacking both Kdm5c and Kdm5d (compound hemizygous X5c- Y5d- males). Both X5c- X5c- females and X5c- Y5d- males showed lower body weights and postnatal lethality. Histological examination of the hearts showed prominent trabecular extension and a thin layer of compacted myocardium in the left and right ventricles, indicating noncompaction cardiomyopathy. However, hemizygous males lacking either Kdm5c or Kdm5d showed no signs of noncompaction cardiomyopathy. These results clearly demonstrate that the function of Kdm5c and Kdm5d in heart development is conserved.
- Published
- 2020
31. The role of actinin-4 (ACTN4) in exosomes as a potential novel therapeutic target in castration-resistant prostate cancer
- Author
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Cong Wang, Ryoichi Imamura, Takeshi Tomonaga, Eisuke Tomiyama, Yu Ishizuya, Kazutoshi Fujita, Atsunari Kawashima, Taigo Kato, Yoko Koh, Koji Hatano, Makoto Matsushita, Ryohei Narumi, Norio Nonomura, Kosuke Nakano, Takeshi Ujike, Motohide Uemura, Yujiro Hayashi, and Jun Adachi
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Male ,Proteomics ,0301 basic medicine ,Biophysics ,Exosomes ,urologic and male genital diseases ,Biochemistry ,Metastasis ,Androgen deprivation therapy ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Downregulation and upregulation ,DU145 ,Cell Line, Tumor ,medicine ,Humans ,Actinin ,Neoplasm Invasiveness ,Molecular Biology ,Cell growth ,business.industry ,Cell Biology ,medicine.disease ,Microvesicles ,Gene Expression Regulation, Neoplastic ,Prostatic Neoplasms, Castration-Resistant ,RNAi Therapeutics ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,RNA Interference ,business - Abstract
Prostate cancer is the second leading cause of cancer death in men in the United States. Several novel therapeutic agents have been developed for castration-resistant prostate cancer (CRPC), but the prognosis for patients with CRPC remains poor. The identification of novel therapeutic targets for CRPC is an urgent issue. Exosomes are small vesicles secreted by a variety of cells, and exosomes derived from cancer cells have been reported to circulate in the patient’s bodily fluids, promoting metastasis and invasion. We aimed to identify novel therapeutic targets for CRPC by proteomic analysis of serum exosomes. Exosomes were isolated by ultracentrifugation of sera from 36 men with metastatic prostate cancer: untreated (n = 8), well-controlled with primary androgen deprivation therapy (ADT) (n = 8), and CRPC (n = 20). We identified 823 proteins in the serum exosomes. Six proteins were increased in CRPC patients compared with untreated patients. In contrast, only ACTN4 was increased in the CRPC patients compared to the ADT patients. We focused on ACTN4 as a candidate for targeted therapeutics. ACTN4 was highly expressed in the prostate cancer cell line DU145 as well as exosomes from this line. RNA interference-mediated downregulation of ACTN4 significantly attenuated cell proliferation and invasion in DU145 cells. ACTN4 could be a potential therapeutic target for CRPC.
- Published
- 2020
32. Valproic acid promotes differentiation of adipose tissue-derived stem cells to neuronal cells selectively expressing functional N-type voltage-gated Ca
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Azusa, Satoh, Shinri, Fujimoto, Tomohiko, Irie, Takehito, Suzuki, Yoko, Miyazaki, Kazuaki, Tanaka, Makoto, Usami, and Tatsuya, Takizawa
- Subjects
Male ,Neurons ,Calcium Channels, N-Type ,Adipose Tissue ,Transcription, Genetic ,Stem Cells ,Valproic Acid ,Animals ,Calcium ,Cell Differentiation ,Rats, Wistar ,Culture Media - Abstract
The differentiation of adipose tissue-derived stem cells (ASCs) to neuronal cells is greatly promoted by valproic acid (VPA), and is synergistically enhanced by the following treatment with neuronal induction medium (NIM) containing cAMP-elevating agents. In the present study, we investigated the synergism between VPA and NIM in neuronal differentiation of ASCs, assessed by the expression of neurofilament medium polypeptide (NeFM), with respect to Ca
- Published
- 2021
33. Roles of the indole ring of Trp396 covalently bound with the imidazole ring of His398 coordinated to type I copper in bilirubin oxidase
- Author
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Takahiro Ito, Takeshi Sakurai, Satoshi Yamashita, Yoko Sakai, Yoko Okuda, and Kunishige Kataoka
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0301 basic medicine ,Models, Molecular ,Oxidoreductases Acting on CH-CH Group Donors ,Indoles ,Stereochemistry ,Protein Conformation ,Biophysics ,chemistry.chemical_element ,Multicopper oxidase ,Biochemistry ,Redox ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Moiety ,Imidazole ,Point Mutation ,Bilirubin oxidase ,Molecular Biology ,Indole test ,Imidazoles ,Cell Biology ,Copper ,Electron transport chain ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Hypocreales ,Oxidation-Reduction ,Protein Processing, Post-Translational - Abstract
Bilirubin oxidase has a post-translationally formed covalent-bond between the imidazole ring of His398 coordinated to type I copper and the indole ring of Trp396 located in the outer-coordination sphere. We performed point mutations at Trp396 with Ala, Thr, Phe, and Tyr with the aim of elucidating the role of the imidazole-indole moiety found only in bilirubin oxidase. The result showed shifts in the redox potential of type I copper towards negative direction by > 100 mV and decreases in cathodic current in electrochemistry, whereas optical and magnetic properties of type I copper were not affected or sparingly affected. Along with the conspicuous changes in redox properties enzymatic activities of the Trp396 mutants were prominently decreased. Further, chemical modification of the Trp residues with N-bromosuccinimide and photo-induced formylations of bilirubin oxidase exerted more pronounced effects on both redox properties and enzymatic activities compared to the Trp396 mutants. All these results unequivocally indicate that the covalent-bond formed between Trp396 and His398 plays a crucial role to enhance enzymatic activities of bilirubin oxidase by shifting the redox potential of type I Cu towards positive direction and also by functioning as the effective pathway of electron transport.
- Published
- 2019
34. Natto extract, a Japanese fermented soybean food, directly inhibits viral infections including SARS-CoV-2 in vitro
- Author
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Oba, Mami, primary, Rongduo, Wen, additional, Saito, Akatsuki, additional, Okabayashi, Tamaki, additional, Yokota, Tomoko, additional, Yasuoka, Junko, additional, Sato, Yoko, additional, Nishifuji, Koji, additional, Wake, Hitoshi, additional, Nibu, Yutaka, additional, and Mizutani, Tetsuya, additional
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- 2021
- Full Text
- View/download PDF
35. CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2
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Kainoh, Kenta, primary, Takano, Ryo, additional, Sekiya, Motohiro, additional, Saito, Kenji, additional, Sugasawa, Takehito, additional, Ma, Yang, additional, Murayama, Yuki, additional, Sugano, Yoko, additional, Osaki, Yoshinori, additional, Iwasaki, Hitoshi, additional, Takeuchi, Yoshinori, additional, Yahagi, Naoya, additional, Suzuki, Hiroaki, additional, Miyamoto, Takafumi, additional, Nakagawa, Yoshimi, additional, Matsuzaka, Takashi, additional, and Shimano, Hitoshi, additional
- Published
- 2021
- Full Text
- View/download PDF
36. Abnormal cleavage is involved in the self-correction of bovine preimplantation embryos
- Author
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Nagai, Hiroki, primary, Okada, Mai, additional, Nagai, Yoko, additional, Sakuraba, Yoshiyuki, additional, Okae, Hiroaki, additional, Suzuki, Ryosuke, additional, and Sugimura, Satoshi, additional
- Published
- 2021
- Full Text
- View/download PDF
37. Identification by nano-LC-MS/MS of NT5DC2 as a protein binding to tyrosine hydroxylase: Down-regulation of NT5DC2 by siRNA increases catecholamine synthesis in PC12D cells
- Author
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Yoko S. Kaneko, Toshiharu Nagatsu, Miho Kawata, Akira Nakashima, Hisateru Yamaguchi, Hiroshi Nagasaki, Yu Kodani, and Akira Ota
- Subjects
0301 basic medicine ,Tyrosine 3-Monooxygenase ,Protein family ,Immunoprecipitation ,Phosphatase ,Biophysics ,Down-Regulation ,PC12 Cells ,Biochemistry ,Cell Line ,03 medical and health sciences ,Catecholamines ,0302 clinical medicine ,Tandem Mass Spectrometry ,Dopamine ,medicine ,Animals ,RNA, Small Interfering ,5'-Nucleotidase ,Molecular Biology ,Tyrosine hydroxylase ,Kinase ,Chemistry ,Cell Biology ,Rats ,030104 developmental biology ,030220 oncology & carcinogenesis ,Phosphorylation ,RNA Interference ,Intracellular ,Chromatography, Liquid ,Protein Binding ,medicine.drug - Abstract
Tyrosine hydroxylase (TH), which catalyzes the conversion of l-tyrosine to l-DOPA, is the rate-limiting enzyme in the biosynthesis of catecholamines. It is well known that both α-synuclein and 14-3-3 protein family members bind to the TH molecule and regulate phosphorylation of its N-terminus by kinases to control the catalytic activity. In this present study we investigated whether other proteins aside from these 2 proteins might also bind to TH molecules. Nano-LC-MS/MS analysis revealed that 5'-nucleotidase domain-containing protein 2 (NT5DC2), belonging to a family of haloacid dehalogenase-type (HAD) phosphatases, was detected in the immunoprecipitate of PC12D cell lysates that had been reacted with Dynabeads protein G-anti-TH antibody conjugate. Surprisingly, NT5DC2 had already been revealed by Genome-Wide Association Studies (GWAS) as a gene implicated in neuropsychiatric disorders such as schizophrenia, bipolar disorder, which are diseases related to the abnormality of dopamine activity in the brain, although the role that NT5DC2 plays in these diseases remains unknown. Therefore, we investigated the effect of NT5DC2 on the TH molecule. The down-regulation of NT5DC2 by siRNA increased the synthesis of catecholamines (dopamine, noradrenaline, and adrenaline) in PC12D cells. These increases might be attributed to the catalytic activity of TH and not to the intracellular stability of TH, because the intracellular content of TH assessed by Western blotting was not changed by the down-regulation of NT5DC2. Collectively, our results indicate that NT5DC2 inhibited the synthesis of dopamine by decreasing the enzymatic activity of TH.
- Published
- 2019
38. A screening for DNA damage response molecules that affect HIV-1 infection
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Yusuke Matsui, Kotaro Shirakawa, Keisuke Shindo, Noriyoshi Yoshinaga, Kayoko Nagata, Hirofumi Fukuda, Yoko Takiuchi, Akifumi Takaori-Kondo, Masayuki Kobayashi, and Shunichi Takeda
- Subjects
0301 basic medicine ,DNA Repair ,DNA damage ,DNA repair ,Ubiquitin-Protein Ligases ,Biophysics ,HIV Infections ,Virus Replication ,Virus-host interactions ,DNA damage response ,Biochemistry ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Retrovirus ,Humans ,Molecular Biology ,Host factor ,Infectivity ,biology ,RAD18 ,Chemistry ,Cell Biology ,Reverse transcription ,biology.organism_classification ,Molecular biology ,Reverse transcriptase ,Long terminal repeat ,DNA-Binding Proteins ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,DNA, Viral ,Host-Pathogen Interactions ,Host factors ,HIV-1 ,DNA ,DNA Damage - Abstract
Host DNA damage response molecules affect retroviral infection, as DNA intermediates of the viruses play essential roles in the viral life cycles. Although several such molecules have been reported, interactions between HIV-1 and host DNA damage response molecules have not been fully elucidated. To screen DNA damage response molecules that might affect HIV-1 infection, a set of 32 DNA-repair-deficient DT40 isogenic mutant cells were tested for HIV-1 infectivity. Seven out of the 32 clones showed less than 50% infectivity compared to parental DT40 cells, implying that DNA repair molecules deficient in these cells might support HIV-1 infection. Of these, EXO1 −/−, TP53BP1 −/− and WRN −/− cells showed more than twofold accumulation of two long terminal repeat circles and less than 50% integrated proviral DNA in quantitative-PCR analyses, indicating that the integration step is impaired. RAD18 −/− cells showed twofold higher HIV-1 infectivity and increased reverse transcription products at earlier time points, suggesting that RAD18 suppresses reverse transcription. The HIV-1 suppressive effects of RAD18 were confirmed by over-expression and knockdown experiments in human cells. L274P, a DNA-binding-impaired mutant of RAD18, showed impaired HIV-1 suppression and DNA binding, suggesting that binding HIV-1 DNA intermediates is critical for RAD18 to suppress reverse transcription and HIV-1 infection. Our data help understand interactions between host DNA damage response molecules and viral DNA.
- Published
- 2019
39. Therapeutic effects and anti-metastasis effects of cationic liposomes against pancreatic cancer metastasis in vitro and in vivo
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Muneaki Motomura, Hideaki Ichihara, and Yoko Matsumoto
- Subjects
0301 basic medicine ,MMP2 ,endocrine system diseases ,Biophysics ,MMP9 ,Biochemistry ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,In vivo ,Cations ,Cell Line, Tumor ,Pancreatic cancer ,Ethylamines ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Cationic liposome ,Molecular Biology ,Mice, Inbred BALB C ,Chemistry ,Matrigel Invasion Assay ,Cell Biology ,medicine.disease ,In vitro ,Pancreatic Neoplasms ,030104 developmental biology ,Ethanolamines ,030220 oncology & carcinogenesis ,Liposomes ,Cancer research ,Dimyristoylphosphatidylcholine - Abstract
The anti-metastatic effects of cationic liposomes (CL) composed of 87 mol% dimyristoylphosphatidylcholine (DMPC), 8 mol% O,O′-ditetradecanoyl-N-(α–trimethylammonioacetyl) diethanolamine chloride (2C14ECl) and 5 mol% polyoxyethylene(21) dodecyl ether (C12(EO)21) was investigated for human pancreatic cancer (BxPC-3) cells. The inhibitory effect of CL on the migration of BxPC-3 cells was observed based on a wound scratch assay. CL suppressed pseudopodium formation of BxPC-3 cells. The anti-invasive effect of CL against BxPC-3 cells was observed via a Matrigel invasion assay. The anti-invasive effect of CL for BxPC-3 cells was found to occur through the inhibition of MMP2, MMP9, and MMP14. Overall, the results of this study revealed for the first time, the therapeutic effects and anti-metastasis activity of CL in xenograft mouse models for peritoneal metastasis of human pancreatic cancer.
- Published
- 2019
40. Azepine derivative T4FAT, a new copper chelator, inhibits tyrosinase
- Author
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Shinya Kato, Hiroshi Takemori, Sayaka Okajima, Masataka Asano, Akie Hamamoto, Yoko Hirata, Kenta Isogawa, Hironari Ito, and Kyoji Furuta
- Subjects
0301 basic medicine ,Tyrosinase ,Melanoma, Experimental ,Biophysics ,Biochemistry ,Melanin ,Hydroxylation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Chelation ,Enzyme Inhibitors ,Molecular Biology ,Chelating Agents ,Melanins ,Monophenol Monooxygenase ,Chemistry ,Skin whitening ,Azepines ,Cell Biology ,Copper Chelation ,Hyperpigmentation ,Thioamides ,030104 developmental biology ,030220 oncology & carcinogenesis ,medicine.symptom ,Agaricales ,Kojic acid ,Copper - Abstract
Melanin plays an important role in the protection of the skin from ultraviolet irradiation. However, excessive melanin deposition leads to hyperpigmentation and freckles, which are recognized as skin problems, and signs of aging. Tyrosinase, a copper-containing protein, is the rate-limiting enzyme in melanin biosynthesis and first catalyzes the hydroxylation of l -tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and the further oxidization to dopaquinone. To assist the proper regulation of melanin production, we screened compounds and found that 5,6,7,8-tetrahydro-4H-furo[3,2-c]azepine-4-thione (T4FAT), a thioamide derivative, inhibited melanogenesis in B16F10 mouse melanoma cells. T4FAT was not toxic to cells and was stable in water; in addition, it inhibited the activity of tyrosinase derived from mushroom and B16F10 cells in a non-competitive manner. T4FAT downregulated tyrosinase protein expression in B16F10 cells without affecting mRNA expression. As copper binding to the tyrosinase protein is required for both enzymatic activity, correct folding, and maturation, we examined the metal-chelating activities of T4FAT. Equimolar amount of T4FAT resulted in almost complete chelation of copper ions. The thioamide group of T4FAT is essential for copper chelation and tyrosinase inhibition, which subsequently resulted in melanogenesis inhibition in B16F10 cells. Although T4FAT has similar in vitro properties to kojic acid, which is also a copper chelator and approved as a component of cosmetic formulations, T4FAT inhibited melanogenesis in B16F10 cells 30 times more efficiently than kojic acid. These results suggested that T4FAT, a novel copper chelator, may be helpful for the development of new cosmetics for skin whitening.
- Published
- 2019
41. Inhibitory effect of hybrid liposomes on the growth of liver cancer stem cells
- Author
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Seiichi Ishida, Yoko Matsumoto, Kosuke Inamura, Mami Yamakuchi, Yuji Komizu, and Taku Matsushita
- Subjects
0301 basic medicine ,Cell ,Biophysics ,Apoptosis ,Biochemistry ,Polyethylene Glycols ,Flow cytometry ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cancer stem cell ,medicine ,Humans ,Viability assay ,Molecular Biology ,Cell Proliferation ,Antibiotics, Antineoplastic ,medicine.diagnostic_test ,Cell growth ,Chemistry ,Liver Neoplasms ,Hep G2 Cells ,Cell Biology ,medicine.disease ,Molecular biology ,030104 developmental biology ,medicine.anatomical_structure ,Doxorubicin ,030220 oncology & carcinogenesis ,Liposomes ,Neoplastic Stem Cells ,Trypan blue ,Stem cell ,Dimyristoylphosphatidylcholine - Abstract
Purpose Cancer stem cells (CSCs), also known as tumor-initiating cells, are involved in tumor progression, metastasis, and drug resistance. Hybrid liposomes (HLs) are nano-sized liposomal particles that can be easily prepared by ultrasonicating a mixture of vesicular and micellar molecules in buffer solutions. In this study, we investigated the inhibitory effects of HL on the growth of CSC subpopulations in liver cancer cells (HepG2) in vitro. Methods HLs composed of 90 mol% L-α-dimyristoylphosphatidylcholine and 10 mol% polyoxyethylene(23) dodecyl ether were prepared by sonication. Cell viability was determined by the trypan blue exclusion assay. In liver cancer cells, CSCs were identified by the presence of the cell surface marker proteins CD133 and EpCAM by flow cytometry. A soft agar colony formation assay was performed using HepG2 cells pretreated with HLs. Results HLs selectively inhibited liver cancer cell growth without affecting normal hepatocytes. Additionally, HLs induced apoptosis of HepG2 cells by a"ctivating caspase-3. Notably, the CD133(+)/EpCAM(+) CSC sub-population of liver cancer cells treated with HLs was reduced. Furthermore, HLs markedly decreased the number of colony-forming cells. Finally, we confirmed the fusion and accumulation of HLs into the cell membranes of CSCs using a fluorescently labeled lipid (NBDPC). Significant accumulation of HL/NBDPC into the CSCs (particularly EpCAM(+) cells) occurred in a dose-dependent manner. Conclusion These results suggest that HLs are a novel nanomedical therapeutic agent for targeting CSCs in liver cancer therapy.
- Published
- 2019
42. Circular orientation fluorescence emitter imaging (COFEI) of rotational motion of motor proteins
- Author
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Mitsuhiro Sugawa, Yoko Y. Toyoshima, Kei Saito, Keitaro Shibata, Fumihiko Fujii, Junichiro Yajima, Shin Yamaguchi, Tomoko Masaike, Nagisa Mikami, and Takayuki Nishizaka
- Subjects
0301 basic medicine ,Materials science ,Rotation ,Biophysics ,Kinesins ,Bacillus ,Fluorescence Polarization ,Biochemistry ,03 medical and health sciences ,Adenosine Triphosphate ,Optics ,Bacterial Proteins ,Molecular Biology ,Common emitter ,030102 biochemistry & molecular biology ,business.industry ,Molecular Motor Proteins ,System of measurement ,Intermolecular force ,Rotation around a fixed axis ,Cell Biology ,Polarization (waves) ,Fluorescence ,Single Molecule Imaging ,Kinetics ,Proton-Translocating ATPases ,030104 developmental biology ,Microscopy, Fluorescence ,Nanorod ,business ,Fluorescence anisotropy ,Protein Binding - Abstract
Single-molecule fluorescence polarization technique has been utilized to detect structural changes in biomolecules and intermolecular interactions. Here we developed a single-molecule fluorescence polarization measurement system, named circular orientation fluorescence emitter imaging (COFEI), in which a ring pattern of an acquired fluorescent image (COFEI image) represents an orientation of a polarization and a polarization factor. Rotation and pattern change of the COFEI image allow us to find changes in the polarization by eye and further values of the parameters of a polarization are determined by simple image analysis with high accuracy. We validated its potential applications of COFEI by three assays: 1) Detection of stepwise rotation of F1-ATPase via single quantum nanorod attached to the rotary shaft γ; 2) Visualization of binding of fluorescent ATP analog to the catalytic subunit in F1-ATPase; and 3) Association and dissociation of one head of dimeric kinesin-1 on the microtubule during its processive movement through single bifunctional fluorescent probes attached to the head. These results indicate that the COFEI provides us the advantages of the user-friendly measurement system and persuasive data presentations.
- Published
- 2018
43. Roles of the indole ring of Trp396 covalently bound with the imidazole ring of His398 coordinated to type I copper in bilirubin oxidase
- Author
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Kataoka, Kunishige, primary, Ito, Takahiro, additional, Okuda, Yoko, additional, Sakai, Yoko, additional, Yamashita, Satoshi, additional, and Sakurai, Takeshi, additional
- Published
- 2020
- Full Text
- View/download PDF
44. Stabilizing cardiac ryanodine receptor prevents the development of cardiac dysfunction and lethal arrhythmia in Ca
- Author
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Yoko, Sufu-Shimizu, Shinichi, Okuda, Takayoshi, Kato, Shigehiko, Nishimura, Hitoshi, Uchinoumi, Tetsuro, Oda, Shigeki, Kobayashi, Takeshi, Yamamoto, and Masafumi, Yano
- Subjects
Muscle Relaxants, Central ,Arrhythmias, Cardiac ,Heart ,Mice, Transgenic ,Ryanodine Receptor Calcium Release Channel ,Dantrolene ,Up-Regulation ,Mice ,Animals ,Calcium ,Gene Knock-In Techniques ,Phosphorylation ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cells, Cultured - Abstract
CaThe TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous CaDefective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.
- Published
- 2019
45. Transcriptional co-repressor CtBP2 orchestrates epithelial-mesenchymal transition through a novel transcriptional holocomplex with OCT1
- Author
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Yoshinori Takeuchi, Takaaki Matsuda, Takafumi Miyamoto, Yoshimi Nakagawa, Hiroaki Suzuki, Hitoshi Shimano, Motohiro Sekiya, Yoko Sugano, Yoshinori Osaki, Takashi Matsuzaka, Kenta Kainoh, Yang Ma, Hitoshi Iwasaki, and Naoya Yahagi
- Subjects
0301 basic medicine ,Epithelial-Mesenchymal Transition ,Biophysics ,Breast Neoplasms ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Transforming Growth Factor beta ,Cell Line, Tumor ,Gene expression ,Animals ,Humans ,Gene Regulatory Networks ,Protein Interaction Domains and Motifs ,Epithelial–mesenchymal transition ,Amino Acid Sequence ,Molecular Biology ,Octamer transcription factor ,Conserved Sequence ,POU domain ,Chemistry ,Activator (genetics) ,Cell Biology ,CTBP2 ,Cell biology ,Rats ,Alcohol Oxidoreductases ,030104 developmental biology ,030220 oncology & carcinogenesis ,embryonic structures ,Mutation ,MCF-7 Cells ,Homeobox ,Female ,Co-Repressor Proteins ,Transforming growth factor ,Octamer Transcription Factor-1 - Abstract
The epithelial to mesenchymal transition (EMT) is a cell intrinsic program controlling cellular morphological and phenotypic remodeling in a wide range of biological processes. Despite the accumulating evidence, the transcriptional networks regulating EMT still remain to be elucidated. In this study, we demonstrate that C-terminal binding protein 2 (CtBP2), a critical transcriptional co-repressor harboring pyridine nucleotide sensing capability, orchestrates the EMT program at least in part through a novel transcriptional interaction with an octamer transcription factor, OCT1 (POU2F1, POU class 2 homeobox 1). We identified novel interactions of CtBP2 with several octamer transcription factors, and CtBP2 exhibits a direct interaction with OCT1 in particular. OCT1 accelerates the EMT program as reported, which is diminished by the mutation of the CtBP-binding motif in OCT1, suggesting OCT1 represses epithelial gene expression through recruiting the co-repressor CtBP2. In accordance with these findings, a canonical EMT activator transforming growth factor-β (TGF-β) promotes the formation of the CtBP2/OCT1 complex. Our observations illustrate the role of CtBP2 to orchestrate the EMT program through the interaction with OCT1 and highlight the potential of therapeutic exploitation of this new transcriptional system for a wide range of diseases.
- Published
- 2019
46. FADS2 inhibition in essential fatty acid deficiency induces hepatic lipid accumulation via impairment of very low-density lipoprotein (VLDL) secretion
- Author
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Ikuyo Ichi, Ayano Shimamura, Yoko Fujiwara, Tomoko Ishikawa, and Yuri Hayashi
- Subjects
Fatty Acid Desaturases ,Male ,0301 basic medicine ,medicine.medical_specialty ,Very low-density lipoprotein ,FADS2 ,Biophysics ,Lipoproteins, VLDL ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,8,11,14-Eicosatrienoic Acid ,0302 clinical medicine ,Essential fatty acid ,Mead acid ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Unsaturated fatty acid ,chemistry.chemical_classification ,biology ,Chemistry ,Cell Biology ,Lipid Metabolism ,Eicosapentaenoic acid ,Fatty Liver ,Mice, Inbred C57BL ,030104 developmental biology ,Fatty acid desaturase ,Endocrinology ,Liver ,030220 oncology & carcinogenesis ,Fatty Acids, Unsaturated ,Phosphatidylcholines ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid ,Oxidation-Reduction - Abstract
Fatty acid desaturase 2 (FADS2) is responsible for the first desaturation reaction in the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5n-3), and is involved in Mead acid (20:3n-9) production during essential fatty acid deficiency (EFAD). In this study, an obvious hepatic lipid accumulation was observed in EFAD mice treated with a FADS2 inhibitor. FADS2 inhibition in the EFAD state reduced secretion of very low-density lipoprotein (VLDL) and markedly diminished Mead acid in phosphatidylcholine (PC) in the liver and plasma. As the results, the amount of C20 HUFAs in hepatic and plasma PC dramatically reduced in the EFAD mice treated with a FADS2 inhibitor, whereas the decrease of C20 HUFA levels of PC in EFAD mice was not observed because of the increased Mead acid in PC. These results supposed that Mead acid in PC is important as a component of VLDL. It is possible that Mead acid plays the role of a substitute of HUFAs in VLDL secretion during EFAD.
- Published
- 2018
47. Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model
- Author
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Ryo Goto, Satoshi Abe, Kohei Ogawa, Isao Sakaida, Takuro Nagoya, Yoshizu Nozawa, Soichi Sugitani, Akira Sakamaki, Koichi Fujisawa, Makoto Furutani-Seiki, Yoko Shinagawa-Kobayashi, Norihiro Sakai, Kenya Kamimura, Ryosuke Inoue, Naoto Koyama, Shuji Terai, Takeshi Yokoo, Masahiko Yanagi, and Hiroshi Nishina
- Subjects
Niacinamide ,0301 basic medicine ,Sorafenib ,Carcinoma, Hepatocellular ,Transgene ,Oryzias ,Biophysics ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,Green fluorescent protein ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Histidine ,Molecular Biology ,chemistry.chemical_classification ,Chemistry ,Cell growth ,Phenylurea Compounds ,Liver Neoplasms ,Cell Biology ,medicine.disease ,Amino acid ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Blood Vessels ,Blood Flow Velocity ,medicine.drug - Abstract
Background Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. Methods The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Results Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. Conclusion We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.
- Published
- 2018
48. CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy
- Author
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Shigehiko Nishimura, Yoko Sufu-Shimizu, Masakazu Fukuda, Masafumi Yano, Sachio Morimoto, Tetsuro Oda, Takeshi Yamamoto, Shigeki Kobayashi, Shinichi Okuda, and Takayoshi Kato
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Biophysics ,030204 cardiovascular system & hematology ,Biochemistry ,Ryanodine receptor 2 ,Dantrolene ,03 medical and health sciences ,0302 clinical medicine ,Ca2+/calmodulin-dependent protein kinase ,Internal medicine ,medicine ,Molecular Biology ,Troponin T ,Chemistry ,Ryanodine receptor ,Kinase ,Endoplasmic reticulum ,Cell Biology ,musculoskeletal system ,030104 developmental biology ,Endocrinology ,cardiovascular system ,Phosphorylation ,tissues ,medicine.drug - Abstract
Aims Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). Methods and results In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1–5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. Conclusions In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia.
- Published
- 2018
49. Rapgef2, a guanine nucleotide exchange factor for Rapl small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression
- Author
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Farag, Maged Ibrahim, Yoshikawa, Yoko, Maeta, Kazuhiro, and Kataoka, Tohru
- Subjects
Rap1 ,ERK ,Small GTPase ,Rapgef2 ,sense organs ,Radial glial cells ,Adherence junction - Abstract
Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex. The results show that Rapgef2-deficient RGCs exhibit a decreased ability of neurosphere formation, morphological changes represented by regression of radial glial (RG) fibers and reduced expression of AJ-constituent proteins such as N-cadherin, zonula occludens-1, E-cadherin and β-catenin. Moreover, siRNA-mediated knockdown of Rapgef2 or Rap1A inhibits the AJ protein expression and RG fiber formation while overexpression of Rapgef2, Rapgef6, Rap1A(G12V) or Rap1B(G12V) in Rapgef2-deficient RGCs restores them. Furthermore, Rapgef2-deficient RGCs exhibit a reduction in phosphorylation of extracellular signal-regulated kinase (ERK) leading to downregulation of the expression of c-jun, which is implicated in the AJ protein expression. These results indicate a crucial role of the Rapgef2-Rap1A-ERK-c-jun pathway in regulation of the AJ formation in RGCs.
- Published
- 2017
50. Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression
- Author
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Tohru Kataoka, Maged Ibrahim Farag, Yoko Yoshikawa, and Kazuhiro Maeta
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,MAP Kinase Signaling System ,Ependymoglial Cells ,Biophysics ,GTPase ,Biology ,Biochemistry ,Mice ,03 medical and health sciences ,Downregulation and upregulation ,Conditional gene knockout ,Animals ,Guanine Nucleotide Exchange Factors ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Kinase ,RAPGEF2 ,Adherens Junctions ,Cell Biology ,Molecular biology ,Up-Regulation ,Cell biology ,030104 developmental biology ,Rap1 ,sense organs ,Guanine nucleotide exchange factor - Abstract
Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex. The results show that Rapgef2-deficient RGCs exhibit a decreased ability of neurosphere formation, morphological changes represented by regression of radial glial (RG) fibers and reduced expression of AJ-constituent proteins such as N-cadherin, zonula occludens-1, E-cadherin and β-catenin. Moreover, siRNA-mediated knockdown of Rapgef2 or Rap1A inhibits the AJ protein expression and RG fiber formation while overexpression of Rapgef2, Rapgef6, Rap1AG12V or Rap1BG12V in Rapgef2-deficient RGCs restores them. Furthermore, Rapgef2-deficient RGCs exhibit a reduction in phosphorylation of extracellular signal-regulated kinase (ERK) leading to downregulation of the expression of c-jun, which is implicated in the AJ protein expression. These results indicate a crucial role of the Rapgef2-Rap1A-ERK-c-jun pathway in regulation of the AJ formation in RGCs.
- Published
- 2017
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