148 results on '"Yamada, Y."'
Search Results
2. pH-Dependent Alterations of Monoepoxides and Monochlorohydrins of Linoleic Acid and Their Existence in Vivo
- Author
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Iwase, H., primary, Takahashi, K., additional, Takatori, T., additional, Shimizu, T., additional, Aono, K., additional, Yamada, Y., additional, Iwadate, K., additional, and Nagao, M., additional
- Published
- 1995
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3. Structural Characterization of Thymidine Phosphorylase Purified from Human Placenta
- Author
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Miyadera, K., primary, Dohmae, N., additional, Takio, K., additional, Sumizawa, T., additional, Haraguchi, M., additional, Furukawa, T., additional, Yamada, Y., additional, and Akiyama, S.I., additional
- Published
- 1995
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4. Synthesis and Secretion of Tobacco Neutral PR-5 Protein by Transgenic Tobacco and Yeast
- Author
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Sato, F., primary, Koiwa, H., additional, Sakai, Y., additional, Kato, N., additional, and Yamada, Y., additional
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- 1995
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5. Regulation of Hepatic Genes and Liver Transcription Factors in Rat Hepatocytes by Extracellular Matrix
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Nagaki, M., primary, Shidoji, Y., additional, Yamada, Y., additional, Sugiyama, A., additional, Tanaka, M., additional, Akaike, T., additional, Ohnishi, H., additional, Moriwaki, H., additional, and Muto, Y., additional
- Published
- 1995
- Full Text
- View/download PDF
6. Retinoid Agonist Activities of Synthetic Geranyl Geranoic Acid Derivatives
- Author
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Araki, H., primary, Shidoji, Y., additional, Yamada, Y., additional, Moriwaki, H., additional, and Muto, Y., additional
- Published
- 1995
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7. Induction of Apoptosis by Acyclic Retinoid in the Human Hepatoma-Derived Cell Line, HuH-7
- Author
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Nakamura, N., primary, Shidoji, Y., additional, Yamada, Y., additional, Hatakeyama, H., additional, Moriwaki, H., additional, and Muto, Y., additional
- Published
- 1995
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8. Hamster Gastric Inhibitory Polypeptide Receptor Expressed in Pancreatic Islets and Clonal Insulin-Secreting Cells: Its Structure and Functional Properties
- Author
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Yasuda, K., primary, Inagaki, N., additional, Yamada, Y., additional, Kubota, A., additional, Seino, S., additional, and Seino, Y., additional
- Published
- 1994
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- View/download PDF
9. Erratum
- Author
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Li, Q., primary, Yamada, Y., additional, Yasuda, K., additional, Ihara, Y., additional, Okamoto, Y., additional, Kaisaki, P.J., additional, Watanabe, R., additional, Ikeda, H., additional, Tsuda, K., additional, and Seino, Y., additional
- Published
- 1994
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10. Multiple Effector Coupling of Somatostatin Receptor Subtype SSTR1
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Kubota, A., primary, Yamada, Y., additional, Kagimoto, S., additional, Yasuda, K., additional, Someya, Y., additional, Ihara, Y., additional, Okamoto, Y., additional, Kozasa, T., additional, Seino, S., additional, and Seino, Y., additional
- Published
- 1994
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11. Human Somatostatin Receptor, SSTR2, Is Coupled to Adenylyl Cyclase in the Presence of Giα1 Protein
- Author
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Kagimoto, S., primary, Yamada, Y., additional, Kubota, A., additional, Someya, Y., additional, Ihara, Y., additional, Yasuda, K., additional, Kozasa, T., additional, Imura, H., additional, Seino, S., additional, and Seino, Y., additional
- Published
- 1994
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12. A Cloned Rat CD38-Homologous Protein and Its Expression in Pancreatic Islets
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Li, Q., primary, Yamada, Y., additional, Yasuda, K., additional, Ihara, Y., additional, Okamoto, Y., additional, Kaisaki, P.J., additional, Watanabe, R., additional, Ikeda, H., additional, Tsuda, K., additional, and Seino, Y., additional
- Published
- 1994
- Full Text
- View/download PDF
13. Identification of Defect in the Genes for Bilirubin UDP-Glucuronosyltransferase in a Patient with Crigler-Najjar Syndrome Type II
- Author
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Aono, S., primary, Yamada, Y., additional, Keino, H., additional, Hanada, N., additional, Nakagawa, T., additional, Sasaoka, Y., additional, Yazawa, T., additional, Sato, H., additional, and Koiwai, O., additional
- Published
- 1993
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14. Cloning, Functional Expression and Pharmacological Characterization of a Fourth (hSSTR4) and a Fifth (hSSTR5) Human Somatostatin Receptor Subtype
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Yamada, Y., primary, Kagimoto, S., additional, Kubota, A., additional, Yasuda, K., additional, Masuda, K., additional, Someya, Y., additional, Ihara, Y., additional, Li, Q., additional, Imura, H., additional, Seino, S., additional, and Seino, Y., additional
- Published
- 1993
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15. Complete deficiency of AMP deaminase in human erythrocytes
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Ogasawara, N., primary, Goto, H., additional, Yamada, Y., additional, Nishigaki, I., additional, Itoh, T., additional, and Hasegawa, I., additional
- Published
- 1984
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16. Laminin a chain synthetic peptide which supports neurite outgrowth
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Sephel, G.C., primary, Tashiro, K-I, additional, Sasaki, M., additional, Greatorex, D., additional, Martin, G.R., additional, Yamada, Y., additional, and Kleinman, H.K., additional
- Published
- 1989
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17. The presence of N-[9-(β-D-ribofuranosyl)purin-6-ylcarbamoyl]threonine in serine, methionine and lysine transfer RNA's from Escherichia coli
- Author
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Ishikura, H., primary, Yamada, Y., additional, Murao, K., additional, Saneyoshi, M., additional, and Nishimura, S., additional
- Published
- 1969
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18. TRPV4 activation in human corneal epithelial cells promotes membrane mucin production.
- Author
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Yamada Y, Terada Y, Yamanaka R, Enoyoshi M, and Ito K
- Subjects
- Humans, CA-125 Antigen metabolism, CA-125 Antigen genetics, Epithelial Cells metabolism, Epithelial Cells cytology, Membrane Proteins metabolism, Membrane Proteins genetics, Epithelium, Corneal metabolism, Epithelium, Corneal cytology, Mucin-1 metabolism, Mucin-1 genetics, Mucin-4 metabolism, Mucin-4 genetics, Mucins metabolism, Mucins biosynthesis, TRPV Cation Channels metabolism, TRPV Cation Channels genetics
- Abstract
Given that the corneal epithelium is situated on the outermost part of the eye, its functions can be influenced by external temperatures and chemical substances. This study aimed to elucidate the expression profile of chemosensory receptors in corneal epithelial cells and analyze their role in eye function regulation. A comprehensive analysis of 425 chemosensory receptors in human corneal epithelial cells-transformed (HCE-T) revealed the functional expression of TRPV4. The activation of TRPV4 in HCE-T cells significantly increased the expression of membrane-associated mucins MUC1, MUC4, and MUC16, which are crucial for stabilizing tear films, with efficacy comparable to the active components of dry eye medications. The present study suggests that TRPV4, which is activated by body temperature, regulates mucin expression and proposes it as a novel target for dry eye treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yuko Terada reports financial support was provided by Japan Society for the Promotion of Science. Keisuke Ito reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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19. Cardiac reprogramming reduces inflammatory macrophages and improves cardiac function in chronic myocardial infarction.
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Abe Y, Tani H, Sadahiro T, Yamada Y, Akiyama T, Nakano K, Honda S, Ko S, Anzai A, and Ieda M
- Subjects
- Humans, Myocardium metabolism, Myocytes, Cardiac metabolism, Macrophages metabolism, Inflammation metabolism, Fibroblasts metabolism, Myocardial Infarction metabolism
- Abstract
Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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20. Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2 Akita mice with progressive diabetic kidney disease.
- Author
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Fujita H, Otomo H, Takahashi Y, and Yamada Y
- Subjects
- Animals, Male, Mice, Adenosine, Albumins, Dinoprostone, Hemodynamics, Insulin, Natriuresis, Sodium-Glucose Transporter 2 Inhibitors pharmacology, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Dipeptidyl-Peptidase IV Inhibitors therapeutic use, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Linagliptin pharmacology, Linagliptin therapeutic use
- Abstract
Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2
Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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21. Exosomal microRNA-1 and MYO15A as a target for therapy and diagnosis in renal cell carcinoma.
- Author
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Yoshino H, Tatarano S, Tamai M, Tsuruda M, Iizasa S, Arima J, Kawakami I, Fukumoto W, Kawahara I, Li G, Sakaguchi T, Inoguchi S, Yamada Y, and Enokida H
- Subjects
- Biomarkers, Tumor metabolism, Cell Line, Tumor, Humans, Myosins metabolism, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell genetics, Exosomes metabolism, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, MicroRNAs metabolism
- Abstract
Exosomes are 40-100 nm nano-sized extracellular vesicles and are receiving increasing attention as novel structures that participate in intracellular communication. We previously found that miRNA-1 (miR-1) functions as a tumor suppressor in renal cell carcinoma (RCC). In this study, we investigated the function of exosomal miR-1 and the possibility that the exosome constitutes a tumor maker in RCC. First, we established the method to collect exosomes from cell lysates and human serum by a spin column-based method. Next, we assessed exosomes using Nanosight nanoparticle tracking analysis and Western blot analysis with exosome marker CD63. We confirmed that exosomes labeled with PKH26 fused with recipient cells. Moreover, miR-1 expression was elevated in RCC cells treated with exosomes derived from miR-1-transfected cells. Functional analyses showed that exosomal miR-1 significantly inhibited cell proliferation, migration and invasion compared to control treatment. Our analyses with TCGA database of RCCs showed that miR-1 expression was significantly downregulated in clinical RCC samples compared to that in normal kidney samples, and patients with low miR-1 expression had poorer overall survival in comparison to patients with high expression. Furthermore, RNA sequence analyses showed that expression levels of several genes were altered by exposure to exosomal miR-1. The analyses with TCGA database indicated that high expression of MYO15A was associated with a poorer outcome in RCC. In addition, RT-qPCR analysis of exosomes from clinical patients' sera showed that MYO15A was significantly upregulated in RCC patients compared to that in healthy controls. This study showed that treatment with exosomal miR-1 might be an effective approach to treating RCCs. In addition, exosomal MYO15A could be a diagnostic tumor marker in RCCs., Competing Interests: Declaration of competing interest None of the authors has any direct or indirect commercial financial incentives associated with the publication of this article entitled “Exosomal microRNA-1 and MY6O15A as a target for therapy and diagnosis in renal cell carcinoma”., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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22. YAP1/TAZ activity maintains vascular integrity and organismal survival.
- Author
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Uemura S, Yamashita M, Aoyama K, Yokomizo-Nakano T, Oshima M, Nishio M, Masuko M, Takizawa J, Sone H, Yamada Y, Suzuki A, and Iwama A
- Subjects
- Animals, Endothelial Cells metabolism, Male, Mice, Transcription Factors metabolism, YAP-Signaling Proteins, Neoplasms metabolism, Trans-Activators metabolism
- Abstract
Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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23. Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.
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Kawakami I, Yoshino H, Fukumoto W, Tamai M, Okamura S, Osako Y, Sakaguchi T, Inoguchi S, Matsushita R, Yamada Y, Tatarano S, Nakagawa M, and Enokida H
- Subjects
- Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glutamine metabolism, Humans, RNA, Small Interfering genetics, Amino Acid Transport System ASC genetics, Amino Acid Transport System ASC metabolism, Carcinoma, Renal Cell genetics, Cellular Senescence, Kidney Neoplasms genetics, Minor Histocompatibility Antigens genetics
- Abstract
In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC., Competing Interests: Declaration of competing interest None of the authors has any direct or indirect commercial financial incentives associated with the publication of this article entitled “Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma”., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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24. 3D-cultured small size adipose-derived stem cell spheroids promote bone regeneration in the critical-sized bone defect rat model.
- Author
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Yamada Y, Okano T, Orita K, Makino T, Shima F, and Nakamura H
- Subjects
- Adipocytes metabolism, Animals, Cells, Cultured, Rats, Stem Cells metabolism, Adipose Tissue, Bone Regeneration
- Abstract
Adipose-derived stem cells (ADSCs), due to their regenerative ability, have beneficial effects on bone and cartilage defects. In addition, spheroid formation of ADSCs obtained using three-dimensional (3D) culture accelerates the regenerative ability of ADSCs. The study investigated the regenerative effect of 3D-cultured small size ADSC spheroids without a scaffold in rats with defects in the critical-sized calvarial bone. ADSC-single cells, ADSC-spheroids, or PBS (as control) were implanted in rats, and radiological and histological assessment of bone regeneration was performed. Bone defects were significantly regenerated in the ADSC-spheroid group compared to that in the control group. ADSC-spheroids also showed the most significant bone regeneration in histological assessment. Immunohistochemistry assessment showed that ADSC-spheroids could survive 12 weeks after cell implantation. In vitro, cell apoptosis in ADSC-spheroids was significantly suppressed compared to that in ADSC-single cells. In addition, gene expression related to bone morphogenesis, angiogenesis, and stemness in ADSC-spheroids was elevated. The scaffold-free 3D-cultured small ADSC-spheroids survived in in vitro and in vivo conditions and promoted bone regeneration. Therefore, injectable small size ADSC-spheroids are a novel and less-invasive therapeutic option for treating bone defects., Competing Interests: Declaration of competing interest T.O. and K.O. have research contracts with Nippon Shokubai and receive a research grant. Other authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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25. Generation of mice for evaluating endogenous p16 Ink4a protein expression.
- Author
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Shimada-Takayama Y, Yasuda T, Ukai T, Taguchi J, Ozawa M, Sankoda N, Ohta S, and Yamada Y
- Subjects
- Animals, Cross Reactions, Cyclin-Dependent Kinase Inhibitor p16 immunology, DNA Damage, Exons, Liver metabolism, Mice, Mice, 129 Strain, Mice, Inbred C57BL, NIH 3T3 Cells, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism
- Abstract
The cyclin-dependent kinase inhibitor p16
Ink4a plays a central role in cellular senescence in vitro. Although previous studies suggested cellular senescence is integrated in the systemic mechanisms of organismal aging, the localization and the dynamics of p16Ink4a in tissues remain poorly understood, which hinders uncovering the role of p16Ink4a under the in vivo context. One of the reasons is due to the lack of reliable reagents; as we also demonstrate here that commonly used antibodies raised against human p16I NK 4 A barely recognize its murine ortholog. Here we generated a mouse model, in which the endogenous p16Ink4a is HA-tagged at its N-terminus, to explore the protein expression of p16Ink4a at the organismal level. p16Ink4a was induced at the protein level along the course of senescence in primary embryonic fibroblasts derived from the mice, consistently to its transcriptional level. Remarkably, however, p16Ink4a was not detected in the tissues of the mice exposed to pro-senescence conditions including genotoxic stress and activation of oncogenic signaling pathways, indicating that there is only subtle p16Ink4a proteins induced. These results in our mouse model highlight the need for caution in evaluating p16Ink4a protein expression in vivo., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
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26. Sp6/Epiprofin is a master regulator in the developing tooth.
- Author
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Rhodes CS, Yoshitomi Y, Burbelo PD, Freese NH, Nakamura T, Chiba Y, and Yamada Y
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- Ameloblasts cytology, Amelogenin genetics, Amelogenin metabolism, Animals, Animals, Newborn, Collagen Type I genetics, Collagen Type I metabolism, Dental Enamel Proteins genetics, Dental Enamel Proteins metabolism, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Kruppel-Like Transcription Factors metabolism, Mice, Mice, Inbred C57BL, Molar cytology, Molar growth & development, Odontoblasts cytology, Promoter Regions, Genetic, Proteoglycans genetics, Proteoglycans metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Analysis, RNA, Signal Transduction, Single-Cell Analysis, Sp7 Transcription Factor genetics, Sp7 Transcription Factor metabolism, Ameloblasts metabolism, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Kruppel-Like Transcription Factors genetics, Molar metabolism, Odontoblasts metabolism, Odontogenesis genetics
- Abstract
Tooth development involves the coordinated transcriptional regulation of extracellular matrix proteins produced by ameloblasts and odontoblasts. In this study, whole-genome ChIP-seq analysis was applied to identify the transcriptional regulatory gene targets of Sp6 in mesenchymal cells of the developing tooth. Bioinformatic analysis of a pool of Sp6 target peaks identified the consensus nine nucleotide binding DNA motif CTg/aTAATTA. Consistent with these findings, a number of enamel and dentin matrix genes including amelogenin (Amelx), ameloblastin (Ambn), enamelin (Enam) and dental sialophosphoprotein (Dspp), were identified to contain Sp6 target sequences. Sp6 peaks were also found in other important tooth genes including transcription factors (Dlx2, Dlx3, Dlx4, Dlx5, Sp6, Sp7, Pitx2, and Msx2) and extracellular matrix-related proteins (Col1a2, Col11a2, Halpn1). Unsupervised UMAP clustering of tooth single cell RNA-seq data confirmed the presence of Sp6 transcripts co-expressed with many of the identified target genes within ameloblasts and odontoblasts. Lastly, transcriptional reporter assays using promoter fragments from the Hapln1 and Sp6 gene itself revealed that Sp6 co-expression enhanced gene transcriptional activity. Taken together these results highlight that Sp6 is a major regulator of multiple extracellular matrix genes in the developing tooth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 National Institutes of Dental and Craniofacial Research. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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27. Prolyl oligopeptidase participates in the cytosine arabinoside-induced nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase in a human neuroblastoma cell line.
- Author
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Sakaguchi M, Nishiuchi R, Bando M, Yamada Y, Kondo R, Mitsumori M, Shiokawa A, Kanazawa M, Ikeguchi S, Kikyo F, and Tanaka S
- Subjects
- Cell Death drug effects, Cell Nucleus metabolism, Cell Survival drug effects, Cytarabine antagonists & inhibitors, Enzyme Inhibitors pharmacology, Humans, Proline analogs & derivatives, Proline pharmacology, Prolyl Oligopeptidases antagonists & inhibitors, Prolyl Oligopeptidases deficiency, Thiazolidines pharmacology, Tumor Cells, Cultured, Cell Nucleus drug effects, Cytarabine pharmacology, Glyceraldehyde-3-Phosphate Dehydrogenases metabolism, Prolyl Oligopeptidases metabolism
- Abstract
Previously, we reported that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a binding partner of prolyl oligopeptidase (POP) in neuroblastoma NB-1 cells and that the POP inhibitor, SUAM-14746, inhibits cytosine arabinoside (Ara-C)-induced nuclear translocation of GAPDH and protects against Ara-C cytotoxicity. To carry out a more in-depth analysis of the interaction between POP and GAPDH, we generated POP-KO NB-1 cells and compared the nuclear translocation of GAPDH after Ara-C with or without SUAM-14746 treatment to wild-type NB-1 cells by western blotting and fluorescence immunostaining. Ara-C did not induce the nuclear translocation of GAPDH and SUAM-14746 did not protect against Ara-C cytotoxicity in POP-KO cells. These results indicate that the anticancer effects of Ara-C not only include the commonly known antimetabolic effects, but also the induction of cell death by nuclear transfer of GAPDH through interaction with POP., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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28. Direct reprogramming with Sendai virus vectors repaired infarct hearts at the chronic stage.
- Author
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Isomi M, Sadahiro T, Fujita R, Abe Y, Yamada Y, Akiyama T, Mizukami H, Shu T, Fukuda K, and Ieda M
- Subjects
- Animals, Chronic Disease, Collagen Type I metabolism, Fibroblasts, Fibrosis, Male, Mice, Inbred C57BL, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardium cytology, Myocardium pathology, Myocytes, Cardiac metabolism, Transcription Factors genetics, Mice, Cellular Reprogramming, Genetic Vectors, Myocardial Infarction therapy, Sendai virus genetics
- Abstract
Adult hearts have limited regenerative capacity. Hence, after acute myocardial infarction (MI), dead myocardial tissues are digested by immune cells and replaced by fibrosis, leading to ventricular remodeling and heart failure at the chronic stage. Direct reprogramming of the cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) with cardiac transcription factors, including Gata4, Mef2c, and Tbx5 (GMT), may have significant potential for cardiac repair. Sendai virus (SeV) vectors expressing GMT have been reported to reprogram the mouse cardiac fibroblasts into iCMs without any risk of insertional mutagenesis. In vivo reprogramming improved the cardiac function after acute MI in immunodeficient mice. However, it is unknown whether the newly generated iCMs could exist in infarct hearts for a prolonged period and SeV-GMT can improve cardiac function after MI at the chronic stage in immunocompetent mice. Here, we show that SeV vectors efficiently infect CFs in vivo and reprogram them into iCMs, which existed for at least four weeks after MI, in fibroblast-linage tracing mice. Moreover, SeV-GMT improved cardiac function and reduced fibrosis and collagen I expression at 12 weeks after MI in immunocompetent mice. Thus, direct cardiac reprogramming with SeV vectors could be a promising therapy for MI., Competing Interests: Declaration of competing interest T.S. is the employee of ID Pharma Co., Ltd., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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29. Gene expression profiling of α-gustducin-expressing taste cells in mouse fungiform and circumvallate papillae.
- Author
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Yamada Y, Takai S, Watanabe Y, Osaki A, Kawabata Y, Oike A, Hirayama A, Iwata S, Sanematsu K, Tabata S, and Shigemura N
- Subjects
- Animals, Cell Differentiation genetics, Female, Galectin 3 genetics, Gene Expression Profiling, Gene Ontology, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, RNA-Seq, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Single-Cell Analysis, Taste Perception genetics, Transducin genetics, Galectin 3 metabolism, Gene Expression Regulation genetics, Taste Buds metabolism, Tongue metabolism, Transducin metabolism
- Abstract
Taste buds are complex sensory organs embedded in the epithelium of fungiform papillae (FP) and circumvallate papillae (CV). The sweet, bitter, and umami tastes are sensed by type II taste cells that express taste receptors (Tas1rs and Tas2rs) coupled with the taste G-protein α-gustducin. Recent studies revealed that the taste response profiles of α-gustducin-expressing cells are different between FP and CV, but which genes could generate such distinctive cell characteristics are still largely unknown. We performed a comprehensive transcriptome analysis on α-gustducin-expressing cells in mouse FP and CV by single-cell RNA sequencing combined with fluorescence-activated cell sorting. Transcriptome profiles of the α-gustducin-expressing cells showed various expression patterns of taste receptors. Our clustering analysis defined the specific cell populations derived from FP or CV based on their distinct gene expression. Immunohistochemistry confirmed the specific expression of galectin-3, encoded by Lgals3, which was recognized as a differentially expressed gene in the transcriptome analysis. Our work provides fundamental knowledge toward understanding the genetic heterogeneity of type II cells, potentially revealing differential characterization of FP and CV taste bud cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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30. RNF4-mediated SUMO-targeted ubiquitination relieves PARIS/ZNF746-mediated transcriptional repression.
- Author
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Nishida T and Yamada Y
- Subjects
- Cell Line, Humans, Poly-ADP-Ribose Binding Proteins metabolism, Proteasome Endopeptidase Complex metabolism, Protein Binding, Protein Inhibitors of Activated STAT metabolism, Proteolysis, Sumoylation, Nuclear Proteins metabolism, Repressor Proteins metabolism, Transcription Factors metabolism, Transcription, Genetic, Ubiquitination, Ubiquitins metabolism
- Abstract
The transcriptional repressor PARIS, which is a substrate of the ubiquitin E3 ligase parkin, represses the expression of the transcriptional co-activator, PGC-1α. However, little is known about how its repression activity is regulated. We have previously shown that PARIS is SUMOylated, and this SUMOylation plays an important role in regulating its transcriptional repression activity. In this study, we demonstrated that PARIS SUMOylation induced its ubiquitination and subsequent proteasomal degradation, which was mediated by the SUMO-targeted ubiquitin ligase RNF4. Reporter gene assays revealed that co-expression of SUMO3 and RNF4 relieved PARIS-mediated transcriptional repression. Conversely, the SUMO E3 ligase PIASy inhibited the RNF4-mediated ubiquitination of PARIS and blocked the RNF4-mediated relief of PARIS-mediated transcriptional repression. These results suggest that RNF4 regulates PARIS ubiquitination to control its transcriptional repression activity., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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31. Smarcb1 maintains the cellular identity and the chromatin landscapes of mouse embryonic stem cells.
- Author
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Sakakura M, Ohta S, Yagi M, Tanaka A, Norihide J, Woltjen K, Yamamoto T, and Yamada Y
- Subjects
- Animals, Cells, Cultured, Chromatin metabolism, Embryonic Development genetics, Gene Expression Profiling methods, Gene Expression Regulation, Developmental, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Nude, Mouse Embryonic Stem Cells cytology, SMARCB1 Protein metabolism, Cell Differentiation genetics, Cell Lineage genetics, Chromatin genetics, Mouse Embryonic Stem Cells metabolism, SMARCB1 Protein genetics
- Abstract
ES cell (ESC) identity is stably maintained through the coordinated regulation of transcription factors and chromatin structure. SMARCB1, also known as INI1, SNF5, BAF47, is one of the subunits of SWI/SNF (BAF) complexes that play a crucial role in regulating gene expression by controlling chromatin dynamics. Genetic ablation of Smarcb1 in mice leads to embryonic lethality at the peri-implantation stage, indicating that Smarcb1 is important for the early developmental stages. However, the role of SMARCB1 in the maintenance of the ESC identity remains unknown. Here we established mouse ESCs lacking Smarcb1 and investigated the effect of Smarcb1 ablation on the differentiation propensity of ESCs. We found an increased expression of trophectoderm-related genes including Cdx2 in Smarcb1-deficient ESCs. Consistently, they exhibited an extended differentiation propensity into the trophectoderm lineage cells in teratomas. However, although Smarcb1-deficient cells were infrequently incorporated into the trophectoderm cell layer of blastocysts, they failed to contribute to mature placental tissues in vivo. Furthermore, Smarcb1-deficient cells exhibited a premature differentiation in the neural tissue of E14.5 chimeric embryos. Notably, we found that binding motifs for CTCF, which is involved in the maintenance of genomic DNA architecture was significantly enriched in chromatin regions whose accessibility was augmented in Smarcb1-deficient cells, while those for pluripotency factors were overrepresented in regions which have more closed structure in those cells. Collectively, we propose that SMARCB1-mediated remodeling of chromatin landscapes is important for the maintenance and differentiation of ESCs., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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32. Analysis of a limb-specific regulatory element in the promoter of the link protein gene.
- Author
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Rhodes CS, Matsunobu T, and Yamada Y
- Subjects
- Animals, Base Sequence, Cartilage embryology, Extracellular Matrix Proteins metabolism, Extremities embryology, Genitalia embryology, Genitalia metabolism, HEK293 Cells, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Mice, Transgenic, Proteoglycans metabolism, Sequence Homology, Nucleic Acid, beta-Galactosidase genetics, beta-Galactosidase metabolism, Cartilage metabolism, Extracellular Matrix Proteins genetics, Gene Expression Regulation, Developmental, Promoter Regions, Genetic genetics, Proteoglycans genetics, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the cartilage matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, Hox-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of Hox-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling cartilage and limb gene expression., (Published by Elsevier Inc.)
- Published
- 2019
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33. Inhibition of GIP signaling extends lifespan without caloric restriction.
- Author
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Hoizumi M, Sato T, Shimizu T, Kato S, Tsukiyama K, Narita T, Fujita H, Morii T, Sassa MH, Seino Y, and Yamada Y
- Subjects
- 3T3-L1 Cells, Adipocytes metabolism, Adipose Tissue metabolism, Animals, Cytokines metabolism, Mice, Mice, Knockout, Nicotinamide Phosphoribosyltransferase metabolism, Receptors, Gastrointestinal Hormone genetics, Sirtuin 1 metabolism, Caloric Restriction, Gastric Inhibitory Polypeptide antagonists & inhibitors, Longevity physiology, Signal Transduction physiology
- Abstract
Aims/introduction: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue., Materials and Methods: Gipr
-/- and Gipr+/+ mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid., Results: We observed that GIP receptor-knockout (Gipr-/- ) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr-/- mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes., Conclusions: Although maintenance of CR is difficult, food intake and muscle endurance of Gipr-/- mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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- View/download PDF
34. In vitro reconstitution of breast cancer heterogeneity with multipotent cancer stem cells using small molecules.
- Author
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Kawamata M, Katsuda T, Yamada Y, and Ochiya T
- Subjects
- Animals, Breast metabolism, Cell Culture Techniques, Disease Progression, Epithelial-Mesenchymal Transition, Female, Humans, Male, Mammary Glands, Human metabolism, Mammary Neoplasms, Animal metabolism, Mice, Mice, SCID, Microscopy, Fluorescence, Multipotent Stem Cells metabolism, Neoplasm Invasiveness, Neoplasm Transplantation, Rats, Tumor Suppressor Protein p53 metabolism, Breast Neoplasms metabolism, Carcinoma metabolism, Neoplastic Stem Cells metabolism, Trans-Activators metabolism, Vimentin metabolism
- Abstract
A small fraction of tumor cells are thought to possess the potential for both multiple-lineage differentiation and self-renewal, which underlies the cancer stem cell hypothesis. However, the differentiation mechanisms of these cells have not been elucidated due to a lack of appropriate culture methods. Here, we established a culture condition for maintaining multipotent tumor cells from rat breast tumors using 4 small molecules. Cultured tumor cells in this condition retained their intrinsic myoepithelial features, expressing p63 and CK14 and vimentin. In a xenograft model, the p63-expressing cells formed epithelial tumors containing glandular, squamous and sebaceous compartments. Upon withdrawal of the small molecules, p63 and CK14 expression was lost, with concurrent increase in expression of mesenchymal markers. These transited cells acquired drug resistance and invasiveness and showed massive sarcomatoid tumorigenicity. Epithelial features could not be recovered by re-exposure to the small molecules in the transited cells. Here, we have identified multipotent cancer cells within primary mammary tumors and demonstrated that their plasticity is maintained by the small molecules., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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35. SUMOylation of the KRAB zinc-finger transcription factor PARIS/ZNF746 regulates its transcriptional activity.
- Author
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Nishida T and Yamada Y
- Subjects
- Cells, Cultured, Humans, Small Ubiquitin-Related Modifier Proteins, Sumoylation, Transcription Factors metabolism, Gene Expression Regulation physiology, Repressor Proteins metabolism, Transcriptional Activation physiology
- Abstract
Parkin-interacting substrate (PARIS), a member of the family of Krüppel-associated box (KRAB)-containing zinc-finger transcription factors, is a substrate of the ubiquitin E3 ligase parkin. PARIS represses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), although the underlying mechanisms remain largely unknown. In the present study, we demonstrate that PARIS can be SUMOylated, and its SUMOylation plays a role in the repression of PGC-1a promoter activity. Protein inhibitor of activated STAT y (PIASy) was identified as an interacting protein of PARIS and shown to enhance its SUMOylation. PIASy repressed PGC-1a promoter activity, and this effect was attenuated by PARIS in a manner dependent on its SUMOylation status. Co-expression of SUMO-1 with PIASy completely repressed PGC-1a promoter activity independently of PARIS expression. PARIS-mediated PGC-1a promoter repression depended on the activity of histone deacetylases (HDAC), whereas PIASy repressed the PGC-1a promoter in an HDAC-independent manner. Taken together, these results suggest that PARIS and PIASy modulate PGC-1a gene transcription through distinct molecular mechanisms., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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36. High affinity nucleotide-binding mutant of the ε subunit of thermophilic F1-ATPase.
- Author
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Kato-Yamada Y
- Subjects
- Bacillus genetics, Binding Sites, Enzyme Activation, Kinetics, Mutagenesis, Site-Directed, Mutation genetics, Protein Binding, Protein Subunits, Proton-Translocating ATPases genetics, Substrate Specificity, Adenosine Triphosphate chemistry, Bacillus enzymology, Protein Engineering methods, Proton-Translocating ATPases chemistry
- Abstract
Specific ATP binding to the ε subunit of thermophilic F1-ATPase has been utilized for the biosensors of ATP in vivo. I report here that the ε subunit containing R103A/R115A mutations can bind ATP with a dissociation constant at 52 nM, which is two orders of magnitude higher affinity than the wild type. The mutant retained specificity for ATP; ADP and GTP bound to the mutant with dissociation constants 16 and 53 μM, respectively. Thus, the mutant would be a good platform for various types of nucleotide biosensor with appropriate modifications., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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37. Epigenetic regulation leading to induced pluripotency drives cancer development in vivo.
- Author
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Ohnishi K, Semi K, and Yamada Y
- Subjects
- Induced Pluripotent Stem Cells metabolism, Cellular Reprogramming, Epigenesis, Genetic, Neoplasms genetics
- Abstract
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo., (Copyright © 2014. Published by Elsevier Inc.)
- Published
- 2014
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38. miR-142-3p enhances FcεRI-mediated degranulation in mast cells.
- Author
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Yamada Y, Kosaka K, Miyazawa T, Kurata-Miura K, and Yoshida T
- Subjects
- Animals, Base Sequence, Cell Line, Cytoskeletal Proteins metabolism, DEAD-box RNA Helicases metabolism, Gene Silencing, Humans, Mice, MicroRNAs genetics, Molecular Sequence Data, Response Elements genetics, Ribonuclease III metabolism, p-Methoxy-N-methylphenethylamine pharmacology, Cell Degranulation, Mast Cells physiology, MicroRNAs metabolism, Receptors, IgE metabolism
- Abstract
Mast cells are immune cells derived from hematopoietic progenitors. When they are activated by stimuli, they immediately release granule-associated mediators, leading to allergic inflammation. Several factors controlling mediator release have been identified; however, little is known whether microRNAs (miRNAs) are involved in this process. miRNAs are a small class of non-coding RNAs that negatively regulate gene expression. In this study, we investigated the relationship between miRNAs and degranulation in LAD2 cells, a human mast cell line. We demonstrated that silencing of Dicer, a key enzyme of miRNA biogenesis, attenuates degranulation, indicating that miRNAs are involved in mast cell degranulation. We furthermore discovered that the overexpression of miR-142-3p enhances FcεRI-mediated degranulation and that miR-142-3p rescues the reduction of degranulation by silencing Dicer. Similar effects were observed in bone marrow-derived mast cells obtained miR-142-3p-deficient mice. Our studies suggest that miR-142-3p is a potential therapeutic target in pathological conditions caused by mast cells, such as mastocytosis and allergies., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
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39. INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors.
- Author
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Mashima H, Ohno H, Yamada Y, Sakai T, and Ohnishi H
- Subjects
- Animals, Autocrine Communication, Biomarkers metabolism, Biomarkers, Tumor metabolism, Cell Line, Tumor, Colorectal Neoplasms metabolism, Humans, Insulin genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuroendocrine Tumors metabolism, Paracrine Communication, Proteins genetics, Colon metabolism, Enteroendocrine Cells metabolism, Insulin metabolism, Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, Peptide metabolism, Rectum metabolism
- Abstract
Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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40. Experimental cerebral malaria is suppressed by disruption of nucleoside transporter 1 but not purine nucleoside phosphorylase.
- Author
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Niikura M, Inoue S, Mineo S, Yamada Y, Kaneko I, Iwanaga S, Yuda M, and Kobayashi F
- Subjects
- Animals, Blood-Brain Barrier parasitology, Disease Models, Animal, Female, Gene Deletion, Humans, Mice, Mice, Inbred C57BL, Nucleoside Transport Proteins genetics, Plasmodium berghei genetics, Plasmodium berghei growth & development, Protozoan Proteins genetics, Purine-Nucleoside Phosphorylase genetics, Malaria, Cerebral parasitology, Nucleoside Transport Proteins metabolism, Plasmodium berghei pathogenicity, Protozoan Proteins metabolism, Purine-Nucleoside Phosphorylase metabolism
- Abstract
Protozoan parasites rely on purine nucleosides supplied by the host because they are unable to synthesise purine rings denovo. Nucleoside transporter 1 (NT1) and purine nucleoside phosphorylase (PNP) play an essential role in purine salvage in Plasmodium. It is unclear whether severe pathology, such as cerebral malaria (CM), develops in hosts infected with Plasmodium parasites that lack activity of NT1 or PNP. Plasmodium berghei (Pb) ANKA-infected mice show features similar to human CM, such as cerebral paralysis and cerebral haemorrhage. Therefore, Pb ANKA infection in mice is a good experimental model of CM. In this study, we generated pbnt1-disrupted Pb ANKA (Δpbnt1 parasites) and pbpnp-disrupted Pb ANKA (Δpbpnp parasites), and investigated the effect of pbnt1 or pbpnp disruption on the outcome of infection with Pb ANKA. We showed that the rapid increase of wild-type Pb ANKA (WT parasites) in mice early in infection was significantly inhibited by disruption of pbnt1. Moreover, Δpbnt1 parasite-infected mice showed neither cerebral paralysis nor cerebral haemorrhage, and all mice spontaneously recovered from infection. By contrast, mice infected with Δpbpnp parasites showed features similar to those of mice infected with WT parasites. In this study, we demonstrated that the high virulence of Pb ANKA in the asexual phase is suppressed by disruption of pbnt1 but not pbpnp., (Copyright © 2013. Published by Elsevier Inc.)
- Published
- 2013
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41. Tumor suppressive microRNA-133a regulates novel targets: moesin contributes to cancer cell proliferation and invasion in head and neck squamous cell carcinoma.
- Author
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Kinoshita T, Nohata N, Fuse M, Hanazawa T, Kikkawa N, Fujimura L, Watanabe-Takano H, Yamada Y, Yoshino H, Enokida H, Nakagawa M, Okamoto Y, and Seki N
- Subjects
- Aged, Carcinoma, Squamous Cell genetics, Cell Line, Tumor, Cell Movement, Cell Proliferation, Female, Genome-Wide Association Study, Head and Neck Neoplasms genetics, Humans, Male, Middle Aged, Neoplasm Invasiveness, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell pathology, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms pathology, MicroRNAs metabolism, Microfilament Proteins genetics
- Abstract
Recently, many studies suggest that microRNAs (miRNAs) contribute to the development, invasion and metastasis of various types of human cancers. Our recent study revealed that expression of microRNA-133a (miR-133a) was significantly reduced in head and neck squamous cell carcinoma (HNSCC) and that restoration of miR-133a inhibited cell proliferation, migration and invasion in HNSCC cell lines, suggesting that miR-133a function as a tumor suppressor. Genome-wide gene expression analysis of miR-133a transfectants and TargetScan database showed that moesin (MSN) was a promising candidate of miR-133a target gene. MSN is a member of the ERM (ezrin, radixin and moesin) protein family and ERM function as cross-linkers between plasma membrane and actin-based cytoskeleton. The functions of MSN in cancers are controversial in previous reports. In this study, we focused on MSN and investigated whether MSN was regulated by tumor suppressive miR-133a and contributed to HNSCC oncogenesis. Restoration of miR-133a in HNSCC cell lines (FaDu, HSC3, IMC-3 and SAS) suppressed the MSN expression both in mRNA and protein level. Silencing study of MSN in HNSCC cell lines demonstrated significant inhibitions of cell proliferation, migration and invasion activities in si-MSN transfectants. In clinical specimen with HNSCC, the expression level of MSN was significantly up-regulated in cancer tissues compared to adjacent non-cancerous tissues. These data suggest that MSN may function as oncogene and is regulated by tumor suppressive miR-133a. Our analysis data of novel tumor-suppressive miR-133a-mediated cancer pathways could provide new insights into the potential mechanisms of HNSCC oncogenesis., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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42. Label-free THz sensing of living body-related molecular binding using a metallic mesh.
- Author
-
Hasebe T, Yamada Y, and Tabata H
- Subjects
- Avidin chemistry, Biotin chemistry, Lectins chemistry, Metals chemistry, Polyvinyls chemistry, Sensitivity and Specificity, Avidin metabolism, Biotin metabolism, Carbohydrate Metabolism, Lectins metabolism, Terahertz Spectroscopy methods
- Abstract
We have demonstrated label-free THz sensing of living body-related molecular binding using a thin metallic mesh and a polyvinylidene difluoride (PVDF) membrane. Metallic meshes in the THz region are designed for anomalous transmission phenomena derived from a resonant excitation of surface waves. Additionally, they are designed to have a sharp dip in transmittance. The metallic mesh is very sensitive to a change of the refractive index of materials attached to the metallic mesh. In this paper, we report sensing of interactions between lectin and sugar using this technique. We found that the dip frequency shift, transmittance attenuation of the dip frequency, and peak shift of the derivative spectrum of the phase shift depend on the bonding amount of lectin-sugar interactions. We also applied this technique to detect avidin-biotin interactions, leading to the detection of a small amount of biotin (0.17 pg/mm(2))., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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43. Activation of peroxisome proliferator-activated receptor-α (PPARα) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes.
- Author
-
Kimura R, Takahashi N, Murota K, Yamada Y, Niiya S, Kanzaki N, Murakami Y, Moriyama T, Goto T, and Kawada T
- Subjects
- Animals, Caco-2 Cells, Enterocytes drug effects, Humans, Male, Mice, Mice, Inbred C57BL, Oxidation-Reduction, Postprandial Period, Triglycerides metabolism, Bezafibrate administration & dosage, Enterocytes metabolism, Fatty Acids metabolism, Hyperlipidemias drug therapy, Hypolipidemic Agents administration & dosage, PPAR alpha agonists
- Abstract
Activation of peroxisome proliferator-activated receptor (PPAR)-α which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPARα activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPARα activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPARα agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and production of CO(2) and acid soluble metabolites in enterocytes. Moreover, bezafibrate treatment suppressed postprandial lipidemia after oral administration of olive oil to the mice. These findings indicate that PPARα activation suppresses postprandial lipidemia through enhancement of fatty acid oxidation in enterocytes, suggesting that intestinal lipid metabolism regulated by PPARα activity is a novel target of PPARα agonist for decreasing circulating levels of lipids under postprandial conditions., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
44. The nucleolar SUMO-specific protease SMT3IP1/SENP3 attenuates Mdm2-mediated p53 ubiquitination and degradation.
- Author
-
Nishida T and Yamada Y
- Subjects
- Animals, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Endopeptidases genetics, Humans, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2 genetics, SUMO-1 Protein metabolism, Endopeptidases metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism, Ubiquitination
- Abstract
SUMO (small ubiquitin-like modifier) modification plays multiple roles in several cellular processes. Sumoylation is reversibly regulated by SUMO-specific proteases. SUMO-specific proteases have recently been implicated in cell proliferation and early embryogenesis, but the underlying mechanisms remain unknown. Here, we show that a nucleolar SUMO-specific protease, SMT3IP1/SENP3, controls the p53-Mdm2 pathway. We found that SMT3IP1 interacts with p53 and Mdm2, and desumoylates both proteins. Overexpression of SMT3IP1 in cells resulted in the accumulation of Mdm2 in the nucleolus and increased stability of the p53 protein. In addition, SMT3IP1 bound to the acidic domain of Mdm2, which also mediates the p53 interaction, and competed with p53 for binding. Increasing expression of SMT3IP1 suppressed Mdm2-mediated p53 ubiquitination and subsequent proteasomal degradation. Interestingly, the desumoylation activity of SMT3IP1 was not necessary for p53 stabilization. These results suggest that SMT3IP1 is a new regulator of the p53-Mdm2 pathway., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
45. Octaarginine-modified liposomes enhance the anti-oxidant effect of Lecithinized superoxide dismutase by increasing its cellular uptake.
- Author
-
Furukawa R, Yamada Y, Takenaga M, Igarashi R, and Harashima H
- Subjects
- Antioxidants chemistry, Flow Cytometry, HeLa Cells, Humans, Liposomes, Phosphatidylcholines chemistry, Superoxide Dismutase chemistry, Antioxidants administration & dosage, Antioxidants metabolism, Oligopeptides chemistry, Phosphatidylcholines administration & dosage, Phosphatidylcholines metabolism, Superoxide Dismutase administration & dosage, Superoxide Dismutase metabolism
- Abstract
The anti-oxidant enzyme superoxide dismutase (SOD) has the potential for use as a therapeutic agent in the treatment of various diseases caused by reactive oxygen species. However, achieving this would be difficult without a suitable delivery system for SOD. We previously reported that PC-SOD, in which four molecules of a phosphatidylcholine (PC) derivative were covalently bound to each dimer of recombinant human CuZnSOD, was a high affinity for the cell membrane [14]. Here, we show that an octaarginine (R8) modified liposome equipped with PC-SOD (R8-LP (PC-SOD)) enhances its anti-oxidant effect. High-density R8-modified liposomes can stimulate macropinocytosis and are taken up efficiently by cells as demonstrated in a previous study [21]. Flow cytometry analyses showed that R8-LP (PC-SOD) was taken up by cells more efficiently than PC-SOD. Moreover, R8-LP (PC-SOD) liposomes were found to scavenge superoxide anions (O(2)(-)) very efficiently. These results suggest that the efficient cytosolic delivery of PC-SOD by R8-modified liposomes would enhance the anti-oxidant effects of PC-SOD., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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46. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice.
- Author
-
Ogawa E, Hosokawa M, Harada N, Yamane S, Hamasaki A, Toyoda K, Fujimoto S, Fujita Y, Fukuda K, Tsukiyama K, Yamada Y, Seino Y, and Inagaki N
- Subjects
- Animals, Glucagon-Like Peptide-1 Receptor, Jejunum metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Perfusion, Receptors, Glucagon genetics, Somatostatin pharmacology, Gastric Inhibitory Polypeptide pharmacology, Gastrointestinal Motility drug effects, Glucose metabolism, Intestinal Absorption drug effects, Jejunum drug effects
- Abstract
Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic β cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [(14)C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [(14)C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather than through a GLP-1-mediated pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
47. Mitochondrial matrix delivery using MITO-Porter, a liposome-based carrier that specifies fusion with mitochondrial membranes.
- Author
-
Yasuzaki Y, Yamada Y, and Harashima H
- Subjects
- Animals, DNA, Mitochondrial analysis, Fluorescent Dyes analysis, HeLa Cells, Humans, Liposomes analysis, Membrane Fusion, Microscopy, Confocal, Mitochondria, Liver chemistry, Mitochondrial Diseases therapy, Mitochondrial Membranes chemistry, Propidium analysis, Rats, Rats, Wistar, DNA, Mitochondrial metabolism, Fluorescent Dyes metabolism, Genetic Therapy, Liposomes metabolism, Mitochondria, Liver metabolism, Mitochondrial Membranes metabolism, Propidium metabolism, Transduction, Genetic
- Abstract
Mitochondria are the principal producers of energy in cells of higher organisms. It was recently reported that mutations and defects in mitochondrial DNA (mtDNA) are associated with various mitochondrial diseases including a variety of neurodegenerative and neuromuscular diseases. Therefore, an effective mitochondrial gene therapy and diagnosis would be expected to have great medical benefits. To achieve this, therapeutic agents need to be delivered into the innermost mitochondrial space (mitochondrial matrix), which contains the mtDNA pool. We previously reported on the development of MITO-Porter, a liposome-based carrier that introduces macromolecular cargos into mitochondria via membrane fusion. In this study, we provide a demonstration of mitochondrial matrix delivery and the visualization of mitochondrial genes (mtDNA) in living cells using the MITO-Porter. We first prepared MITO-Porter containing encapsulated propidium iodide (PI), a fluorescent dye used to stain nucleic acids to detect mtDNA. We then confirmed the emission of red-fluorescence from PI by conjugation with mtDNA, when the carriers were incubated in the presence of isolated rat liver mitochondria. Finally, intracellular observation by confocal laser scanning microscopy clearly verified that the MITO-Porter delivered PI to the mitochondrial matrix., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
48. Modulation of nucleotide binding to the catalytic sites of thermophilic F(1)-ATPase by the epsilon subunit: implication for the role of the epsilon subunit in ATP synthesis.
- Author
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Yasuno T, Muneyuki E, Yoshida M, and Kato-Yamada Y
- Subjects
- Adenosine Diphosphate chemistry, Adenosine Diphosphate metabolism, Adenosine Triphosphate metabolism, Catalytic Domain, Escherichia coli Proteins chemistry, Escherichia coli Proteins metabolism, Guanosine Diphosphate chemistry, Guanosine Diphosphate metabolism, Proton-Translocating ATPases chemistry, Adenosine Triphosphate biosynthesis, Bacillus enzymology, Proton-Translocating ATPases metabolism
- Abstract
Effect of epsilon subunit on the nucleotide binding to the catalytic sites of F(1)-ATPase from the thermophilic Bacillus PS3 (TF(1)) has been tested by using alpha(3)beta(3)gamma and alpha(3)beta(3)gammaepsilon complexes of TF(1) containing betaTyr341 to Trp substitution. The nucleotide binding was assessed with fluorescence quenching of the introduced Trp. The presence of the epsilon subunit weakened ADP binding to each catalytic site, especially to the highest affinity site. This effect was also observed when GDP or IDP was used. The ratio of the affinity of the lowest to the highest nucleotide binding sites had changed two orders of magnitude by the epsilon subunit. The differences may relate to the energy required for the binding change in the ATP synthesis reaction and contribute to the efficient ATP synthesis.
- Published
- 2009
- Full Text
- View/download PDF
49. Inhibition of ischemia-induced angiogenesis by benzo[a]pyrene in a manner dependent on the aryl hydrocarbon receptor.
- Author
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Ichihara S, Yamada Y, Gonzalez FJ, Nakajima T, Murohara T, and Ichihara G
- Subjects
- Angiotensin I biosynthesis, Animals, Aryl Hydrocarbon Receptor Nuclear Translocator biosynthesis, Cytochrome P-450 CYP1A1 biosynthesis, Femoral Artery physiopathology, Hypoxia-Inducible Factor 1, alpha Subunit biosynthesis, Interleukin-6 biosynthesis, Lower Extremity blood supply, Male, Metallothionein biosynthesis, Mice, Mice, Inbred Strains, Receptors, Angiotensin biosynthesis, Receptors, Aryl Hydrocarbon agonists, Receptors, Aryl Hydrocarbon genetics, Receptors, Vascular Endothelial Growth Factor biosynthesis, Up-Regulation, Vascular Endothelial Growth Factor A biosynthesis, Benzo(a)pyrene toxicity, Carcinogens toxicity, Ischemia physiopathology, Neovascularization, Physiologic drug effects, Receptors, Aryl Hydrocarbon physiology
- Abstract
We have investigated the effect of benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke and an agonist for the aryl hydrocarbon receptor (AHR), on hypoxia-induced angiogenesis. Ischemia was induced by femoral artery ligation in wild-type and AHR-null mice, and the animals were subjected to oral administration of B[a]P (125 mg/kg) once a week. Exposure to B[a]P up-regulated the expression of metallothionein in the ischemic hindlimb and markedly inhibited ischemia-induced angiogenesis in wild-type mice. The amounts of interleukin-6 and of vascular endothelial growth factor (VEGF) mRNA in the ischemic hindlimb of wild-type mice were reduced by exposure to B[a]P. These various effects of B[a]P were markedly attenuated in AHR-null mice. Our observations suggest that the loss of the inhibitory effect of B[a]P on ischemia-induced angiogenesis apparent in AHR-null mice may be attributable to maintenance of interleukin-6 expression and consequent promotion of angiogenesis through up-regulation of VEGF expression.
- Published
- 2009
- Full Text
- View/download PDF
50. Insulin gene is a target in activin receptor-like kinase 7 signaling pathway in pancreatic beta-cells.
- Author
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Watanabe R, Shen ZP, Tsuda K, and Yamada Y
- Subjects
- Activins metabolism, Animals, Base Sequence, Cell Line, Dogs, Guinea Pigs, Homeodomain Proteins metabolism, Humans, Mice, Molecular Sequence Data, Nodal Protein metabolism, Phosphatidylinositol 3-Kinases metabolism, Promoter Regions, Genetic, Rats, Sequence Alignment, Smad2 Protein metabolism, Smad3 Protein metabolism, Trans-Activators metabolism, Activin Receptors, Type I metabolism, Insulin genetics, Insulin-Secreting Cells metabolism, Transcriptional Activation
- Abstract
Activins regulate pancreatic development, differentiation and insulin secretion. Activin receptor-like kinase 7 (ALK7) has been identified as a receptor for Nodal and Activin AB and B, and is expressed in pancreatic islets and beta-cell lines. In this study, human insulin promoter was activated by Smad2, Smad3 and the pancreatic and duodenal homeobox factor-1 (PDX-1) in the ALK7 pathway. A conserved Smad binding element was related to the promoter activation. Phosphorylated Smad2/Smad3 and PDX-1 were bound to insulin gene with Nodal and Activin AB, and the phosphorylated Smad2/Smad3 interacted with PDX-1. These results indicate that one of the direct target genes of Nodal and Activin AB signals is the insulin gene in pancreatic beta-cells and that PDX-1 is directly involved in the ALK7-Smad pathway.
- Published
- 2008
- Full Text
- View/download PDF
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