34 results on '"Ai Yamada"'
Search Results
2. CRISPR/Cas9 Screening for Identification of Genes Required for the Growth of Ovarian Clear Cell Carcinoma Cells
- Author
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Ayako Kawabata, Tomoatsu Hayashi, Yoko Akasu-Nagayoshi, Ai Yamada, Naomi Shimizu, Naoko Yokota, Ryuichiro Nakato, Katsuhiko Shirahige, Aikou Okamoto, and Tetsu Akiyama
- Subjects
ovarian cancer ,ovarian clear cell carcinoma ,CRISPR/Cas9 system ,proliferation ,tumorigenesis ,Biology (General) ,QH301-705.5 - Abstract
Epithelial ovarian cancer is classified into four major histological subtypes: serous, clear cell, endometrioid and mucinous. Ovarian clear cell carcinoma (OCCC) responds poorly to conventional chemotherapies and shows poor prognosis. Thus, there is a need to develop new drugs for the treatment of OCCC. In this study, we performed CRISPR/Cas9 screens against OCCC cell lines and identified candidate genes important for their proliferation. We found that quite different genes are required for the growth of ARID1A and PIK3CA mutant and wild-type OCCC cell lines, respectively. Furthermore, we found that the epigenetic regulator KDM2A and the translation regulator PAIP1 may play important roles in the growth of ARID1A and PIK3CA mutant, but not wild-type, OCCC cells. The results of our CRISPR/Cas9 screening may be useful in elucidating the molecular mechanism of OCCC tumorigenesis and in developing OCCC-targeted drugs.
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- 2022
- Full Text
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3. The splicing factor DHX38/PRP16 is required for ovarian clear cell carcinoma tumorigenesis, as revealed by a CRISPR‐Cas9 screen
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Brandon Cona, Tomoatsu Hayashi, Ai Yamada, Naomi Shimizu, Naoko Yokota, Ryuichiro Nakato, Katsuhiko Shirahige, and Tetsu Akiyama
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apoptosis ,DHX38 ,ovarian cancer ,PRP16 ,splicing factor ,tumorigenesis ,Biology (General) ,QH301-705.5 - Abstract
Certain cancers, such as ovarian clear cell carcinoma (OCCC), display high levels of genetic variation between patients, making it difficult to develop effective therapies. In order to identify novel genes critical to OCCC growth, we carried out a comprehensive CRISPR‐Cas9 knockout screen against cell growth using an OCCC cell line and a normal ovarian surface epithelium cell line. We identified the gene encoding DHX38/PRP16, an ATP‐dependent RNA helicase involved in splicing, as critical for the growth and tumorigenesis of OCCC. DHX38/PRP16 knockdown in OCCC cells, but not normal cells, induces apoptosis and impairs OCCC tumorigenesis in a mouse model. Our results suggest that DHX38/PRP16 may play a role in OCCC tumorigenesis and could potentially be a promising therapeutic target.
- Published
- 2022
- Full Text
- View/download PDF
4. TAE226, a dual inhibitor of focal adhesion kinase and insulin‐like growth factor‐I receptor, is effective for Ewing sarcoma
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Hiroshi Moritake, Yusuke Saito, Daisuke Sawa, Naoki Sameshima, Ai Yamada, Mariko Kinoshita, Sachiyo Kamimura, Takao Konomoto, and Hiroyuki Nunoi
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Ewing sarcoma ,focal adhesion kinase ,insulin‐like growth factor‐I receptor ,metastasis ,TAE226 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.
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- 2019
- Full Text
- View/download PDF
5. EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase
- Author
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Yusuke Saito, Daisuke Sawa, Mariko Kinoshita, Ai Yamada, Sachiyo Kamimura, Akira Suekane, Honami Ogoh, Hidemasa Matsuo, Souichi Adachi, Takashi Taga, Daisuke Tomizawa, Motomi Osato, Tomoyoshi Soga, Kazuhiro Morishita, and Hiroshi Moritake
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.
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- 2020
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6. Administration of high-dose estradiol and progesterone in hormone replacement therapy improves results of frozen-thawed embryo transfer in a patient with 21-hydroxylase deficiency and persistently high serum progesterone levels: a case report
- Author
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Yuri Mizusawa, Kunihiro Enatsu, Ai Yamada, Nao Hayashi, Yihsien Enatsu, Eri Okamoto, Shoji Kokeguchi, Toshiro Iwasaki, and Masahide Shiotani
- Abstract
Background Women with 21-hydroxylase deficiency have reduced fertility because of excessive production of adrenal androgen and progesterone, which can inhibit folliculogenesis, disturb the normal gonadotropin secretion pattern and development of the endometrium, and affect endometrial receptivity. The use of high doses of estradiol and progesterone in frozen-thawed embryo transfer with hormone replacement therapy may improve the results of fertility treatment in women with 21-hydroxylase deficiency and high progesterone. Case presentation: A 40-year-old woman with 21-hydroxylase deficiency and persistently high progesterone levels who was receiving steroid treatment visited our institution because she wanted to have a second child. Previously, she had had difficulties with frozen-thawed embryo transfer because of a gradual increase in progesterone levels. After reduction of progesterone levels with steroid hormone treatment, she had succeeded having a healthy baby after frozen-thawed embryo transfer with hormone replacement therapy. She hoped to have a second child with the same method, but steroid hormone treatment did not decrease her progesterone level. Frozen-thawed embryo transfer with hormone replacement therapy was attempted despite the high progesterone level, but the patient had two miscarriages. In the third attempt, the patient was given a high dose of estradiol and progesterone medication, which led to a better result than with the first two attempts. Conclusions Administering a high dose of estradiol and progesterone medication during frozen-thawed embryo transfer with hormone replacement therapy might achieve better results in women with 21-hydroxylase deficiency and persistently high progesterone levels.
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- 2023
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7. Acrylamide in Cooked Sprouts of Mung Bean (Vigna radiata)
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Kazuhiro Chiku, Ai Yamada, Yui Shibasaki, Yoshiki Makino, Taidoh Komatsuzaki, and Mitsuru Yoshida
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General Environmental Science - Published
- 2023
- Full Text
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8. 若年層における森林および都市散策の心理学的・生理学的影響の評価
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Ai, Yamada, Da-Hong, Wang, Masamitsu, Miyanaga, 岡山理科大学理学部生物化学科, and Department of Biochemistry, Okayama University of Science
- Published
- 2020
9. PHOSPHATE exporter XPR1/SLC53A1 is required for the tumorigenicity of epithelial ovarian cancer
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Yoko Akasu‐Nagayoshi, Tomoatsu Hayashi, Ayako Kawabata, Naomi Shimizu, Ai Yamada, Naoko Yokota, Ryuichiro Nakato, Katsuhiko Shirahige, Aikou Okamoto, and Tetsu Akiyama
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Ovarian Neoplasms ,Cancer Research ,Mice ,Oncology ,Animals ,Humans ,Female ,General Medicine ,Carcinoma, Ovarian Epithelial ,Prognosis ,Adenocarcinoma, Clear Cell ,Phosphates - Abstract
Ovarian cancer is the fifth most common cause of cancer-related death in women. Ovarian clear cell carcinoma (OCCC) is a chemotherapy-resistant epithelial ovarian cancer with poor prognosis. As a basis for the development of therapeutic agents that could improve the prognosis of OCCC, we performed a screen for proteins critical for the tumorigenicity of OCCC using the CRISPR/Cas9 system. Here we show that knockdown of the phosphate exporter XPR1/SLC53A1 induces the growth arrest and apoptosis of OCCC cells in vitro. Moreover, we show that knockdown of XPR1/SLC53A1 inhibits the proliferation of OCCC cells xenografted into immunocompromised mice. These results suggest that XPR1/SLC53A1 plays a critical role in the tumorigenesis of OCCC cells. We speculate that XPR1/SLC53A1 might be a promising molecular target for the therapeutic treatment of OCCC.
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- 2022
10. The splicing factor DHX38/PRP16 is required for ovarian clear cell carcinoma tumorigenesis, as revealed by a CRISPR-Cas9 screen
- Author
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Brandon Cona, Tomoatsu Hayashi, Ai Yamada, Naomi Shimizu, Naoko Yokota, Ryuichiro Nakato, Katsuhiko Shirahige, and Tetsu Akiyama
- Subjects
DEAD-box RNA Helicases ,Gene Expression Regulation, Neoplastic ,Ovarian Neoplasms ,Mice ,Carcinogenesis ,Animals ,Humans ,Female ,RNA Splicing Factors ,CRISPR-Cas Systems ,General Biochemistry, Genetics and Molecular Biology ,Adenocarcinoma, Clear Cell - Abstract
Certain cancers, such as ovarian clear cell carcinoma (OCCC), display high levels of genetic variation between patients, making it difficult to develop effective therapies. In order to identify novel genes critical to OCCC growth, we carried out a comprehensive CRISPR-Cas9 knockout screen against cell growth using an OCCC cell line and a normal ovarian surface epithelium cell line. We identified the gene encoding DHX38/PRP16, an ATP-dependent RNA helicase involved in splicing, as critical for the growth and tumorigenesis of OCCC. DHX38/PRP16 knockdown in OCCC cells, but not normal cells, induces apoptosis and impairs OCCC tumorigenesis in a mouse model. Our results suggest that DHX38/PRP16 may play a role in OCCC tumorigenesis and could potentially be a promising therapeutic target.
- Published
- 2021
11. Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia
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Ai Yamada, Midori Nakagawa, Shuhei Yamada, Hiroshi Moritake, Sayaka Kawano, Syun Nagasawa, Sachiyo Kamimura, Mariko Kinoshita, Tadao Taguchi, Yusuke Saito, and Hong-Shan Liu
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Cancer Research ,THP-1 Cells ,Citric Acid Cycle ,hematopoietic organ ,Mannose ,Pentose phosphate pathway ,Pentose Phosphate Pathway ,chemistry.chemical_compound ,Mice ,leukemia metabolism ,Cell, Molecular, and Stem Cell Biology ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Glycolysis ,activation and metabolism of carcinogens ,Leukemia ,Mannose-6-Phosphate Isomerase ,Chemistry ,Myeloid leukemia ,General Medicine ,Metabolism ,Original Articles ,glycolysis ,medicine.disease ,Prognosis ,Xenograft Model Antitumor Assays ,Up-Regulation ,Citric acid cycle ,Gene Expression Regulation, Neoplastic ,Oncology ,Biochemistry ,mannose metabolism ,Female ,Original Article ,Energy source ,K562 Cells - Abstract
Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene‐independent leukemia., Leukemia cells utilize mannose as a glycolytic energy source under glucose starvation. High PMI expression is associated with poor prognosis in acute myeloid leukemia due to energy starvation resistance and anticancer drug resistance. Mannose load that exceeds the processing capacity of PMI inhibits leukemia cell proliferation and energy metabolism.
- Published
- 2021
12. EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase
- Author
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Hiroshi Moritake, Mariko Kinoshita, Kazuhiro Morishita, Sachiyo Kamimura, Yusuke Saito, Souichi Adachi, Tomoyoshi Soga, Daisuke Sawa, Takashi Taga, Hidemasa Matsuo, Daisuke Tomizawa, Akira Suekane, Motomi Osato, Ai Yamada, and Honami Ogoh
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Acute Myeloid Leukemia ,Adult ,Asparagine synthetase ,Oxidative phosphorylation ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Proto-Oncogenes ,medicine ,Asparaginase ,Humans ,Chemistry ,Myeloid leukemia ,Articles ,Hematology ,medicine.disease ,MDS1 and EVI1 Complex Locus Protein ,DNA-Binding Proteins ,Glutamine ,Citric acid cycle ,Leukemia, Myeloid, Acute ,Leukemia ,Cancer research ,Energy source ,Flux (metabolism) ,Transcription Factors ,030215 immunology - Abstract
Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.
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- 2019
- Full Text
- View/download PDF
13. Association of Vegetable and Fruit Consumption with Urinary Oxidative Biomarkers in Teenaged Girls: A School-Based Pilot Study in Japan
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Yoshiko, Sato, Ai, Yamada, Masamitsu, Miyanaga, and Da-Hong, Wang
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Oxidative Stress ,Adolescent ,Japan ,Fruit ,Health, Toxicology and Mutagenesis ,vegetable/fruit consumption ,oxidative biomarkers ,hexanoyl-lysine ,8-hydroxy-2′deoxyguanosine ,dityrosine ,hydrogen peroxide ,physical exercise ,urine ,teenaged girls ,Vegetables ,Public Health, Environmental and Occupational Health ,Humans ,Female ,Pilot Projects ,Biomarkers ,Diet - Abstract
Hexanoyl-lysine (HEL), 8-hydroxy-2′deoxyguanosine (8-OHdG), and dityrosine (DT) have served as potential biomarkers for detecting oxidative modified lipids, DNA, and proteins in biological samples, respectively. Whether regular higher levels of consumption of vegetables/fruit (V/F) would decrease oxidative modification of these biomolecules in the body remain unelucidated. To examine the association of regular V/F consumption with the generation of these reactive oxygen species-induced biomarkers, this study evaluated V/F consumption in a school-based sample of teenaged girls (mean age 15.6 ± 1.7 years, n = 103), and quantified the formation of oxidative stress biomarkers in their urine. Only 19.4% and 23.3% of participants reported that they consumed the recommended daily amount of vegetables and fruits, respectively. Individuals who consumed lower levels of fruit (
- Published
- 2022
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14. Measurement of methotrexate in human cerebrospinal fluid using a chemiluminescence immunoassay intended for serum and plasma matrices
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Ryuji Ikeda, Yasutoshi Hirabara, Naoki Yoshikawa, Hiroshi Moritake, Tsubasa Yokota, and Ai Yamada
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0301 basic medicine ,Microbiology (medical) ,Chemiluminescence immunoassay ,Clinical Biochemistry ,high‐performance liquid chromatography ,Passing‐Bablok ,High-performance liquid chromatography ,cerebrospinal fluid ,methotrexate ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Limit of Detection ,medicine ,Humans ,Immunology and Allergy ,Hplc method ,Chromatography, High Pressure Liquid ,Research Articles ,Immunoassay ,Hplc analysis ,Chromatography ,Chemistry ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Reproducibility of Results ,Hematology ,chemiluminescence immunoassay ,Medical Laboratory Technology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Calibration ,Luminescent Measurements ,Methotrexate ,Research Article ,medicine.drug - Abstract
Background The concentration of MTX in blood is often measured quickly and easily by immunoassays. Thus, immunoassays may facilitate the easy determination of the concentration of MTX in the cerebrospinal fluid (CSF). In this study, we measured methotrexate (MTX) concentrations in the CSF using a high‐performance liquid chromatography (HPLC) method intended for analyzing CSF matrices and a chemiluminescence immunoassay (CLIA) method intended for assessing serum and plasma matrices and verified the differences in the results of the two methods. Methods HPLC analysis for MTX in the CSF was performed using a Prominence UFLC system with a C18 column. The HPLC method was validated in accordance with the 2018 FDA guideline. The CLIA method was performed using an ARCHITECT i1000SR system intended for serum and plasma matrices. A total of 47 CSF samples (14 clinical and 33 spiked specimens) were analyzed using the two methods. Results The HPLC method passed the validation criteria. The concentration of MTX in the same sample, determined using the HPLC and CLIA methods, differed proportionally; the percent difference in the concentrations averaged −23.0% (95% confidence interval: −36.9% to −9.1%) as revealed by the Bland‐Altman plot. The relationship between the measured values, evaluated using the Passing‐Bablok regression, was as follows: HPLC = 1.205 × CLIA – 0.024. Conclusion The equation deduced in this study can be used to correct the concentration of MTX measured using the CLIA method., MTX concentrations in the CSF were measured using a HPLC method intended for analyzing CSF matrices and a CLIA method intended for assessing serum and plasma matrices, and the differences in the results of the two methods were verified. The concentration of MTX in the same sample, determined using the HPLC and CLIA methods, differed proportionally.
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- 2020
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15. Spontaneous differentiation to ganglioneuroma from neuroblastoma with multiple bone metastases
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Mariko Kinoshita, Kazuhiko Nakame, Ai Yamada, Hiroshi Moritake, and Sachiyo Kamimura
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Pathology ,medicine.medical_specialty ,business.industry ,Neuroblastoma ,Medicine ,Ganglioneuroma ,business ,medicine.disease - Published
- 2020
- Full Text
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16. Effects of a Forest Walk on Urinary Dityrosine and Hexanoyl-Lysine in Young People: A Pilot Study
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Ai Yamada, Da Hong Wang, Masamitsu Miyanaga, Tokushi Horike, and Yoshiko Sato
- Subjects
hexanoyl-lysine ,Adolescent ,Health, Toxicology and Mutagenesis ,lcsh:Medicine ,Pilot Projects ,Walking ,Biology ,Forests ,Protein oxidation ,Young Adult ,Urinary levels ,Japan ,forest walk ,Humans ,protein oxidation ,Cities ,Downtown area ,Brief Report ,Lysine ,lcsh:R ,Public Health, Environmental and Occupational Health ,lipid peroxidation ,dityrosine ,Oxidative Stress ,Tyrosine ,phytoncides ,human activities ,Demography - Abstract
A few studies indicate exposure to forests may alleviate oxidative stress in the body. However, more evidence is needed to support this potentiality. The purpose of the current study aimed at examining whether there is any difference in urinary levels of oxidatively modified proteins or lipids—dityrosine (DT) and hexanoyl-lysine (HEL), respectively, after a forest or urban walk. The study was performed on 29 university students who took part in forest walks (Shinjo Village) in Okayama Prefecture of Japan and on 42 university students who took part in urban walks in the downtown area of Okayama City. Urine samples before and after the walks were analyzed for DT and HEL excretion. Air phytoncides during the walks were also measured. We found a decreased tendency in urinary DT and HEL (p < 0.05) in most participants after the forest walks, but not after the urban walks. We further found the total levels of air phytoncides in the forest field were 1.50 times higher compared with those in the urban field. This study suggests the possibility that regular immersion in a forest environment might contribute toward weakening of the oxidative modifications of proteins or lipids in the body.
- Published
- 2020
17. PREPARATION OF OPTICALLY ACTIVE 2,2-DISUBSTITUTED 5-HYDROXYCHROMENES BY ENZYMATIC RESOLUTION OF RACEMIC ESTERS
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Takuya Kumamoto, Kazuaki Katakawa, Ai Yamada, and Mika Kainuma
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Pharmacology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Resolution (electron density) ,Optically active ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Analytical Chemistry - Abstract
Enzymatic kinetic resolution of racemic esters of 2,2-disubstituted 5-hydroxychromenes was examined. Transesterification of acetate using Amano Lipase PS in the presence of t-BuOH was most effective to give the corresponding optically active acetate in 18% yield and 95% ee. The absolute configuration of the acetate was determined as R based on the conversion to teretifolione B with natural absolute configuration.
- Published
- 2018
18. TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma
- Author
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Daisuke Sawa, Hiroshi Moritake, Naoki Sameshima, Yusuke Saito, Ai Yamada, Mariko Kinoshita, Sachiyo Kamimura, Takao Konomoto, and Hiroyuki Nunoi
- Subjects
0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,medicine.medical_treatment ,Morpholines ,Apoptosis ,Sarcoma, Ewing ,lcsh:RC254-282 ,Metastasis ,Receptor, IGF Type 1 ,Focal adhesion ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,metastasis ,Radiology, Nuclear Medicine and imaging ,Phosphorylation ,Receptor ,Protein kinase B ,Protein Kinase Inhibitors ,insulin‐like growth factor‐I receptor ,Neoplasm Staging ,Original Research ,Cancer Biology ,Dose-Response Relationship, Drug ,Chemistry ,Growth factor ,TAE226 ,focal adhesion kinase ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Metastatic Ewing Sarcoma ,Tyrosine kinase 2 ,030220 oncology & carcinogenesis ,Focal Adhesion Protein-Tyrosine Kinases ,Cancer research ,Biomarkers ,Ewing sarcoma - Abstract
The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future., Systemic TAE226 treatment potently reduced the size of local tumors and inhibited micrometastasis in vivo through cell cycle inhibition, induction of apoptosis, and inhibition of AKT signaling. Furthermore, combined therapy with TAE226 and conventional anticancer drugs for EWS has synergistic anticancer effects. Overall, the results of the present study suggest that TAE226 is a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.
- Published
- 2019
19. Effect of Pressure on Regression Shape Formed by Stabilized Combustion
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Mai Hukada, Masashi Wakita, Ai Yamada, Harunori Nagata, and Ayumu Tsuji
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Materials science ,Composite material ,Combustion ,Regression - Published
- 2020
- Full Text
- View/download PDF
20. Changes in Urinary Hydrogen Peroxide and 8-Hydroxy-2′-Deoxyguanosine Levels after a Forest Walk: A Pilot Study
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Da Hong Wang, Ai Yamada, and Masamitsu Miyanaga
- Subjects
0301 basic medicine ,Adult ,Male ,urban walk ,Health, Toxicology and Mutagenesis ,Urinary system ,H2O2 ,Physiology ,lcsh:Medicine ,Pilot Projects ,Walking ,Health benefits ,Forests ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,Human health ,Young Adult ,0302 clinical medicine ,Japan ,forest walk ,Medicine ,oxidative biomarker ,Humans ,030212 general & internal medicine ,Cities ,Hydrogen peroxide ,Downtown area ,business.industry ,Communication ,lcsh:R ,Public Health, Environmental and Occupational Health ,8-Hydroxy-2'-deoxyguanosine ,Deoxyguanosine ,Hydrogen Peroxide ,Spot urine ,Oxidative Stress ,030104 developmental biology ,chemistry ,8-Hydroxy-2'-Deoxyguanosine ,Female ,business ,human activities ,Oxidative stress ,Biomarkers ,8-OHdG - Abstract
Some studies have shown that exposure to forests has positive effects on human health, although the mechanisms underlying the health benefits of a forest environment have not been elucidated yet. The current study was aimed at examining how the levels of urinary hydrogen peroxide (H2O2) and 8-hydroxy-2’deoxyguanosine (8-OHdG) change after a forest or urban walk in healthy subjects. Twenty-eight volunteers (19 men and 9 women) participated in the study. The forest walks were carried out in a forest in Okayama Prefecture, Japan, and the urban walks (15 men and 7 women) were carried out in the downtown area of Okayama city, each for two hours. Spot urine samples were collected before the walk, the next day and one week after the forest or urban walk. Compared with pre-forest walk levels, urinary H2O2 (p < 0.1) and 8-OHdG (p < 0.1) concentrations significantly decreased in the participants the day after the forest walk; furthermore, urinary 8-OHdG remained at a low level even at one week after the forest walk (p < 0.05). However, there were no significant changes in the concentrations of these oxidative biomarkers after the urban walk. These findings suggest the possibility that exposure to forests may alleviate oxidative stress in the body.
- Published
- 2018
21. Structure–activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists
- Author
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Taro Noguchi, Koki Yamamoto, Shinya Oishi, Hiroaki Okamura, Hiroaki Ohno, Nobutaka Fujii, Fuko Matsuda, Ai Yamada, Takashi Yamamura, Satoshi Ohkura, and Ryosuke Misu
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Pharmacology ,medicine.medical_specialty ,Organic Chemistry ,Pharmaceutical Science ,Biology ,Biochemistry ,Gonadotropin secretion ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Hypothalamus ,Internal medicine ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Secretion ,Neurokinin B ,Receptor ,Neprilysin ,Hormone - Abstract
Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate neurokinin-3 receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.
- Published
- 2015
22. Acute megakaryoblastic leukemia and severe pulmonary fibrosis in a child with down syndrome: Successful treatment with ultra low-dose cytarabine using GATA1 mutation to monitor minimal residual disease
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Hiroshi Moritake, Ai Yamada, Hidemi Shimonodan, Hiroyuki Nunoi, Yasuhiro Kimoto, and Daisuke Sawa
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medicine.medical_specialty ,Down syndrome ,Ultra low dose ,business.industry ,Hematology ,medicine.disease ,Minimal residual disease ,Gastroenterology ,Acute megakaryoblastic leukemia ,Internal medicine ,Pulmonary fibrosis ,medicine ,Cytarabine ,business ,GATA1 Mutation ,medicine.drug - Published
- 2012
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23. EVI1 in Acute Myeloid Leukemia Triggers Metabolic Reprograming Associated with Leukemogenesis and Increases Sensitivity to L-Aspalaginase
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Ai Yamada, Yusuke Saito, Kazuhiro Morishita, Daisuke Sawa, Tomoyoshi Soga, Mariko Kinoshita, Sachiyo Kamimura, and Hiroshi Moritake
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Glutaminolysis ,Chemistry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Oxidative phosphorylation ,medicine.disease ,Biochemistry ,Molecular biology ,Glutamine ,Metabolic pathway ,Leukemia ,Cell culture ,hemic and lymphatic diseases ,medicine ,Energy source ,neoplasms - Abstract
Leukemia cells survive and proliferate under conditions of metabolic stress by acquiring mutations that increase energy metabolism. Here, we aimed to identify a specific metabolic inhibitor and examine transcription factor-enhanced changes in energy metabolism by refractory leukemia cells. Overexpression of Ecotropic Virus Integration site 1 protein homolog (EVI1) in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. We focused on metabolic reprograming of MLL leukemia cells expressing EVI1, since the metabolic relationship between MLL and EVI1 is unclear. We used an extracellular flux analyze to examine metabolic changes during leukemia development in a mouse model of MLL-r AML expressing high levels of EVI1 (EVI1+). To examine whether EVI1 regulates energy metabolism in MLL-rearranged leukemia cells, we used transgenic mice expressing EVI1 (TG) in LSK and GMP cells model in which AML is driven by the MLL-AF9 oncogene. We measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a flux analyzer. TG MLL-AF9 mice showed a significantly higher basal and capacity of OCR than WT MLL-AF9 mice ex vivo. EVI1+ cells showed accelerated oxidative phosphorylation (OXPHOS) prior to activation of glycolysis, and higher dependency on glutamine as an energy source. To identify the metabolic pathways regulated by EVI1, we performed capillary electrophoresis time-of-fight mass spectrometry-based metabolome profiling of WT and TG MLL-AF9 leukemia cells. We found significant differences between the cells in terms of the amounts of metabolites derived from the glycolytic and TCA cycles. Fructose 1,6-bisphosphate and lactate were up-regulated in TG MLL-AF9 cells, implying activation of glycolysis. Moreover, the amounts of fumarate and malate (metabolites of the TCA cycle) were significantly higher in TG MLL-AF9 cells. EVI1 played a role in glycolysis as well as driving expression of genes engaged in the tricarboxylic acid cycle. Next, we tested whether pharmacological inhibition of glycolysis and glutaminolysis suppresses MLL-AF9. L-asparaginase (ASP) [which catalyzes hydrolysis of asparagine (Asn) and glutamine (Gln) to asparatic acid or glutamic acid, respectively] markedly suppressed proliferation of TG MLL-AF9 cells, EVI1highAML cell lines. To examine the therapeutic potential of ASP in vivo, we treated secondary recipients of TG MLL-AF9 AML cells with ASP or control (vehicle), beginning 5 days post-transplantation. Mice then received intraperitoneal injections (five times per week) of distilled water or ASP (1000 U/kg). ASP led to a significant reduction in the number of GFP+ AML cells in the peripheral blood and increased the survival of recipient mice. Next, we examined an AML xenograft model. Two groups of NOG mice were injected subcutaneously with UCSD/AML1 cells and then treated with ASP or control. ASP -treated mice showed a significant reduction in the growth of AML tumors. Overall, these findings indicate that ASP -mediated inhibition of OXPHOS is a potential treatment for AML. We clarified that increased glutamine dependency by MLL-r AML cells showing high EVI1 expression makes them sensitive to ASP. We found that the energy advantage of AML cells is acquired via transcription factor-mediated activation of mitochondrial metabolism, leading to a poor prognosis. Furthermore, we show that new therapeutic options can be identified by examining the energy-based metabolic characteristics of leukemia cells. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
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24. Gelation behavior with acetylation of chitosan for membrane preparation
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Tomoki Takahashi, Katsuto Otake, Masanao Imai, Ai Yamada, and Atsushi Shono
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Chromatography ,Syneresis ,technology, industry, and agriculture ,Membrane structure ,Ocean Engineering ,macromolecular substances ,Pollution ,Chemical reaction ,Chitosan ,chemistry.chemical_compound ,Acetic anhydride ,Acetic acid ,Membrane ,chemistry ,Chemical engineering ,Methanol ,Water Science and Technology - Abstract
The aim of this work is to investigate the gelation behavior of chitosans which has various degree of acetylation (DA) of amino group to ensure the preparation of the designed membrane structure. The DA was controlled by the amount of acetic anhydride added to the solution of chitosan/acidified water/methanol mixture. The gelation behavior was evaluated by the gelation time and the quantity of syneresis. The mechanical strength of acetylated chitosan gels was also measured. The optimum condition for the formation of the membrane, i.e. chitosan concentration, acetic acid/ chitosan mass ratio, methanol/water mass ratio, and amount of acetic anhydride for acetylation, was determined. This composition gives low contractility, shorter gelation time, and high mechanical strength to the membrane and the gel. Useful information not only for a preparation of a membrane but also for an immobilized carrier or a chemical reaction system was obtained in this work.
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- 2010
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25. Influence of Rosemary Extract on the Oxidative Stability of Tuna Orbital Oil and on the Effect in vivo of the Oxidized Oil on Rat Liver
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Keiko Yoshioka, Shun Wada, and Ai Yamada
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Biochemistry ,Autoxidation ,In vivo ,Chemistry ,General Chemical Engineering ,Rat liver ,Rosemary extract ,General Medicine ,General Chemistry ,Oxidative phosphorylation ,Peroxide value ,Food science ,Tuna - Published
- 2002
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26. Development of novel neurokinin 3 receptor (NK3R) selective agonists with resistance to proteolytic degradation
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Takashi Yamamura, Nobutaka Fujii, Ryosuke Misu, Satoshi Ohkura, Shinya Oishi, Taro Noguchi, Ai Yamada, Koki Yamamoto, Hiroaki Ohno, Fuko Matsuda, and Hiroaki Okamura
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Agonist ,Serum ,medicine.drug_class ,Peptidomimetic ,Isostere ,Neurokinin B ,Swine ,Ovariectomy ,Hypothalamus ,Substance P ,Pharmacology ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Dipeptide ,Protein Stability ,Goats ,Receptors, Neurokinin-3 ,Peptide Fragments ,nervous system ,chemistry ,Molecular Medicine ,Female ,Peptidomimetics ,Peptide Hydrolases - Abstract
Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the neurokinin-3 receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.
- Published
- 2014
27. Placental mesenchymal dysplasia, a case of intrauterine sudden death
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Ai, Yamada, Noriko, Sakaida, Akiharu, Okamura, Takashi, Yamada, Takehito, Ota, and Masaki, Bo
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Adult ,Mesoderm ,Rupture, Spontaneous ,Pregnancy ,Perinatal Death ,Placenta ,Humans ,Female ,Gestational Age ,Chorionic Villi ,Ultrasonography, Prenatal - Abstract
Placental mesenchymal dysplasia (PMD) is a rare condition presenting with enlarged, multicystic placenta like molar changes. Although PMD usually features a normal fetus and the pregnancy often extends into the third trimester, PMD is clinically significant lesion with high rates of FGR, IUFD, and is associated with Beckwith-Wiedemann syndrome (BWS). We report a 30-year old woman at her first pregnancy with intrauterine sudden death at 31 weeks of gestation. The vesicular lesion in her uterus was detected at 10 weeks on ultrasound. The fetus was normal size without any anomaly on ultrasound and normal trophoblastic vascularization by Doppler study during the pregnancy. As the pregnancy advanced, the vesicular lesion decreased in size and no fetal abnormalities were detected. At 28 weeks of gestation an ultrasound detected dilated periumbilical chorionic vessels. We didn't detect severe FGR or abnormal trophoblastic vascularization. At 31 weeks of gestation an intrauterine sudden death of a normal-sized fetus without any anomaly occurred. The placenta was enlarged, and microscopic morphology confirmed a diagnosis of PMD. The chorionic vessels were cirsoid, dilated and tortuous. We determined the rupture of expanded periumbilical chorionic vessels led to fetal death.
- Published
- 2014
28. Response of corneal epithelial cells to Staphylococcus aureus
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Michael S. Gilmore, Ai Yamada, Susan R. Heimer, and Hugh Russell
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Microbiology (medical) ,Chemokine ,Cell type ,Staphylococcus aureus ,Immunology ,medicine.disease_cause ,Microbiology ,Cornea ,Immune system ,medicine ,Humans ,RNA, Messenger ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Chemokine CCL20 ,biology ,Virulence ,Gene Expression Profiling ,Epithelium, Corneal ,Proteins ,Epithelial Cells ,Dendritic cell ,Staphylococcal Infections ,Epithelium ,CCL20 ,TLR2 ,Infectious Diseases ,medicine.anatomical_structure ,Gene Expression Regulation ,Host-Pathogen Interactions ,biology.protein ,Parasitology ,Research Paper - Abstract
Staphylococcus aureus is a leading cause of invasive infection. It also infects wet mucosal tissues including the cornea and conjunctiva. Conflicting evidence exists on the expression of Toll-like receptors by human corneal epithelial cells. It was therefore of interest to determine how epithelial cells from this immune privileged tissue respond to S. aureus. Further, it was of interest to determine whether cytolytic toxins, with the potential to cause ion flux or potentially permit effector molecule movement across the target cell membrane, alter the response. Microarrays were used to globally assess the response of human corneal epithelial cells to S. aureus. A large increase in abundance of transcripts encoding the antimicrobial dendritic cell chemokine, CCL20, was observed. CCL20 release into the medium was detected, and this response was found to be largely TLR2 and NOD2 independent. Corneal epithelial cells also respond to S. aureus by increasing the intracellular abundance of mRNA for inflammatory mediators, transcription factors, and genes related to MAP kinase pathways, in ways similar to other cell types. The corneal epithelial cell response was surprisingly unaffected by toxin exposure. Toxin exposure did, however, induce a stress response. Although model toxigenic and non-toxigenic strains of S. aureus were employed in the present study, the results obtained were strikingly similar to those reported for stimulation of vaginal epithelial cells by clinical toxic shock toxin expressing isolates, demonstrating that the initial epithelial cellular responses to S. aureus are largely independent of strain as well as epithelial cell tissue source.
- Published
- 2010
29. Release of soluble tumor necrosis factor receptor 1 from corneal epithelium by TNF-alpha-converting enzyme-dependent ectodomain shedding
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Mitsuru Sawa, Tohru Sakimoto, and Ai Yamada
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Male ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Peptidoglycan ,Biology ,ADAM17 Protein ,Hydroxamic Acids ,Immunoenzyme Techniques ,Mice ,Cornea ,Burns, Chemical ,medicine ,Animals ,Humans ,Sodium Hydroxide ,Corneal epithelium ,Cell Line, Transformed ,Tissue Inhibitor of Metalloproteinase-3 ,Mice, Inbred BALB C ,Epithelium, Corneal ,Dipeptides ,Molecular biology ,eye diseases ,Epithelium ,In vitro ,ADAM Proteins ,Eye Burns ,Cytokine ,medicine.anatomical_structure ,Ectodomain ,Solubility ,Cell culture ,Receptors, Tumor Necrosis Factor, Type I ,Tetradecanoylphorbol Acetate ,Tumor necrosis factor alpha ,sense organs - Abstract
PURPOSE An involvement of tumor necrosis factor-alpha-converting enzyme (TACE)-dependent ectodomain shedding in the release of soluble tumor necrosis factor receptor 1 (sTNFR1) from corneal epithelium was evaluated. METHODS In vitro experiments were performed using the human SV40-transformed human corneal epithelial cell (HCEC) line. Ectodomain shedding was stimulated by phorbol myristate acetate (PMA, 3 microM) or peptidoglycan (PGN, 100 microg/mL), with or without TACE inhibition, using TNF-alpha processing inhibitor-1 (TAPI-1, 250 microg/mL) or tissue inhibitor of metalloproteinase-3 (TIMP-3, 2 microg/mL) by addition to the HCEC culture medium. The concentrations of sTNFR1 in culture medium were analyzed by enzyme-linked immunosorbent assay. To induce an inflammatory response in the ocular surface, corneal alkali burn of BALB/c mice was made from a filter paper dipped in 1 N NaOH solution. TNFR1 expression in corneal and conjunctival epithelia was evaluated by immunohistochemistry 28 days after wounding. RESULTS In HCEC culture medium, sTNFR1 release was significantly increased by the addition of PMA (t-test, P < 0.01) or PGN (P < 0.01). The increased release of sTNFR1 was significantly inhibited by the addition of TAPI-1 or TIMP-3, indicating the possibility of TACE-dependent ectodomain shedding of TNFR1. In the corneal alkali burn model, TNFR1 was expressed in corneal and conjunctival epithelia. CONCLUSIONS TACE-dependent ectodomain shedding of sTNFR1 was recognized in corneal epithelium. In the inflamed ocular surface, TNFR1 was expressed in the corneal and conjunctival epithelia after alkali burn treatment. sTNFR1, released from the ocular surface, may play an anti-inflammatory role in the inflammatory condition.
- Published
- 2009
30. Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis
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Eriko Inokuchi, Hiroaki Ohno, Kenji Tomita, Motoyoshi Nomizu, Nobutaka Fujii, Kentaro Hozumi, Shinya Oishi, and Ai Yamada
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Ions ,chemistry.chemical_classification ,Molecular Structure ,Nitrile ,Peptidomimetic ,Stereochemistry ,Organic Chemistry ,Amidines ,Oxide ,Esters ,Oxides ,Peptide ,Biochemistry ,Amino acid ,Amidine ,chemistry.chemical_compound ,chemistry ,Drug Design ,Nitriles ,Molecule ,Peptide bond ,Peptidomimetics ,Amino Acids ,Physical and Theoretical Chemistry ,Peptides - Abstract
Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent. This nitrile oxide-mediated C-N bond formation was also used for peptide macrocyclization, in which the amidoxime group was converted to peptide bonds under mild acidic conditions. Syntheses of the cyclic RGD peptide and a peptidomimetic using both approaches, and their inhibitory activity against integrin-mediated cell attachment, are presented.
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- 2011
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31. Acid-Sensing Ion Channels Drive the Generation of Tactile Impulses in Merkel Cell-Neurite Complexes of the Glabrous Skin of Rodent Hindpaws.
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Yamada A, Gautam M, Yamada AI, Ling J, Gupta S, Furue H, Luo W, and Gu JG
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- Animals, Mice, Male, Rats, Female, Hindlimb, Mice, Knockout, Mice, Inbred C57BL, Physical Stimulation, Vibrissae physiology, Vibrissae innervation, Rats, Wistar, Merkel Cells physiology, Acid Sensing Ion Channels metabolism, Acid Sensing Ion Channels genetics, Acid Sensing Ion Channels physiology, Touch physiology, Skin innervation
- Abstract
Merkel cell-neurite complexes (MNCs) are enriched in touch-sensitive areas, including whisker hair follicles and the glabrous skin of the rodent's paws, where tactile stimulation elicits slowly adapting type 1 (SA1) tactile impulses to encode for the sense of touch. Recently, we have shown with rodent whisker hair follicles that SA1 impulses are generated through fast excitatory synaptic transmission at MNCs and driven by acid-sensing ion channels (ASICs). However, it is currently unknown whether, besides whisker hair follicles, ASICs also play an essential role in generating SA1 impulses from MNCs of other body parts in mammals. In the present study, we attempted to address this question by using the skin-nerve preparations made from the hindpaw glabrous skin and tibial nerves of both male and female rodents and applying the pressure-clamped single-fiber recordings. We showed that SA1 impulses elicited by tactile stimulation to the rat hindpaw glabrous skin were largely diminished in the presence of amiloride and diminazene, two ASIC channel blockers. Furthermore, using the hindpaw glabrous skin and tibial nerve preparations made from the mice genetically deleted of ASIC3 channels (ASIC3
-/- ), we showed that the frequency of SA1 impulses was significantly lower in ASIC3-/- mice than in littermate wild-type ASIC3+/+ mice, a result consistent with the pharmacological experiments with ASIC channel blockers. Our findings suggest that ASIC channels are essential for generating SA1 impulses to underlie the sense of touch in the glabrous skin of rodent hindpaws., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)- Published
- 2024
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32. Author Correction: Distinct local and global functions of mouse Aβ low-threshold mechanoreceptors in mechanical nociception.
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Gautam M, Yamada A, Yamada AI, Wu Q, Kridsada K, Ling J, Yu H, Dong P, Ma M, Gu J, and Luo W
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- 2024
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33. Distinct local and global functions of mouse Aβ low-threshold mechanoreceptors in mechanical nociception.
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Gautam M, Yamada A, Yamada AI, Wu Q, Kridsada K, Ling J, Yu H, Dong P, Ma M, Gu J, and Luo W
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- Mice, Animals, Nociception, Mechanoreceptors physiology, Inflammation genetics, Hyperalgesia genetics, Chronic Pain
- Abstract
The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of Split
Cre labeled mouse Aβ-LTMRs in this regard. Genetic ablation of SplitCre -Aβ-LTMRs increased mechanical nociception but not thermosensation in both acute and chronic inflammatory pain conditions, indicating a modality-specific role in gating mechanical nociception. Local optogenetic activation of SplitCre -Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a model, in which Aβ-LTMRs play distinctive local and global roles in transmitting or alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia., (© 2024. The Author(s).)- Published
- 2024
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34. Properties of Nav1.8 ChR2 -positive and Nav1.8 ChR2 -negative afferent mechanoreceptors in the hindpaw glabrous skin of mice.
- Author
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Yamada A, Yamada AI, Ling J, Furue H, Luo W, and Gu JG
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- Animals, Mice, Light, Mechanoreceptors, Pain, Rhodopsin, Touch
- Abstract
Nav1.8-positive afferent fibers are mostly nociceptors playing a role in mediating thermal and mechanical pain, but mechanoreceptors within these afferents have not been fully investigated. In this study, we generated mice expressing channel rhodopsin 2 (ChR2) in Nav1.8-positive afferents (Nav1.8
ChR2 ), which showed avoidance responses to mechanical stimulation and nocifensive responses to blue light stimulation applied to hindpaws. Using ex vivo hindpaw skin-tibial nerve preparations made from these mice, we characterized properties of mechanoreceptors on Nav1.8ChR2 -positive and Nav1.8ChR2 -negative afferent fibers that innervate the hindpaw glabrous skin. Of all Aβ-fiber mechanoreceptors, small portion was Nav1.8ChR2 -positive. Of all Aδ-fiber mechanoreceptors, more than half was Nav1.8ChR2 -positive. Of all C-fiber mechanoreceptors, almost all were Nav1.8ChR2 -positive. Most Nav1.8ChR2 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors displayed slowly adapting (SA) impulses in response to sustained mechanical stimulation, and their mechanical thresholds were high in the range of high threshold mechanoreceptors (HTMRs). In contrast, sustained mechanical stimulation applied to Nav1.8ChR2 -negative Aβ- and Aδ-fiber mechanoreceptors evoked both SA and rapidly adapting (RA) impulses, and their mechanical thresholds were in the range of low threshold mechanoreceptors (LTMRs). Our results provide direct evidence that in the mouse glabrous skin, most Nav1.8ChR2 -negative Aβ-, Aδ-fiber mechanoreceptors are LTMRs involving in the sense of touch, whereas Nav1.8ChR2 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors are mainly HTMRs involving in mechanical pain., (© 2023. The Author(s).)- Published
- 2023
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- View/download PDF
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