71 results on '"Kenji Wakabayashi"'
Search Results
2. Case of laryngeal venous malformations requiring repeated advanced airway management in the perioperative course
- Author
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Fumi Maruyama, Takahiro Masuda, Nobuyuki Nosaka, and Kenji Wakabayashi
- Subjects
awake tracheal intubation ,difficult airway management ,laryngeal venous malformation ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract Laryngeal venous malformations rarely but do cause airway obstruction resulting in life‐threatening events. The perioperative airway management for the patients with them has not been well established. We suggest a strategy for laryngeal venous malformations management in the patients who undergo surgery in addition to planning for airway management.
- Published
- 2022
- Full Text
- View/download PDF
3. Mizuo–Nakamura phenomenon in X-linked retinoschisis
- Author
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Kenji Wakabayashi, Yuka Sakai-Wakabayashi, and Chie Ishigami
- Subjects
Mizuo–Nakamura phenomenon ,Oguchi's disease ,X-linked retinoschisis ,XLRS1 ,G-protein-coupled receptor kinase 1 (RHOK) ,S-antigen visual arrestin (SAG) ,Ophthalmology ,RE1-994 - Abstract
Purpose: To determine whether the Mizuo–Nakamura phenomenon, which is an important diagnostic sign of Oguchi's disease, also occurs in patients with genetically proven X-linked retinoschisis (XLRS). Methods: We examined three patients with a clinical and genetic diagnosis of XLRS and one patient who was clinically diagnosed with Oguchi's disease, with an emphasis on the Mizuo–Nakamura phenomenon. We obtained color fundus photographs, especially in the fully dark-adapted state, using the non-mydriatic mode on a digital retinal camera and infrared observation monitor to avoid the bleaching effects caused by the viewing light, which alters the fundus color in a short time. Results: The Mizuo–Nakamura phenomenon was observed in all patients with molecularly proven XLRS, similar to that in the patient with Oguchi's disease. The sets of photographs were obtained in the light- and dark-adapted states using our newly devised techniques needed to witness the Mizuo-Nakamura phenomenon. Conclusions and Importance: The Mizuo–Nakamura phenomenon was identified in three patients with genetically proven XLRS. To the best of our knowledge, this study provided the first genetic evidence of the Mizuo–Nakamura phenomenon in a patient with molecularly proven XLRS without the causative genetic abnormalities for Oguchi's disease. Our findings suggest that XLRS is responsible for the Mizuo–Nakamura phenomenon and its presence in XLRS is not a rare exception but may be a consistent manifestation of XLRS.
- Published
- 2022
- Full Text
- View/download PDF
4. Rapid and sensitive SARS-CoV-2 detection using a homogeneous fluorescent immunosensor Quenchbody with crowding agents
- Author
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Bo Zhu, Nobuyuki Nosaka, Shuji Kanamaru, Jinhua Dong, Yancen Dai, Akihito Inoue, Yinghui Yang, Kaori Kobayashi, Tetsuya Kitaguchi, Hiroshi Iwasaki, Ryuji Koike, Kenji Wakabayashi, and Hiroshi Ueda
- Subjects
Immunoassay ,SARS-CoV-2 ,Electrochemistry ,Humans ,COVID-19 ,Environmental Chemistry ,Biosensing Techniques ,Nucleocapsid Proteins ,Pandemics ,Biochemistry ,Spectroscopy ,Analytical Chemistry - Abstract
Antigen tests for SARS-CoV-2 are widely used by the public during the ongoing COVID-19 pandemic, which demonstrates the societal impact of homogeneous immunosensor-related technologies. In this study, we used the PM Q-probe and Quenchbody technologies to develop a SARS-CoV-2 nucleocapsid protein (N protein) homogeneous immunosensor based on a human anti-N protein antibody. For the first time, we uncovered the crowding agent's role in improving the performance of the double-labeled Quenchbody, and the possible mechanisms behind this improvement are discussed. The 5% polyethylene glycol 6000 significantly improved both the response speed and sensitivity of SARS-CoV-2 Quenchbodies. The calculated limit of detection for recombinant N protein was 191 pM (9 ng mL
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- 2022
5. Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19
- Author
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Tadashi Hosoya, Seiya Oba, Yoji Komiya, Daisuke Kawata, Mari Kamiya, Hideyuki Iwai, Sho Miyamoto, Michiyo Kataoka, Minoru Tobiume, Takayuki Kanno, Akira Ainai, Hiroyuki Sato, Akihiro Hirakawa, Yuichi Mitsui, Takashi Satoh, Kenji Wakabayashi, Tetsuya Yamada, Yasuhiro Otomo, Yasunari Miyazaki, Hideki Hasegawa, Tadaki Suzuki, and Shinsuke Yasuda
- Subjects
Multidisciplinary - Abstract
Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute–based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.
- Published
- 2023
6. Intensive care education for dental students through online visits to ICU rounds
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Kenichiro Ozaki, Nobuyuki Nosaka, Kenji Wakabayashi, and Haruka Tohara
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General Medicine - Published
- 2023
7. Apple-shaped obesity; a risky soil for cytokine-accelerated severity in COVID-19
- Author
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Tadashi Hosoya, Seiya Oba, Yoji Komiya, Daisuke Kawata, Mari Kamiya, Hideyuki Iwai, Sho Miyamoto, Michiyo Kataoka, Minoru Tobiume, Takayuki Kanno, Akira Ainai, Hiroyuki Sato, Akihiro Hirakawa, Takashi Satoh, Kenji Wakabayashi, Tetsuya Yamada, Yasuhiro Otomo, Yasunari Miyazaki, Hideki Hasegawa, Tadaki Suzuki, and Shinsuke Yasuda
- Abstract
Obesity is one of the most significant risk factors for the deterioration and mortality associated with COVID-19 [1]. A certain proportion of COVID-19 patients experience marked elevations of inflammatory mediators, termed “cytokine storm”, resulting in the deterioration of the respiratory condition [2,3]. In the present study, we elucidate that the high visceral adipose tissue (VAT) burden was more closely related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients than other obesity-associated markers, including body mass index (BMI). To explore a novel stratification of COVID-19 patients, we infected mouse-adapted SARS-CoV-2 in several obese mice, revealing that VAT-dominant ob/ob mice and diet-induced obesity obese mice died after infection with low-titer mouse-adapted SARS-CoV-2 virus due to the subsequent cytokine storm, whereas none of the subcutaneous adipose tissue (SAT) dominant db/db mice or control lean wild-type mice died. SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased production of inflammatory cytokine represented by IL-6. As well as the anti-IL-6 treatment, the prevention of obesity by leptin administration improved the survival of SARS-CoV-2 infected ob/ob mice by reducing the viral protein burden and excessive immune responses.
- Published
- 2022
8. A case of laryngeal venous malformations requiring repeated advanced airway management in the perioperative course
- Author
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Fumi Maruyama, Takahiro Masuda, Nobuyuki Nosaka, and Kenji Wakabayashi
- Abstract
Laryngeal venous malformations rarely but do cause airway obstruction resulting in life-threatening events. The perioperative airway management for the patients with them have not been well established. We suggest a strategy for laryngeal venous malformations management in the patients who undergo surgery in addition to planning for airway management.
- Published
- 2022
9. Effectiveness of remdesivir with corticosteroids for COVID‐19 patients in intensive care unit: A hospital‐based observational study
- Author
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Mariko Hanafusa, Nobutoshi Nawa, Yuki Goto, Tomoki Kawahara, Shigeru Miyamae, Yutaka Ueki, Nobuyuki Nosaka, Kenji Wakabayashi, Shuji Tohda, Ukihide Tateishi, and Takeo Fujiwara
- Subjects
Infectious Diseases ,Virology - Abstract
The effectiveness of remdesivir on survival in coronavirus disease 2019 (COVID-19), especially in cases treated in the intensive care unit (ICU), is controversial. We investigated the effectiveness of remdesivir with corticosteroids on the survival of COVID-19 patients in a real ICU clinical practice. For laboratory-confirmed COVID-19 patients admitted to the ICU of a tertiary hospital in Tokyo (April 2020-November 2021) and who received corticosteroids, the effectiveness of remdesivir for survival, stratified by interval length (within 9 or 10+ days), was retrospectively analyzed using Cox regression model. A total of 168 patients were included: 35 with no remdesivir use (control), 96 with remdesivir use within 9 days, and 37 with remdesivir use with an interval of 10+ days. In-hospital mortality was 45.7%, 10.4%, and 16.2%, respectively. After adjusting for possible covariates including comorbidities, laboratory data, oxygen demand, or level of pneumonia, remdesivir use within 9 days from symptom onset reduced mortality risk (hazard ratio [HR]: 0.10; 95% confidence interval (CI): 0.025-0.428) compared to the control group. However, remdesivir use with an interval of 10+ days showed no significant association with mortality (HR: 0.42; 95% CI: 0.117-1.524). Among COVID-19 patients who received corticosteroids in ICU, remdesivir use within 9 days from symptom onset was associated with reduced in-hospital mortality risk.
- Published
- 2022
10. A case report of localized chronic periodontitis after 29 years of follow-up
- Author
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Kenji Wakabayashi
- Subjects
medicine.medical_specialty ,business.industry ,Localized chronic periodontitis ,Medicine ,General Medicine ,business ,Dermatology - Published
- 2021
11. Discovery of a Novel Class of ERRα Agonists
- Author
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Masanori Izumi, Shuichiro Ito, Takako Kimura, Tsuyoshi Shinozuka, and Kenji Wakabayashi
- Subjects
chemistry.chemical_classification ,Benzimidazole ,Transcriptional activity ,010405 organic chemistry ,Organic Chemistry ,Peptide ,Computational biology ,Ligand (biochemistry) ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Coactivator ,Receptor - Abstract
[Image: see text] A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure–activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate 5c and the key interaction between the protein and ligand. Since both analogues avoided PPARγ transcriptional activity, they can be useful tool compounds for investigating biological ERRα functions.
- Published
- 2021
12. Mizuo-Nakamura phenomenon in X-linked retinoschisis
- Author
-
Kenji Wakabayashi, Yuka Sakai-Wakabayashi, and Chie Ishigami
- Subjects
Ophthalmology - Abstract
To determine whether the Mizuo-Nakamura phenomenon, which is an important diagnostic sign of Oguchi's disease, also occurs in patients with genetically proven X-linked retinoschisis (XLRS).We examined three patients with a clinical and genetic diagnosis of XLRS and one patient who was clinically diagnosed with Oguchi's disease, with an emphasis on the Mizuo-Nakamura phenomenon. We obtained color fundus photographs, especially in the fully dark-adapted state, using the non-mydriatic mode on a digital retinal camera and infrared observation monitor to avoid the bleaching effects caused by the viewing light, which alters the fundus color in a short time.The Mizuo-Nakamura phenomenon was observed in all patients with molecularly proven XLRS, similar to that in the patient with Oguchi's disease. The sets of photographs were obtained in the light- and dark-adapted states using our newly devised techniques needed to witness the Mizuo-Nakamura phenomenon.The Mizuo-Nakamura phenomenon was identified in three patients with genetically proven XLRS. To the best of our knowledge, this study provided the first genetic evidence of the Mizuo-Nakamura phenomenon in a patient with molecularly proven XLRS without the causative genetic abnormalities for Oguchi's disease. Our findings suggest that XLRS is responsible for the Mizuo-Nakamura phenomenon and its presence in XLRS is not a rare exception but may be a consistent manifestation of XLRS.
- Published
- 2021
13. The Safety and Effect of Early Mobilization in the Intensive Care Unit According to Cancellation Criteria
- Author
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Kenji Wakabayashi, Atsushi Okawa, Hidenobu Shigemitsu, Chisato Hoshino, and Tomoko Sakai
- Subjects
early mobilization ,medicine.medical_specialty ,Rehabilitation ,Goal planning ,business.industry ,medicine.medical_treatment ,Clinical course ,Vital signs ,General Medicine ,Age and sex ,risk management ,Intensive care unit ,law.invention ,law ,ICU ,medicine ,Physical therapy ,Early mobilization ,Original Article ,protocol ,Adverse effect ,business - Abstract
Objective: The aim of this study was to investigate the effect and risk management of early mobilization in the intensive care unit (ICU) with multidisciplinary collaboration and daily goal planning. Methods: Rehabilitation of ICU patients in our hospital between April 1, 2019, and September 30, 2019, was investigated retrospectively. The following factors were evaluated: age and sex of the subjects; diseases; the total number of early mobilization therapy sessions done at a lowered goal level; the clinical course of the step-down sessions; reasons for lowering goal levels that corresponded to the cancellation criteria from the officially issued guidelines of the Japanese Association of Rehabilitation Medicine, the expert consensus on ICU, or other reasons for step down; and the rate of planned goals that were achieved. Results: Of the 1908 overall rehabilitation sessions carried out during the period of investigation, 9.6% had the planned level lowered; changes in vital signs accounted for 54.6% of the reasons for lowering the level. Of the step-down sessions, 92.3% corresponded with the cancellation criteria of rehabilitation. Early mobilization in the ICU in accordance with daily goal planning via collaboration within the multidisciplinary team during rounds was accomplished in 90.4% of sessions. No serious mobilization-related adverse events were noted during the study period. Conclusion: Early mobilization should be performed with daily goal planning by a multidisciplinary team during rounds and should be governed by the cancellation criteria of rehabilitation.
- Published
- 2020
14. Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury
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Kate Colette, Tatham, Kieran Patrick, O'Dea, Rosalba, Romano, Hannah Elizabeth, Donaldson, Kenji, Wakabayashi, Brijesh Vipin, Patel, Louit, Thakuria, Andre Rudiger, Simon, Padmini, Sarathchandra, Nandor, Marczin, and Mark, Griffiths
- Subjects
Neutrophils ,Pneumonia ,respiratory system ,Innate Immunity ,Monocytes ,Tissue Donors ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Macrophage Biology ,Cell Movement ,Reperfusion Injury ,Animals ,Cytokines ,Humans ,Primary Graft Dysfunction ,Lung ,Lung Transplantation - Abstract
Rationale Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown. Objective To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction. Methods Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function. Results In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours. Conclusions These results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.
- Published
- 2017
15. Neutrophil-Derived Microvesicles as a Novel Biomarker in Hyperoxic Bronchopulmonary Dysplasia in Mice
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Masao Takata, S. Matsumoto, M. Abe, H. Shigemitsu, Kenji Wakabayashi, Y. Iki, and Kieran P. O'Dea
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Bronchopulmonary dysplasia ,business.industry ,Cancer research ,Medicine ,Biomarker (medicine) ,business ,medicine.disease ,Microvesicles - Published
- 2019
16. Serum biotin in Japanese children: Enzyme-linked immunosorbent assay measurement
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Mitsuyoshi Suzuki, Hiroko Kodama, Yasuhiro Sato, Kenji Wakabayashi, Eishin Ogawa, and Kahoko Motoyama
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,medicine.medical_specialty ,030109 nutrition & dietetics ,business.industry ,Biotin deficiency ,030209 endocrinology & metabolism ,Milk allergy ,medicine.disease ,Molecular biology ,Hemolysis ,03 medical and health sciences ,chemistry.chemical_compound ,Elisa kit ,0302 clinical medicine ,Endocrinology ,Enzyme ,Biotin ,chemistry ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Medicine ,Frozen storage ,Biotin measurement ,business - Abstract
Background Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. Methods Serum biotin in 188 healthy Japanese children aged 0–4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. Results Median biotin in children aged 0–4 years was 10.4 ng/dL (IQR, 7.9–13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8–15.8 ng/dL). Normal range was 4.7–22.0 ng/dL in children and 8.4–20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze–thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. Conclusions Serum biotin was significantly lower in children than in adults, with the normal range being 4.7–22.0 ng/dL in children and 8.4–20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.
- Published
- 2016
17. Low serum biotin in Japanese children fed with hydrolysate formula
- Author
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Yasuhiro Sato, Kenji Wakabayashi, Eishin Ogawa, Masakazu Mimaki, and Hiroko Kodama
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business.industry ,Biotin deficiency ,Physiology ,Milk allergy ,Breast milk ,medicine.disease ,Hydrolysate ,03 medical and health sciences ,chemistry.chemical_compound ,Elisa kit ,0302 clinical medicine ,Infant formula ,Biotin ,chemistry ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Medicine ,030212 general & internal medicine ,Food science ,business - Abstract
BACKGROUND Given that nutritional biotin deficiency in Japanese infants has been reported, a straightforward method for estimating biotin level is needed. The biotin content in infant formula, breast milk, and the sera of infants fed with various types of formula were measured using avidin-binding assay. METHODS A commercially available ELISA kit was used for the measurement of biotin in 54 types of formula, including hydrolysate formulas for milk allergy, as well as in breast milk and in the sera of 27 infants fed with these formulas. RESULTS The biotin content reached the recommended value in only five formulas. All of the hydrolysate formulas and more than half of the special formulas contained biotin
- Published
- 2016
18. Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists
- Author
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Takanori Yamazaki, Kenji Wakabayashi, Kazuhiko Tamaki, Shoko Honzumi, Takahiro Yamaguchi, Daisuke Nakai, Naoki Terasaka, Yumi Matsui, Masayuki Yoshida, Masami Arai, Shinko Hayashi, and Hiroyuki Hanzawa
- Subjects
Models, Molecular ,Hydrocarbons, Fluorinated ,Stereochemistry ,Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Crystal structure ,Benzoates ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,Transcription (biology) ,Drug Discovery ,medicine ,Animals ,Humans ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,Orphan Nuclear Receptors ,medicine.anatomical_structure ,chemistry ,ABCA1 ,biology.protein ,Molecular Medicine - Abstract
To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.
- Published
- 2015
19. Investigation of the bactericidal effects of generating active oxygen species and ultraviolet wavelengths in a sterilization system using ultraviolet irradiation
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Yohei Nakayama, Yorimasa Ogata, and Kenji Wakabayashi
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Active oxygen ,Chemistry ,Ultraviolet irradiation ,medicine ,Sterilization (microbiology) ,medicine.disease_cause ,Photochemistry ,Ultraviolet - Published
- 2015
20. Importance of the team medicine in periodontal therapy -Future concept of periodontal therapy
- Author
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Kenji Wakabayashi
- Published
- 2015
21. The role of ex vivo lung perfusion in lung transplantation
- Author
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Kenji Wakabayashi, Masao Takata, Kate Tatham, Nandor Marczin, and KP O'Dea
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Pathology ,medicine.medical_specialty ,Lung ,business.industry ,medicine.medical_treatment ,Primary Graft Dysfunction ,Inflammation ,Perioperative ,respiratory system ,Lung injury ,Bench to Bedside ,Critical Care and Intensive Care Medicine ,Critical Care Nursing ,respiratory tract diseases ,Transplantation ,Clinical trial ,medicine.anatomical_structure ,medicine ,Lung transplantation ,medicine.symptom ,business - Abstract
Whilst lung transplantation is a viable solution for end-stage lung disease, donor shortages, donor lung inflammation and perioperative lung injury remain major limitations. Ex vivo lung perfusion has emerged as the next frontier in lung transplantation to address and overcome these limitations, with multicentre clinical trials ongoing in the UK, rest of Europe and North America. Our research seeks to identify the poorly understood cellular and molecular mechanisms of primary graft dysfunction through the development of an isolated perfused lung model of transplantation and investigation of the role of pulmonary inflammation in this paradigm.
- Published
- 2014
22. Volutrauma, but not Atelectrauma, Induces Systemic Cytokine Production by Lung-Marginated Monocytes*
- Author
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Kieran P. O'Dea, Kate Tatham, Masao Takata, Michael R. Wilson, and Kenji Wakabayashi
- Subjects
Male ,ATELECTASIS ,END-EXPIRATORY PRESSURE ,VIVO MOUSE MODEL ,Ventilator-Induced Lung Injury ,medicine.medical_treatment ,RESPIRATORY-DISTRESS-SYNDROME ,1110 Nursing ,Atelectasis ,Critical Care and Intensive Care Medicine ,Monocytes ,Positive-Pressure Respiration ,Mice ,Edema ,Medicine ,Lung ,biotrauma ,Tidal volume ,TUMOR-NECROSIS-FACTOR ,INDUCED INJURY ,respiratory system ,Flow Cytometry ,Pulmonary edema ,medicine.anatomical_structure ,Anesthesia ,Breathing ,Cytokines ,stretch ,Life Sciences & Biomedicine ,PULMONARY-EDEMA ,mechanical ventilation ,Lung injury ,1117 Public Health and Health Services ,Proinflammatory cytokine ,Critical Care Medicine ,General & Internal Medicine ,Tidal Volume ,ALVEOLAR ,Animals ,HIGH TIDAL VOLUME ,Mechanical ventilation ,Science & Technology ,business.industry ,1103 Clinical Sciences ,acute respiratory distress syndrome ,medicine.disease ,Emergency & Critical Care Medicine ,Mice, Inbred C57BL ,business - Abstract
Objectives: Ventilator-induced lung injury has substantive impact on mortality of patients with acute respiratory distress syndrome. Although low tidal volume ventilation has been shown to reduce mortality, clinical benefits of open-lung strategy are controversial. In this study, we investigated the impact of two distinct forms of ventilator-induced lung injury, i.e., volutrauma and atelectrauma, on the progression of lung injury and inflammation, in particular alveolar and systemic cytokine production. Design: Ex vivo study. Setting: University research laboratory. Subjects: C57BL/6 mice. Interventions: Isolated, buffer-perfused lungs were allocated to one of three ventilatory protocols for 3 hours: control group received low tidal volume (7 mL/kg) with positive end-expiratory pressure (5 cm H2O) and regular sustained inflation; high-stretch group received high tidal volume (30–32 mL/kg) with positive end-expiratory pressure (3 cm H2O) and sustained inflation; and atelectasis group received the same tidal volume as control but neither positive end-expiratory pressure nor sustained inflation. Measurements and Main Results: Both injurious ventilatory protocols developed comparable levels of physiological injury and pulmonary edema, measured by respiratory system mechanics and lavage fluid protein. High-stretch induced marked increases in proinflammatory cytokines in perfusate and lung lavage fluid, compared to control. In contrast, atelectasis had no effect on perfusate cytokines compared to control but did induce some up-regulation of lavage cytokines. Depletion of monocytes marginated within the lung microvasculature, achieved by pretreating mice with IV liposome-encapsulated clodronate, significantly attenuated perfusate cytokine levels, especially tumor necrosis factor, in the high-stretch, but not atelectasis group. Conclusions: Volutrauma (high-stretch), but not atelectrauma (atelectasis), directly activates monocytes within the pulmonary vasculature, leading to cytokine release into systemic circulation. We postulate this as a potential explanation why open-lung strategy has limited mortality benefits in ventilated critically ill patients.
- Published
- 2014
23. Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice
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Michael R, Wilson, Kenji, Wakabayashi, Szabolcs, Bertok, Charlotte M, Oakley, Brijesh V, Patel, Kieran P, O'Dea, Joanna C, Cordy, Peter J, Morley, Andrew I, Bayliffe, and Masao, Takata
- Subjects
acid aspiration ,inflammation ,respiratory mechanics ,TNFRSF1a ,Immunology ,CD120a ,Original Research - Abstract
Background Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment. Methods We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting “dummy” dAb, 1 or 4 h before acid instillation. Results Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase. Conclusion These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.
- Published
- 2016
24. Synthesis and biological evaluation of novel (−)-cercosporamide derivatives as potent selective PPARγ modulators
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Kouichi Nakamura, Takeshi Honda, Jun Tanaka, Jun Ohsumi, Masanori Kuroha, Kenji Wakabayashi, Akihiro Furukawa, Satoko Wakimoto, Tsuyoshi Arita, Yumi Matsui, Shinko Hayashi, Osamu Suzuki, Makoto Mori, Takehiro Fukuzaki, Kazushi Araki, and Susumu Satoh
- Subjects
Models, Molecular ,medicine.medical_specialty ,Protein Conformation ,Potassium ,chemistry.chemical_element ,Chemistry Techniques, Synthetic ,Cercosporamide ,Genes, Reporter ,Oral administration ,Transcription (biology) ,Cell Line, Tumor ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Solubility ,Receptor ,Benzofurans ,Pharmacology ,Organic Chemistry ,General Medicine ,Peroxisome ,Rats ,Bioavailability ,PPAR gamma ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Female - Abstract
Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.
- Published
- 2012
25. Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists
- Author
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Takeshi Honda, Shinko Hayashi, Takehiro Fukuzaki, Kazushi Araki, Kenji Wakabayashi, Jun Ohsumi, Tsuyoshi Arita, Yumi Matsui, Susumu Satoh, Akihiro Furukawa, and Makoto Mori
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Naphthalenes ,Crystallography, X-Ray ,Biochemistry ,Partial agonist ,Cercosporamide ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Hypoglycemic Agents ,Receptor ,Molecular Biology ,Benzofurans ,Naphthalene ,Regulation of gene expression ,chemistry.chemical_classification ,Molecular Structure ,Organic Chemistry ,Peroxisome ,Ligand (biochemistry) ,PPAR gamma ,Gene Expression Regulation ,chemistry ,Molecular Medicine - Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential drug target for treating type 2 diabetes. The selective PPARγ modulators (SPPARMs), which partially activate the PPARγ transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARγ related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARγ transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARγ transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARγ partial agonist.
- Published
- 2012
26. Abstract 13972: Dexmedetomidine Ameliorates Monocrotaline Induced Pulmonary Arterial Hypertension in Rats
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Yasuhiro Maejima, Kenji Wakabayashi, Shouzaburoh Doi, Susumu Hosokawa, Mitsuaki Isobe, and Yusuke Kajikawa
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Agonist ,medicine.medical_specialty ,TUNEL assay ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Intraperitoneal injection ,Inflammation ,Endocrinology ,Apoptosis ,Physiology (medical) ,Internal medicine ,polycyclic compounds ,medicine ,Ventricular pressure ,Dexmedetomidine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Receptor ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
[Introduction] Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Dexmedetomidine (DEX) is a selective α2-aderenergic receptor agonist that is used for sedation in clinical practice. It has been reported that DEX inhibits inflammatory responses through cytokines, such as TNF-alpha, IL-6. Furthermore other reports show that G-protein-coupled receptors (GPCRs) are regulated by β-arrestins, which are also involved with inflammation. [Hypothesis] DEX ameliorates monocrotaline (MCT)-induced PAH in rats by its anti-inflammatory effect. [Methods] We treated 6 weeks-old male Sprague-Dawley rats with a single 60mg/kg intraperitoneal injection of MCT. After 14 days of injection, one group of rats was started to administer dexmedetomidine (dose: 2μg/kg/hour, MCT+DEX group) continuously using osmotic pumps, the other group was not treated with DEX (MCT group). We performed physiological examination and cardiac catheterization to measure right ventricular systolic pressure (RVSP) at day 23. [Results] Both RVSP and survival rate of rats in MCT+DEX group markedly improved compared with those in MCT group (RVSP; 38mmHg±11mmHg vs 91mmHg±6mmHg, survival rate; 42% vs 0% at day 30). In histological analysis, DEX reduced the medial hypertrophy of pulmonary arterioles, and decreased phosphorylated-NF-kB p65 (p-p65) positive PASMCs in MCT+DEX group compared with those of MCT group. In addition, DEX suppressed PASMCs proliferation with PCNA staining, and induced apoptosis of PASMCs with TUNEL assay. Then we examined the involvement of β-arrestins in PAH. It showed that βarrestin1 expressions reduced in MCT group compared with that of MCT+DEX group with western blotting and immunohistochemistry. However β-arrestin2 expressions had no significant difference between the two groups. [Conclusions] DEX ameliorates MCT-induced PAH in rats, one of the mechanism of which may be NF-kB inhibition through β-arrestin1. DEX can be a new therapeutic tool for PAH.
- Published
- 2015
27. Structural Basis of Digoxin That Antagonizes RORγt Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production
- Author
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Fujio Isono, Takao Ohyama, Saori Fujita-Sato, Takashi Isobe, Kaoru Morishita, Kenji Wakabayashi, Shuichiro Ito, and Osamu Ando
- Subjects
CD4-Positive T-Lymphocytes ,Digoxin ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Cellular differentiation ,Biology ,Crystallography, X-Ray ,Biochemistry ,Autoimmune Diseases ,Mice ,RAR-related orphan receptor gamma ,Internal medicine ,Coactivator ,medicine ,Animals ,Receptor ,Molecular Biology ,Molecular Structure ,Interleukin-17 ,Experimental autoimmune encephalomyelitis ,Interleukin ,Cell Differentiation ,Cell Biology ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,medicine.disease ,Cell biology ,Endocrinology ,Nuclear receptor ,Th17 Cells ,Interleukin 17 - Abstract
The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.
- Published
- 2011
28. A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake
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Koji Abe, Minoru Uchiyama, Ken Kitayama, Tomiichiro Oda, Yoshiya Amemiya, Tomohiro Nishizawa, Naoko Ubukata, Kenji Wakabayashi, Toshimori Inaba, and Makiko Yamada
- Subjects
CD36 Antigens ,Male ,medicine.medical_specialty ,Metabolite ,Biology ,Piperazines ,Mice ,chemistry.chemical_compound ,High-density lipoprotein ,In vivo ,Cricetinae ,Internal medicine ,Hyperlipidemia ,medicine ,Animals ,Humans ,Scavenger receptor ,Cell Line, Transformed ,Dose-Response Relationship, Drug ,Mesocricetus ,Cholesterol ,Cholesterol, HDL ,nutritional and metabolic diseases ,Scavenger Receptors, Class B ,medicine.disease ,Rats ,Endocrinology ,Gene Expression Regulation ,Mechanism of action ,chemistry ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Lipoprotein - Abstract
High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [(3)H]cholesterol ether ([(3)H]COE)-labeled and [(125)I]-labeled HDL in mice. R-138329 delayed the clearance of [(3)H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [(125)I]-labeled HDL particles was unaffected by the compound. In vitro analysis showed that R-154716, a metabolite of R-138329, dramatically inhibited the uptake of [(3)H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100 nM of R-154716 completely inhibited [(3)H]COE-labeled HDL uptake induced by overexpression of scavenger receptor BI (SR-BI) in HEK293 cells. Taken together, these findings suggest that the mechanism by which R-138329 elevates HDL-C in vivo is principally involved in the inhibition of SR-BI-mediated selective lipid uptake in the liver.
- Published
- 2007
29. Glass Transitions of Ordinary and Heavy Water within Silica-Gel Nanopores
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Masaharu Oguni, Kenji Wakabayashi, Atsushi Nagoe, and Satoshi Maruyama
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Heavy water ,Properties of water ,Nitrogen ,Silica gel ,Organic Chemistry ,Molecular Conformation ,Silica Gel ,General Chemistry ,Calorimetry ,Silicon Dioxide ,Biochemistry ,chemistry.chemical_compound ,Nanopore ,chemistry ,Chemical physics ,Nanotechnology ,Thermodynamics ,Molecule ,Glass ,Deuterium Oxide ,Glass transition ,Supercooling - Abstract
The dynamic properties of water confined within nanospaces are of interest given that such water plays important roles in geological and biological systems. The enthalpy-relaxation properties of ordinary and heavy water confined within silica-gel voids of 1.1, 6, 12, and 52 nm in average diameter were examined by adiabatic calorimetry. Most of the water was found to crystallize within the pores above about 2 nm in diameter but to remain in the liquid state down to 80 K within the pores less than about 1.6 nm in diameter. Only one glass transition was observed, at T(g) = 119, 124, and 132 K for ordinary water and T(g) = 125, 130, and 139 K for heavy water, in the 6-, 12-, and 52-nm diameter pores, respectively. On the other hand, two glass transitions were observed at T(g) = 115 and 160 K for ordinary water and T(g) = 118 and 165 K for heavy water in the 1.1-nm pores. Interfacial water molecules on the pore wall, which remain in the noncrystalline state in each case, were interpreted to be responsible for the glass transitions in the region 115-139 K, and internal water molecules, surrounded only by water molecules in the liquid state, are responsible for those at 160 or 165 K in the case of the 1.1-nm pores. It is suggested that the glass transition of bulk supercooled water takes place potentially at 160 K or above due to the development of an energetically more stable hydrogen-bonding network of water molecules at low temperatures.
- Published
- 2007
30. Relation between Clinical status and Oral Malodor as Assessed by Breathtron®
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Kenjiro Ohashi, Hiroshi Masunaga, Momoko Suzuki, Masahide Imajyo, Ryoichiro Saito, Kenji Wakabayashi, Akemi Koyama, and Yorimasa Ogata
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Gynecology ,medicine.medical_specialty ,business.industry ,Medicine ,General Medicine ,business - Abstract
本研究の目的は,口臭と臨床症状の関係について調査し,歯周基本治療による臨床所見と口臭の改善度の関係について検討することである。口臭測定器ブレストロン®を用い,日本大学松戸歯学部付属病院歯周科に通院中の軽度の慢性歯周炎患者87名を対象として臨床パラメーターと口臭の関係について検討を行った。歯周基本治療前後における臨床的改善度と口臭の改善度との関係について慢性歯周炎患者38名について検討した結果,以下の結論を得た。(1)ブレストロン値を用いた口臭測定では,臨床パラメーターのうち,BOP,PCRとの関連性を認めた。舌苔の付着を認めた患者が少なかったため,舌苔と口臭との関連性は特定できなかった。(2)歯周基本治療により口臭の減少を認め,その傾向は他の臨床所見の改善と一致していた。(3)口臭の改善率は,PD, BOP,PCRの改善率と多くの部位で一致することを認めた。ブレストロン®による口臭測定値を利用することにより口臭を臨床における動機付けを向上にもちいることは有用であることが示された。
- Published
- 2007
31. Low serum biotin in Japanese children fed with hydrolysate formula
- Author
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Yasuhiro, Sato, Kenji, Wakabayashi, Eishin, Ogawa, Hiroko, Kodama, and Masakazu, Mimaki
- Subjects
Adult ,Male ,Japan ,Protein Hydrolysates ,Child, Preschool ,Infant, Newborn ,Biotin ,Humans ,Infant ,Nutritional Status ,Female ,Infant Nutritional Physiological Phenomena ,Infant Formula - Abstract
Given that nutritional biotin deficiency in Japanese infants has been reported, a straightforward method for estimating biotin level is needed. The biotin content in infant formula, breast milk, and the sera of infants fed with various types of formula were measured using avidin-binding assay.A commercially available ELISA kit was used for the measurement of biotin in 54 types of formula, including hydrolysate formulas for milk allergy, as well as in breast milk and in the sera of 27 infants fed with these formulas.The biotin content reached the recommended value in only five formulas. All of the hydrolysate formulas and more than half of the special formulas contained biotin0.1 μg/dL. Serum biotin was low in infants fed only with the hydrolysate formulas, and one of them had alopecia related to biotin deficiency.While many were asymptomatic, infants fed with formulas lacking biotin are at risk of developing symptomatic disease. The addition of biotin to breast milk substitutes was finally approved in the middle of 2014, however pediatricians in Japan should still be vigilant with regard to nutritional biotin deficiency in infants for the time being.
- Published
- 2015
32. Serum biotin in Japanese children: Enzyme-linked immunosorbent assay measurement
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Kenji, Wakabayashi, Hiroko, Kodama, Eishin, Ogawa, Yasuhiro, Sato, Kahoko, Motoyama, and Mitsuyoshi, Suzuki
- Subjects
Adult ,Male ,Myristates ,Infant, Newborn ,Nicotinic Acids ,Biotin ,Infant ,Reproducibility of Results ,Enzyme-Linked Immunosorbent Assay ,Drug Combinations ,Japan ,Child, Preschool ,Cetrimonium Compounds ,Simethicone ,Humans ,Female ,Milk Hypersensitivity ,Stearic Acids - Abstract
Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults.Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined.Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples.Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.
- Published
- 2015
33. Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice
- Author
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Kenji Wakabayashi, Toshimori Inaba, Koji Abe, Yoshiya Amemiya, Tomiichiro Oda, Tomohiro Nishizawa, and Ken Kitayama
- Subjects
Male ,Apolipoprotein E ,medicine.medical_specialty ,Pharmaceutical Science ,Transfection ,Piperazines ,Cell Line ,Lesion ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,High-density lipoprotein ,Internal medicine ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Scavenger receptor ,IC50 ,Mice, Knockout ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Triglyceride ,Cholesterol ,Cholesterol, HDL ,Scavenger Receptors, Class B ,Atherosclerosis ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,COS Cells ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Lipoprotein - Abstract
Recent accumulating evidence supports the concept that raising high-density lipoprotein (HDL) may represent an additional therapeutic target for prevention of cardiovascular disease. Scavenger receptor class B type I plays a critical role in plasma HDL cholesterol concentration and structure. This study investigated the effect of scavenger receptor class B type I blockade by a synthetic scavenger receptor class B type I blocker on plasma lipids and atherosclerosis lesion formation in apolipoprotein E (apoE)-deficient mice. N-[4-(4-tert-Butoxycarbonylpiperazin-1-yl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (R-138329), a novel scavenger receptor class B type I blocker, was identified by screening with a half-maximal inhibitory potency (IC50 value) of around 1 μM in scavenger receptor class B type I-expressing COS-1 cells. Male apoE-deficient mice were fed a chow diet with or without R-138329 (0.01-0.10%, approximately 10–100 mg kg−1, n = 9 or 10) for 12 weeks. Compared with control, treatment with R-138329 at 0.10% caused significant (P < 0.05) increases in plasma HDL cholesterol levels, and decreases in non-HDL cholesterol and triglyceride levels. Furthermore, R-138329 at 0.01% significantly increased the extent of atherosclerotic lesion formation in the aorta by 98% (P < 0.05), while favourable changes in plasma lipid parameters were achieved. The results of quantitative analysis of atherosclerosis lesion areas were: control, 102691 ±22871 μm2 (n = 10); R-138329 0.01%, 119792 ± 30842 μm2 (n = 9); R-138329 0.03%, 141346 ± 21934 μm2 (n = 10); and R-138329 0.10% 203732 ± 36326 μm2 (n = 10). To clarify the mechanistic basis underlying this preferential deterioration, we examined the potential impact on closely related cellular functions. Further studies revealed that the active metabolite of R-138329 inhibited scavenger receptor class B type I-mediated cholesterol efflux. This study demonstrates for the first time pharmacological blockade of scavenger receptor class B type I in apoE-deficient mice. Blockade of scavenger receptor class B type I deteriorates atherosclerotic lesion formation in apoE-deficient mice even though it favourably affects plasma lipid parameters such as raising HDL cholesterol and decreasing non-HDL cholesterol. These results provide new insights for pharmaceutical industry research and development issues.
- Published
- 2006
34. Platelet-Derived Growth Factor BB Secreted From Osteoclasts Acts as an Osteoblastogenesis Inhibitory Factor
- Author
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Takemichi Nakamura, Mutsumi Katsumata, Chisa Sakikawa, Kenji Wakabayashi, and Kazuishi Kubota
- Subjects
musculoskeletal diseases ,Macrophage colony-stimulating factor ,medicine.medical_specialty ,Platelet-derived growth factor ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Becaplermin ,Osteoclasts ,Bone Morphogenetic Protein 4 ,Mice ,chemistry.chemical_compound ,Osteoprotegerin ,Osteoclast ,Internal medicine ,medicine ,Animals ,Orthopedics and Sports Medicine ,Cells, Cultured ,Platelet-Derived Growth Factor ,Membrane Glycoproteins ,Osteoblasts ,Receptor Activator of Nuclear Factor-kappa B ,biology ,Stem Cells ,Growth factor ,RANK Ligand ,Cell Differentiation ,Osteoblast ,Proto-Oncogene Proteins c-sis ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,RANKL ,Culture Media, Conditioned ,Bone Morphogenetic Proteins ,biology.protein ,Carrier Proteins ,Platelet-derived growth factor receptor - Abstract
Osteoclasts and osteoblasts are responsible for strict bone maintenance with a balance between bone formation and resorption by interacting with each other. Recently, it has been revealed that osteoblasts/stromal cells regulate differentiation of osteoclasts/hematopoietic cells by two factors, the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) on the plasma membrane, and secreted osteoprotegerin (OPG). However, no factors have yet been reported by which osteoclasts/hematopoietic cells regulate osteoblasts/stromal cells. To elucidate the possibility of signal transduction from osteoclasts to osteoblasts, we studied the conditioned medium of mouse osteoclast-like myeloma cell line RAW264.7 treated with RANKL. We found that this medium contains a factor that inhibits differentiation of mouse osteoblast precursor-like cell line MC3T3-E1 to osteoblasts induced by bone morphogenetic protein 4 (BMP-4) and named this factor osteoblastogenesis inhibitory factor (OBIF). OBIF was purified by successive three-step chromatography by heparin affinity, anion exchange, and reversed-phase columns. Osteoblastogenesis inhibitory activity made one peak in each chromatography step, showing the factor is a single entity. Active fractions were loaded on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and bands of proteins were excised, digested by trypsin, and analyzed by liquid chromatography equipped with tandem mass spectrometry (LC/MS/MS). Consequently, we have identified this factor to be platelet-derived growth factor BB (PDGF BB) homodimer. Furthermore, this identification of PDGF BB as OBIF was confirmed by neutralization of the inhibitory activity of the medium with anti-PDGF antibody. These results show, for the first time, that osteoclasts regulate osteoblasts directly and suggest that PDGF BB is a key factor in bone remodeling.
- Published
- 2002
35. Crystal Structure of the Extracellular Domain of Mouse RANK Ligand at 2.2-Å Resolution
- Author
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Shinko Hayashi, Tadashi Hata, Shuichiro Ito, Fumihiko Okada, Osamu Ubukata, and Kenji Wakabayashi
- Subjects
Models, Molecular ,musculoskeletal diseases ,Macromolecular Substances ,Stereochemistry ,Recombinant Fusion Proteins ,Protein subunit ,Molecular Sequence Data ,Osteoclasts ,Receptors, Cytoplasmic and Nuclear ,Crystallography, X-Ray ,Sensitivity and Specificity ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Bone remodeling ,Mice ,Extracellular ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Lymphotoxin-alpha ,Molecular Biology ,Glycoproteins ,Membrane Glycoproteins ,Receptor Activator of Nuclear Factor-kappa B ,Sequence Homology, Amino Acid ,biology ,Activator (genetics) ,Chemistry ,RANK Ligand ,NF-kappa B ,Osteoprotegerin ,Cell Biology ,Ligand (biochemistry) ,Peptide Fragments ,Cell biology ,RANKL ,biology.protein ,Bone Remodeling ,Carrier Proteins ,Sequence Alignment - Abstract
Bone remodeling involves the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts. Receptor activator of NF-kappa B ligand (RANKL, also known as ODF and OPGL), a member of the tumor necrosis factor (TNF) family, triggers osteoclastogenesis by forming a complex with its receptor, RANK. We have determined the crystal structure of the extracellular domain of mouse RANKL at 2.2-A resolution. The structure reveals that the RANKL extracellular domain is trimeric, which was also shown by analytical ultracentrifugation, and each subunit has a beta-strand jellyroll topology like the other members of the TNF family. A comparison of RANKL with TNF beta and TNF-related apoptosis-inducing ligand (TRAIL), whose structures were determined to be in the complex form with their respective receptor, reveals conserved and specific features of RANKL in the TNF superfamily and suggests the presence of key residues of RANKL for receptor binding.
- Published
- 2002
36. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism
- Author
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Ryszard T. Smolenski, Kenji Wakabayashi, Hector C. Keun, Marianne E. Fletcher, Nandor Marczin, Ian M. Adcock, Piers R. Boshier, Paul Kirkham, Masao Takata, Paul J.R. Barton, and Wellcome Trust
- Subjects
Cell Membrane Permeability ,Physiology ,Respiratory System ,medicine.disease_cause ,MOUSE ,Antioxidants ,Pathogenesis ,Immunoenzyme Techniques ,chemistry.chemical_compound ,Mice ,Enzyme Inhibitors ,RNA, Small Interfering ,IN-VIVO ,Cells, Cultured ,Glutathione Transferase ,chemistry.chemical_classification ,reactive oxygen species ,Reverse Transcriptase Polymerase Chain Reaction ,Lung Injury ,Glutathione ,GENOTYPE ,medicine.anatomical_structure ,Glutathione S-transferase ,Ethacrynic Acid ,Biochemistry ,Life Sciences & Biomedicine ,Pulmonary and Respiratory Medicine ,Cell Survival ,Blotting, Western ,PULMONARY-EDEMA ,Biology ,Lung injury ,Real-Time Polymerase Chain Reaction ,ETHACRYNIC-ACID ,Caffeic Acids ,Physiology (medical) ,medicine ,Animals ,Metabolomics ,RNA, Messenger ,POLYMORPHISMS ,Reactive oxygen species ,Science & Technology ,TRANSPLANTATION ,viability ,Epithelial Cells ,Cell Biology ,Metabolism ,Hydrogen Peroxide ,0606 Physiology ,PERFORMANCE LIQUID-CHROMATOGRAPHY ,Epithelium ,N-acetylcysteine ,Oxidative Stress ,chemistry ,MYOCARDIAL-INFARCTION ,1116 Medical Physiology ,biology.protein ,OVEREXPRESSION ,caffeic acid ,Oxidative stress - Abstract
Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione- S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
- Published
- 2014
37. Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury.
- Author
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Tatham, Kate Colette, O'Dea, Kieran Patrick, Romano, Rosalba, Donaldson, Hannah Elizabeth, Kenji Wakabayashi, Patel, Brijesh Vipin, Thakuria, Louit, Simon, Andre Rudiger, Sarathchandra, Padmini, Marczin, Nandor, Masao Takata, Wakabayashi, Kenji, Harefield POPSTAR investigators,, and Takata, Masao
- Subjects
MONOCYTES ,REPERFUSION injury ,LEUCOCYTES ,LUNG transplantation ,TRANSPLANTATION immunology ,ANIMAL experimentation ,BIOLOGICAL models ,COMPARATIVE studies ,CYTOKINES ,LUNGS ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,NEUTROPHILS ,ORGAN donors ,PNEUMONIA ,RESEARCH ,RESEARCH funding ,EVALUATION research - Abstract
Rationale: Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.Objective: To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.Methods: Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.Results: In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.Conclusions: These results indicate that lung-marginated intravascular monocytes are retained as a 'passenger' leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
38. Purification and characterization of a thermophilic alkaline xylanase from thermoalkaliphilic Bacillus sp. strain TAR-1
- Author
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Yutaka Ishiguro, Satoshi Nakamura, Ryuichiro Nakai, Koki Horikoshi, Rikizo Aono, and Kenji Wakabayashi
- Subjects
chemistry.chemical_classification ,Chromatography ,Molecular mass ,Chemistry ,Process Chemistry and Technology ,Thermophile ,Bioengineering ,Bacillus sp ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,Enzyme ,Isoelectric point ,Xylobiose ,Extracellular ,Xylanase - Abstract
Thermoalkaliphilic Bacillus sp. strain TAR-1 isolated from soil produced an extracellular xylanase. The enzyme (xylanase R) was purified to homogeneity by ammonium sulfate fractionation and anion-exchange chromatography. The molecular mass of xylanase R was 40 kDa and the isoelectric point was 4.1. The enzyme was most active over the range of pH 5.0 to 10.0 at 50°C. The optimum temperatures for activity were 75°C at pH 7.0 and 70°C at pH 9.0. Xylanase R was stable up to 65°C at pH 9.0 for 30 min in the presence of xylan. Mercury(ll) ion at 1 mM concentration abolished all the xylanase activity. The predominant products of xylan-hydrolysate were xylobiose, xylotriose, and higher oligosaccharides, indicating that xylanase R was an endo-acting enzyme. Xylanase R had a K m of 0.82 mg/ml and a V max of 280 μmol min −1 mg −1 for xylan at 50°C and pH 9.0.
- Published
- 1995
39. Thermophilic Alkaline Xylanase from Newly Isolated Alkaliphilic and ThermophilicBacillussp. Strain TAR-1
- Author
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Satoshi Nakamura, Yutaka Ishiguro, Koki Horikoshi, Kenji Wakabayashi, Rikizo Aono, and Ryuichiro Nakai
- Subjects
biology ,Thermophile ,Organic Chemistry ,General Medicine ,Xylose ,biology.organism_classification ,Applied Microbiology and Biotechnology ,Biochemistry ,Xylan ,Bacillales ,Hydrolysate ,Analytical Chemistry ,chemistry.chemical_compound ,Isoelectric point ,chemistry ,Xylobiose ,Xylanase ,Molecular Biology ,Biotechnology - Abstract
Alkaliphilic and thermophilic Bacillus sp. strain TAR-1, isolated from soil, produced a xylanase extracellularly. The xylanase was most active over a pH range of 5.0 to 9.5 at 50°C. Optimum temperatures of the crude xylanase preparation were 75°C at pH 7.0 and 70°C at pH 9.0. Zymogram analyses of the culture supernatant showed that the molecular mass of the xylanase was 40 kDa and the isoelectric point was pH 4.1. The predominant products of xylan hydrolysate were xylobiose, xylotriose, and higher oligosaccharides, indicating that the enzyme was an endoxylanase. Production of the thermophilic alkaline xylanase was induced by xylan and xylose, but was repressed in the presence of glucose.
- Published
- 1994
40. Pharmacology and in vitro profiling of a novel peroxisome proliferator-activated receptor γ ligand, Cerco-A
- Author
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Jun Ohsumi, Akihiro Furukawa, Jun Tanaka, Masanori Kuroha, Tsuneaki Ogata, Yumi Matsui, Satoko Wakimoto, Naomi Tanaka, Tomoko Inaba, Takuo Matsumoto, Ryo Okuyama, Kazushi Araki, Kenji Wakabayashi, Shoichi Kanda, and Shinko Hayashi
- Subjects
medicine.medical_specialty ,Pharmaceutical Science ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Fluorescence Polarization ,Pharmacology ,Biology ,Ligands ,Partial agonist ,chemistry.chemical_compound ,Internal medicine ,Adipocyte ,Cell Line, Tumor ,medicine ,Adipocytes ,Animals ,Humans ,Receptor ,Benzofurans ,DNA Primers ,chemistry.chemical_classification ,Triglyceride ,Base Sequence ,Molecular Structure ,Cell Differentiation ,General Medicine ,Rats ,Rats, Zucker ,PPAR gamma ,Endocrinology ,chemistry ,Rosiglitazone ,Pioglitazone ,medicine.drug - Abstract
Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.
- Published
- 2011
41. Atelectasis Induces Chemokine Upregulation And Lung Injury In The Isolated Perfused Mouse Lung
- Author
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Kieran P. O'Dea, Masao Takata, Michael R. Wilson, and Kenji Wakabayashi
- Subjects
Pathology ,medicine.medical_specialty ,Chemokine ,Downregulation and upregulation ,biology ,business.industry ,medicine ,biology.protein ,Atelectasis ,Lung injury ,Mouse Lung ,business ,medicine.disease - Published
- 2011
42. Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies
- Author
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Nico van Rooijen, Kieran P. O'Dea, Alicia A. C. Waite, Brijesh Vipinchandra Patel, Anthony D. Dorr, Kenji Wakabayashi, Michael R. Wilson, Masao Takata, Molecular cell biology and Immunology, and CCA - Immuno-pathogenesis
- Subjects
Lipopolysaccharides ,Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Physiology ,Ventilator-Induced Lung Injury ,Acute Lung Injury ,Vascular permeability ,Inflammation ,Lung injury ,Capillary Permeability ,Mice ,Physiology (medical) ,Macrophages, Alveolar ,medicine ,Animals ,Receptors, Tumor Necrosis Factor, Type II ,Respiratory system ,Lung ,medicine.diagnostic_test ,business.industry ,Epithelial Cells ,Articles ,Pneumonia ,respiratory system ,Pulmonary edema ,medicine.disease ,Respiration, Artificial ,respiratory tract diseases ,Up-Regulation ,Mice, Inbred C57BL ,Pulmonary Alveoli ,Disease Models, Animal ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Receptors, Tumor Necrosis Factor, Type I ,Immunology ,Alveolar macrophage ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid - Abstract
Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.
- Published
- 2011
43. Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives
- Author
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Tsuyoshi Arita, Shinko Hayashi, Kazushi Araki, Susumu Satoh, Masanori Kuroha, Jun Ohsumi, Akihiro Furukawa, Kenji Wakabayashi, and Yumi Matsui
- Subjects
Male ,Models, Molecular ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Carboxamide ,Crystallography, X-Ray ,Biochemistry ,Partial agonist ,Cercosporamide ,Mice ,Drug Discovery ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Hypoglycemic Agents ,Molecular Biology ,Benzofurans ,Heart weight ,chemistry.chemical_classification ,Organic Chemistry ,Ligand binding domain ,PPAR gamma ,Glucose ,chemistry ,Hyperglycemia ,Molecular Medicine - Abstract
In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.
- Published
- 2009
44. PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF)
- Author
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Kazuishi, Kubota, Chisa, Sakikawa, Mutsumi, Katsumata, Takemichi, Nakamura, and Kenji, Wakabayashi
- Subjects
Articles - Abstract
The functions of bone-forming osteoblasts and bone-resorbing osteoclasts are intimately linked. Recently it has been revealed that osteoblasts regulate differentiation of osteoclasts by two factors: as a stimulator of osteoclastogenesis, the receptor activator of NF-B ligand (RANKL); and as an inhibitor, osteoprotegerin (OPG). However, no signaling factors from osteoclasts to osteoblasts have yet been identified. In this study, we found that the conditioned medium of mouse osteoclast-like RAW264.7 cells treated with RANKL contains activity that inhibits differentiation of mouse osteoblast-like MC3T3-E1 cells. We named this factor osteoblastogenesis inhibitory factor (OBIF). We partially purified OBIF with successive three-step chromatography by heparin affinity, anion exchange, and reverse-phase columns. This inhibitory activity appeared as one peak in each chromatography step, indicating that the factor was a single entity. Active fractions were loaded on SDS-PAGE, digested in gel by trypsin, and analyzed by liquid chromatography equipped with tandem mass spectrometry (LC/MS/MS). Subsequently, we found platelet-derived growth factor BB homodimer (PDGF BB) to be an OBIF candidate protein, and neutralization of the inhibitory activity of the medium with anti-PDGF antibody confirmed this identification. These results demonstrate, for the first time, that osteoclasts regulate osteoblasts directly and suggest that PDGF BB is a key factor in bone remodeling.
- Published
- 2009
45. Injurious Ventilation and Intratracheal Lipopolysaccharide Increase Soluble TNF Receptors in the Alveoli Via Distinct Mechanisms
- Author
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Kenji Wakabayashi, Anthony D. Dorr, Masao Takata, Wilson, and KP O'Dea
- Subjects
chemistry.chemical_compound ,Lipopolysaccharide ,chemistry ,business.industry ,Immunology ,Breathing ,Medicine ,Tumor necrosis factor alpha ,business ,Receptor - Published
- 2009
46. Mobilization and margination of bone marrow Gr-1high monocytes during subclinical endotoxemia predisposes the lungs toward acute injury
- Author
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Kenji Wakabayashi, Louise Tatton, Justina O. Dokpesi, Nico van Rooijen, Masao Takata, Kieran P. O'Dea, Michael R. Wilson, Molecular cell biology and Immunology, and CCA - Immuno-pathogenesis
- Subjects
Lipopolysaccharides ,Male ,Immunology ,Acute Lung Injury ,Dose-Response Relationship, Immunologic ,Vascular permeability ,Bone Marrow Cells ,Lung injury ,Systemic inflammation ,Monocytes ,Article ,Sepsis ,Capillary Permeability ,chemistry.chemical_compound ,Mice ,Cell Movement ,Immunology and Allergy ,Medicine ,Animals ,business.industry ,Monocyte ,Macrophages ,Zymosan ,Cell Differentiation ,medicine.disease ,Endotoxemia ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,Tumor necrosis factor alpha ,Receptors, Chemokine ,Bone marrow ,Endothelium, Vascular ,medicine.symptom ,Inflammation Mediators ,business - Abstract
The specialized role of mouse Gr-1high monocytes in local inflammatory reactions has been well documented, but the trafficking and responsiveness of this subset during systemic inflammation and their contribution to sepsis-related organ injury has not been investigated. Using flow cytometry, we studied monocyte subset margination to the pulmonary microcirculation during subclinical endotoxemia in mice and investigated whether marginated monocytes contribute to lung injury in response to further septic stimuli. Subclinical low-dose i.v. LPS induced a rapid (within 2 h), large-scale mobilization of bone marrow Gr-1high monocytes and their prolonged margination to the lungs. With secondary LPS challenge, membrane TNF expression on these premarginated monocytes substantially increased, indicating their functional priming in vivo. Zymosan challenge produced small increases in pulmonary vascular permeability, which were markedly enhanced by the preadministration of low-dose LPS. The LPS-zymosan-induced permeability increases were effectively abrogated by pretreatment (30 min before zymosan challenge) with the platelet-activating factor antagonist WEB 2086 in combination with the phosphatidylcholine-phospholipase C inhibitor D609, suggesting the involvement of platelet-activating factor/ceramide-mediated pathways in this model. Depletion of monocytes (at 18 h after clodronate-liposome treatment) significantly attenuated the LPS-zymosan-induced permeability increase. However, restoration of normal LPS-induced Gr-1high monocyte margination to the lungs (at 48 h after clodronate-liposome treatment) resulted in the loss of this protective effect. These results demonstrate that mobilization and margination of Gr-1high monocytes during subclinical endotoxemia primes the lungs toward further septic stimuli and suggest a central role for this monocyte subset in the development of sepsis-related acute lung injury.
- Published
- 2009
47. Thermal Properties of Supercooled Water Confined within Silica Gel Pores
- Author
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Masaharu Oguni, Satoshi Maruyama, and Kenji Wakabayashi
- Subjects
Materials science ,Silica gel ,Analytical chemistry ,Thermodynamics ,Calorimetry ,Heat capacity ,law.invention ,Hysteresis ,chemistry.chemical_compound ,chemistry ,law ,Crystallization ,Glass transition ,Porosity ,Supercooling - Abstract
Adiabatic calorimetry of water confined within nano‐pores of silica gel was carried out. The water within pores was classified into two parts, namely interfacial water and internal water. Water within 3 nm pores was well prevented from crystallization, and showed a heat capacity peak at 227 K and two glass transitions at 115 K and 160 K. Meanwhile, in the cases of 6 nm and 50 nm, water showed only one glass transition at 125 K and 132 K, respectively. The glass transition at 160 K and the broad heat capacity peak at 227 K are attributed to the internal water. The interfacial water shows a glass transition at lower temperature than internal water and no heat capacity anomaly at around 227 K. The heat capacity curve of internal water seemed to be connected smoothly with the other data obtained so far, indicating that the properties of the internal water is close to those of bulk water.
- Published
- 2004
48. Proteome analysis of secreted proteins during osteoclast differentiation using two different methods: two-dimensional electrophoresis and isotope-coded affinity tags analysis with two-dimensional chromatography
- Author
-
Tatsuji Matsuoka, Kazuishi Kubota, and Kenji Wakabayashi
- Subjects
musculoskeletal diseases ,Proteomics ,Proteome ,Cellular differentiation ,Osteoclasts ,Biochemistry ,Bone resorption ,Chromatography, Affinity ,Bone remodeling ,Cell Line ,Mice ,Osteoclast ,medicine ,Animals ,Electrophoresis, Gel, Two-Dimensional ,Osteopontin ,Bone Resorption ,Molecular Biology ,Cathepsin ,Membrane Glycoproteins ,biology ,Receptor Activator of Nuclear Factor-kappa B ,RANK Ligand ,Cell Differentiation ,Cathepsins ,medicine.anatomical_structure ,RANKL ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,Bone Remodeling ,Carrier Proteins - Abstract
Bone is maintained by two cell types, bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts express two factors, osteoprotegerin and receptor activator of NF-kappaB ligand (RANKL), inhibiting and promoting osteoclast differentiation, respectively. In contrast, modulators of bone resorption expressed by osteoclasts have not been so well studied enough. In the present study, we demonstrate proteome analysis of secreted proteins during osteoclast differentiation to elucidate the molecular mechanism of bone resorption and bone remodeling. To achieve this objective, we chose RAW264.7 cells with RANKL as a homogeneous osteoclast differentiation model and used two methods, two-dimensional gel electrophoresis (2-DE) and isotope-coded affinity tags (ICAT) analysis with two-dimensional liquid chromatography. We found 23 spots in 2-DE and 19 proteins in ICAT analysis which were expressed differently during osteoclast differentiation. These two methods gave us closely related but different information about proteins, suggesting they are complementary or at least supplementary methods at present. Cathepsins, osteopontin, legumain, macrophage inflammatory protein-1alpha, and other proteins were observed as up- or down-regulated proteins and are discussed in the context of osteoclast differentiation and bone resorption. In addition to confirming previous observations, this study indicates novel proteins related to osteoclast differentiation which are potential therapeutic targets for the treatment of bone diseases, such as osteoporosis.
- Published
- 2003
49. E01 Study on cutting of tantalum materials with binder-less diamond tools
- Author
-
Hitoshi Sumiya, Kazuhiro Shintani, Kenji Wakabayashi, and Yuka Higuchi
- Subjects
Materials science ,chemistry ,Metallurgy ,engineering ,Tantalum ,Diamond ,chemistry.chemical_element ,engineering.material - Published
- 2012
50. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand
- Author
-
Kenji Wakabayashi, Hiromi Oda, Hiroshi Takayanagi, Toshiki Miura, Toshiaki Katada, Kozo Nakamura, Aiichiro Yamamoto, Yuho Kadono, Hiroshi Nishina, Sakae Tanaka, and Tsuyoshi Miyazaki
- Subjects
musculoskeletal diseases ,Male ,Endocrinology, Diabetes and Metabolism ,Osteoclasts ,MAP Kinase Kinase 7 ,Mice, Inbred Strains ,IκB kinase ,Biology ,Protein Serine-Threonine Kinases ,Adenoviridae ,Mice ,Osteoclast ,medicine ,Animals ,Orthopedics and Sports Medicine ,Protein kinase A ,Cells, Cultured ,Genes, Dominant ,Mitogen-Activated Protein Kinase Kinases ,Membrane Glycoproteins ,Receptor Activator of Nuclear Factor-kappa B ,Kinase ,Activator (genetics) ,Stem Cells ,RANK Ligand ,JNK Mitogen-Activated Protein Kinases ,Cell Differentiation ,I-kappa B Kinase ,Enzyme Activation ,medicine.anatomical_structure ,RANKL ,Mitogen-activated protein kinase ,biology.protein ,Cancer research ,Signal transduction ,Mitogen-Activated Protein Kinases ,Carrier Proteins - Abstract
Recent studies have revealed the essential role of the receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) in osteoclast differentiation and activation. Adenovirus vector could efficiently transduce genes into RAW264.7 cells, which differentiate into osteoclast-like multinucleated cells in the presence of RANKL. The role of NF-kappaB and c-jun N-terminal kinase (JNK) activation in RANKL-induced osteoclast differentiation was investigated using an adenovirus vector carrying the dominant negative 1kappaB kinase 2 gene (AxIKK2DN) or dominant negative MKK7 gene (AxMKK7DN). IKK2DN and MKK7DN overexpression in RAW cells specifically suppressed the NF-kappaB activation and JNK activation in response to RANKL, respectively, without affecting other signaling pathways. Either inhibition of NF-kappaB or JNK pathways dose-dependently inhibited osteoclast formation induced by RANKL. These results suggest that both NF-kappaB and JNK activation are independently required for osteoclast differentiation.
- Published
- 2002
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