2024/02/02 更新

写真a

フジワラ　メグミ
藤原　めぐみ
Fujiwara Megumi
所属
医学部 形態解析研究室 助教
職名
助教
外部リンク

学位

  • 獣医学 （ 日本大学 ）

論文

  • Hypoxanthine Reduces Radiation Damage in Vascular Endothelial Cells and Mouse Skin by Enhancing ATP Production via the Salvage Pathway. 国際誌

    Megumi Fujiwara, Nana Sato, Ken Okamoto

    Radiation research   197 ( 6 )   583 - 593   2022年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    An effective method that can protect radiation-damaged tissues from apoptosis and promote tissue repair has not been reported to date. Hypoxanthine (Hx) is an intermediate metabolite in the purine degradation system that serves as a substrate for ATP synthesis via the salvage pathway. In this study, we focused on the transient decrease in intracellular ATP concentration after radiation exposure and examined the protective effect of Hx against radiation-induced tissue damage. Human umbilical vein endothelial cells were X irradiated, and the cell viability and incidence of apoptosis and DNA double-strand breaks (DSBs) were evaluated at different Hx concentrations. We found that in the presence of 2-100 µM Hx, the percentages of DSBs and apoptotic cells after 2, 6 and 10 Gy dose of radiation significantly decreased, whereas cell viability increased in a concentration-dependent manner. Moreover, the addition of Hx increased the levels of AMP, ADP, and ATP in the cells at 2 h postirradiation, suggesting that Hx was used for adenine nucleotide synthesis through the salvage pathway. Administration of a xanthine oxidoreductase inhibitor to a mouse model of radiation dermatitis resulted in increased blood Hx levels that inhibited severe dermatitis and accelerated recovery. In conclusion, the findings provide evidence that increasing the levels of Hx to replenish ATP could be an effective strategy to reduce radiation-induced tissue damage and elucidating the detailed mechanisms underlying the protective effects of Hx could help develop new protective strategies against radiation.

    DOI： 10.1667/RADE-21-00223.1

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  • Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model. 国際誌

    Takashi Tani, Megumi Fujiwara, Hideo Orimo, Akira Shimizu, Sonoko Narisawa, Anthony B Pinkerton, José Luis Millán, Shuichi Tsuruoka

    The Journal of pathology   250 ( 1 )   30 - 41   2020年1月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI-425, protects against MAC and improves survival probability in a CKD-mineral and bone disorder (MBD) mouse model. CKD-MBD mice were divided in three groups: vehicle, SBI-10, and SBI-30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high-phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14-20 weeks of age, mice in the SBI-10 and SBI-30 groups were given 10 and 30 mg/kg SBI-425 by gavage once a day, respectively, while vehicle-group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI-425 nearly halted the formation of MAC. Mice in the control, SBI-10 and SBI-30 groups exhibited 100% survival, which was significantly better than vehicle-treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI-425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD-MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI： 10.1002/path.5346

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  • Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury. 国際誌

    Takashi Tani, Ken Okamoto, Megumi Fujiwara, Akira Katayama, Shuichi Tsuruoka

    Molecular medicine (Cambridge, Mass.)   25 ( 1 )   40 - 40   2019年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Clinically applied as anti-gout drugs, xanthine oxidoreductase (XOR) inhibitors, especially the potent, selective, non-purine-analog XOR inhibitors febuxostat and topiroxostat, exert organ-protective effects. We tested the hypothesis that preservation of tissue concentrations of high-energy phosphates, such as ATP and ADP, contributes to organ-protective effects through CE-TOFMS metabolomics. METHODS: Rats were subjected to 30 min of renal ischemia-reperfusion (I/R) injury 60 min after oral administration of 10 mg/kg febuxostat, 10 mg/kg topiroxostat, 50 mg/kg allopurinol, or vehicle. RESULTS: In non-purine-analog XOR inhibitor-treated groups, renal concentrations of high-energy phosphates were greater before and after I/R injury, and renal adenine compounds were less depleted by I/R injury than in the vehicle and allopurinol groups. These findings were well in accordance with the proposed hypothesis that the recomposition of high-energy phosphates is promoted by non-purine-analog XOR inhibitors via the salvage pathway through blockade of hypoxanthine catabolism, whereas non-specific inhibitory effects of allopurinol on purine/pyrimidine enzymes impede this re-synthesis process. CONCLUSIONS: This metabolic approach shed light on the physiology of the organ-protective effects of XOR inhibitors.

    DOI： 10.1186/s10020-019-0109-y

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  • Changes in fatty acid composition in tissue and serum of obese cats fed a high fat diet. 国際誌

    Megumi Fujiwara, Nobuko Mori, Touko Sato, Hiroyuki Tazaki, Shingo Ishikawa, Ichiro Yamamoto, Toshiro Arai

    BMC veterinary research   11   200 - 200   2015年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Obesity and overweight have been frequently observed in dogs and cats in recent years as in humans. The compositions of fatty acids (FAs) in the accumulated lipids in tissues of obese animals may have important roles in the process and mechanisms related to the onset of metabolic disorders. The purpose of this study was to evaluate the effects of a high fat (HF) diet, which contained a higher proportion of saturated FAs, on FA metabolism and distribution in obese cats. Cats (N = 12) were divided into control diet group (crude fat; 16.0 %) (n = 4) or a high fat (HF) diet group (crude fat; 23.9 %) (n = 8). The HF diet contained up to 60 % of calories from fat and was rich in stearic acid. Blood samples were collected at 0, 2, 4 and 6 weeks after the feeding. Adipose and liver tissues were collected at the 6(th) week after feeding. We performed analysis of histological findings and fatty acid composition in serum and tissues. RESULTS: Body weights of the cats significantly increased in the HF group. The increased activities of hepatic enzymes and the accumulation of lipid droplets were found in hepatocytes in the HF group at the 6(th) week after feeding. In this study, the stearic acid (C18:0)-rich HF diet contained less oleic acid (C18:1n-9) and more linoleic acid (C18:2n-6) than the control. However, the composition of oleic acid in the liver was higher, and those of stearic acid and linoleic acid were lower in the HF group at the 6(th) week after feeding. The higher oleic acid:stearic acid ratio suggests an increase in the conversion from saturated FA to mono-unsaturated FAs, which may reflect the hepatic storage of FAs as a relatively harmless form. CONCLUSION: The stearic acid-rich HF diet increased hepatic lipid accumulation accompanied by the increased of hepatic oleic acid, increased serum oleic acid and activation of hepatic enzymes. These findings could be an important sign of early stages of dyslipidemia and hepatic damage. Also, the higher oleic acid:stearic acid ratio might be related to the increased activity of SCD-1, which suggests that the stearic acid-rich HF diet evoked hepatic lipogenesis in the feline liver.

    DOI： 10.1186/s12917-015-0519-1

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  • Lipotoxicity observed at the early phase of obesity in cats fed on high-fat diet 査読

    Nobuko Mori, Gebin Li, Megumi Fujiwara, Shingo Ishikawa, Koh Kawasumi, Ichiro Yamamoto, Toshiro Arai

    Asian Journal of Animal and Veterinary Advances   9 ( 2 )   134 - 143   2014年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Academic Journals Inc.  

    The prevalence of obese cats has increased because of over calorie diet and physical inactivity. Obesity has been found to be associated with oxidative stress and Reactive Oxygen Species (ROS). Unfortunately oxidative stress status at the early phase of obesity in high fat fed cats is not well understood. The objectives of this study were (1) To evaluate lipid and glucose metabolism using enzymatic, hormonal and oxidative stress biomarkers at the early obese phase of cats fed on a high-fat diet and (2) To identify rapidly changing variables to use as a diagnostic marker for lipid metabolic disorders in cats. Total 13 domestic female cats were divided into two groups which were fed on control and high-fat diet for eight weeks, respectively. After the feeding period, they were compared in metabolic variables and oxidative stress markers in plasma and tissues. As results, High-fat diet including much long chain fatty acids promoted rapid changes in lipid metabolism, particularly accelerated β-oxidation of fatty acids and oxidative stress in the liver of the cats. G6PD, GPx and SOD were increased in the liver. Insulin resistance was not apparent at the early phase of obesity in cats. Plasma activities of SOD also increased at the early phase of obesity in cats. Remarkable alternation for oxidative stress in liver was observed at the early phase of obesity in cats fed on high fat diet and SOD may be a potential marker of the early phase of obesity in cats. © 2014 Academic Journals Inc.

    DOI： 10.3923/ajava.2014.134.143

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  • Change in mRNA expression of sirtuin 1 and sirtuin 3 in cats fed on high fat diet. 国際誌

    Shingo Ishikawa, Gebin Li, Hiroshi Takemitsu, Megumi Fujiwara, Nobuko Mori, Ichiro Yamamoto, Toshiro Arai

    BMC veterinary research   9   187 - 187   2013年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Mammalian sirtuins are homologs to the yeast silent information regulator 2 (Sir2), which is an NAD-dependent deacetylase. Sirtuins are comprised of 7 proteins, and each has different target proteins. Sirtuin 1 (SIRT1) plays important roles in maintaining metabolic functions and immune responses, and SIRT3 protects cells from oxidative stress-induced cell death. Both SIRT1 and SIRT3 are regulated by metabolic status and aging. Hence, SIRT1 and SIRT3 have been researched in metabolic diseases, such as type 2 diabetes mellitus (DM), fatty liver, and heart diseases. Although these diseases have been increasing, there is little information about relation between the diseases and SIRT1 and SIRT3 in cats. Therefore we cloned SIRT1 and SIRT3 cDNA, examined mRNA expression in cat tissues, and investigated the changes in SIRT1 and SIRT3 mRNA expression in peripheral blood leukocyte of cats fed on HFD for 6 weeks. RESULTS: Cat SIRT1 and SIRT3 contained a catalytic core region and showed high sequence homology with other vertebrate SIRT1 (>61.3%) and SIRT3 (>65.9%) amino acids. Real-time polymerase chain reaction analyses revealed that high expression levels were observed in the liver and skeletal muscle for SIRT1 and in the heart for SIRT3 in cats. In addition, both cat SIRT1 and SIRT3 expression levels in the pancreas were different between individuals. Cat SIRT1 mRNA expression in peripheral blood leukocytes was significantly elevated in obese cats fed on HFD (P < 0.05). CONCLUSIONS: Cat SIRT1 and SIRT3 genes are highly conserved among vertebrates, and HFD feeding may be related to SIRT1 mRNA expression mechanisms in cat peripheral blood leukocytes.

    DOI： 10.1186/1746-6148-9-187

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  • 高脂肪食給与ネコにおけるSirtuin1、3遺伝子発現量の変動

    石川 真悟, 李 格賓, 武光 浩史, 藤原 めぐみ, 森 伸子, 山本 一郎, 新井 敏郎

    日本獣医学会学術集会講演要旨集   156回   372 - 372   2013年8月

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    記述言語：日本語   出版者・発行元：(公社)日本獣医学会  

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  • Changes in plasma fatty acid composition in hyperlipidemia dogs 査読

    Megumi Fujiwara, Toko Sato, Hiroyuki Tazaki, Ichiro Yamamoto, Koh Kawasumi, Toshiro Arai

    Asian Journal of Animal and Veterinary Advances   8 ( 4 )   639 - 646   2013年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Hyperlipidemia refers to increase of triglyceride (TG) and/or total cholesterol (T-cho) in blood. Fatty Acids (FAs) have important roles in the lipid metabolism. The aim of this study was to determine the FA composition of plasma lipid fractions in dogs with hyperlipidemia and to evaluate the FA composition as a new diagnostic marker for obesity at early stage. Thirty-nine dogs were classified into healthy or hyperlipidemia based on the criteria to diagnose hyperlipidemia. The blood biochemical values, such as TG, T-cho, glucose, insulin, adiponectin and Non-Esterified Fatty Acid (NEFA) were measured. FA composition profile was performed on GC/MS system. The values of plasma TG, insulin and NEFA of the hyperlipidemia group were significantly higher than that of control group. Hyperlipidemia group tended to show lower concentration of adiponectin. It was found that only the levels of TG and NEFA, but not T-cho increased significantly in early stage of hyperlipidemia. In hyperlipidemia group, percentages of myristic acid (C14:0), parmitoleic acid (C16:1) and oleic acid (C18:1) increased in total FAs. And the percentage of C18:1 increased in NEFA. Indeed, the higher level of insulin and lower adiponectin concentration were seen in hyperlipidemia group. These results suggest that appearance of insulin resistance may be the result of increases of certain FAs in early stage of insulin resistance. © 2013 Academic Journals Inc.

    DOI： 10.3923/ajava.2013.639.646

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  • Estimating glomerular filtration rate in healthy dogs using inulin without urine collection. 国際誌

    Miki Nishida, Masami Uechi, Shota Kono, Kayoko Harada, Megumi Fujiwara

    Research in veterinary science   93 ( 1 )   398 - 403   2012年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    The goals of this study were to determine if the glomerular filtration rate (GFR) in dogs could be estimated by plasma inulin clearance and/or infusion inulin clearance analyses without urine collection, and to compare these results with GFR values obtained by urinary inulin clearance analysis. The dogs included in this study were healthy 20 beagles. Inulin clearance values were obtained by urinary inulin clearance, infusion inulin clearance, and plasma inulin clearance techniques. Urinary inulin clearance was 4.09±0.52 ml min(-1) kg(-1) (body weight); infusion inulin clearance, 4.01±0.49 ml min(-1) kg(-1); and plasma inulin clearance, 4.14±0.66 ml min(-1) kg(-1). The urinary inulin clearance was strongly correlated with infusion inulin clearance and weakly correlated with plasma inulin clearance. The GFR for dogs can be estimated by infusion and plasma inulin clearance analyses by blood sampling alone, without urine collection.

    DOI： 10.1016/j.rvsc.2011.08.003

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  • Mitral valve repair under cardiopulmonary bypass in small-breed dogs: 48 cases (2006-2009). 国際誌

    Masami Uechi, Takahiro Mizukoshi, Takeshi Mizuno, Masashi Mizuno, Kayoko Harada, Takashi Ebisawa, Junichirou Takeuchi, Tamotsu Sawada, Shuhei Uchida, Asako Shinoda, Arane Kasuya, Masaaki Endo, Miki Nishida, Shota Kono, Megumi Fujiwara, Takashi Nakamura

    Journal of the American Veterinary Medical Association   240 ( 10 )   1194 - 201   2012年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    OBJECTIVE: To determine whether mitral valve repair (MVR) under cardiopulmonary bypass would be an effective treatment for mitral regurgitation in small-breed dogs. DESIGN: Retrospective case series. ANIMALS: 48 small-breed dogs (body weight, 1.88 to 4.65 kg [4.11 to 10.25 lb]; age, 5 to 15 years) with mitral regurgitation that underwent surgery between August 2006 and August 2009. PROCEDURES: Cardiopulmonary bypass was performed with a cardiopulmonary bypass circuit. After induction of cardiac arrest, a mitral annuloplasty was performed, and the chordae tendineae were replaced with expanded polytetrafluoroethylene chordal prostheses. After closure of the left atrium and declamping to restart the heart, the thorax was closed. RESULTS: Preoperatively, cardiac murmur was grade 3 of 6 to 6 of 6, thoracic radiography showed cardiac enlargement (median vertebral heart size, 12.0 vertebrae; range, 9.5 to 14.5 vertebrae), and echocardiography showed severe mitral regurgitation and left atrial enlargement (median left atrium-to-aortic root ratio, 2.6; range, 1.7 to 4.0). 45 of 48 dogs survived to discharge. Three months after surgery, cardiac murmur grade was reduced to 0/6 to 3/6, and the heart shadow was reduced (median vertebral heart size, 11.1 vertebrae, range, 9.2 to 13.0 vertebrae) on thoracic radiographs. Echocardiography confirmed a marked reduction in mitral regurgitation and left atrium-to-aortic root ratio (median, 1.7; range, 1.0 to 3.0). CONCLUSIONS AND CLINICAL RELEVANCE: We successfully performed MVR under cardiopulmonary bypass in small-breed dogs, suggesting this may be an effective surgical treatment for dogs with mitral regurgitation. Mitral valve repair with cardiopulmonary bypass can be beneficial for the treatment of mitral regurgitation in small-breed dogs.

    DOI： 10.2460/javma.240.10.1194

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  • New Criteria for Canine Metabolic Syndrome in Japan

    Koh Kawasumi, Tomoko Suzuki, Megumi Fujiwara, Nobuko Mori, Ichiro Yamamoto, Toshiro Arai

    JOURNAL OF ANIMAL AND VETERINARY ADVANCES   11 ( 21 )   4005 - 4007   2012年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MEDWELL ONLINE  

    Researchers attempted to establish temporary criteria for Metabolic Syndrome (MS) diagnosis in dogs. To verify the usefulness of the selected criteria, researchers measured plasma Glucose (GLU), Triglyceride (TG), Total Cholesterol (TC), Non-Esterified Fatty Acid (NEFA), Alanine Aminotransferase (ALT) and insulin levels as diagnostic markers in 105 clinically healthy dogs. Dog with obesity as an essential factor (BCS = 3.5) in addition to any two of the following three factors 1-3 namely increased plasma GLU levels (>= 120 mg dL(-1)), hyperlipidemic condition, diagnosed with any two of the following three factors, elevated TG (>= 165 mg dL(-1)), TC (>= 200 mg dL(-1)), NEFA (>= 1.5 m Eq(-1)) levels and higher ALT activit (>= 100 IU L-1) were diagnosed as MS. Presence of additional factors such as raised insulin levels (>= 2.5 ng mL(-1)), confirmed the MS diagnosis. Based on these criteria, 13 (12.9%) of 101 dogs were diagnosed as MS. In these dogs, NEFA, TC and ALT levels were significantly higher than those in the control dogs (n = 88) without MS. MS was not detected in dogs with Body Condition Score (BC S)<3.

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  • Alterations with age in peripheral blood lymphocyte subpopulations and cytokine synthesis in beagles. 国際誌

    Megumi Fujiwara, Tomohiro Yonezawa, Toshiro Arai, Ichiro Yamamoto, Hiromichi Ohtsuka

    Veterinary medicine (Auckland, N.Z.)   3   79 - 84   2012年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    PURPOSE: The immune system is considered to be affected by aging, which is linked to various immune pathogeneses. The purpose of this study was to determine age-associated changes in immune function of healthy dogs (beagles), specifically those of naive and memory T lymphocytes, based on cytokine synthesis. PATIENTS AND METHODS: Blood samples were obtained from 44 healthy beagles that were divided into three age-groups: young (<4 years), middle-aged (4-8 years), and older dogs (>8 years). Subpopulations of T lymphocytes were determined by flow cytometry. Transcriptional (mRNA) levels of cytokines were determined for primary-cultured leukocytes using quantitative real-time polymerase chain reaction. RESULTS: There were negative correlations between dogs' ages and the number of peripheral blood mononuclear cells, T cells, and B cells. In particular, the number of naive CD4+ CD45RA+ T cells and CD8+ CD45RA+ T cells significantly decreased with age. The mRNA levels for interleukin (IL)-2, IL-2Rα, and interferon-gamma were significantly higher in young or middle-aged dogs (P < 0.05), whereas IL-4 mRNA expression was not significantly different over the different age-groups. IL-2Rγ mRNA expression tended to decrease with age. CONCLUSION: Decreases of naive CD4+ and naive CD8+ T cells may be related to age-related immunosenescence in dogs. With regard to cytokine production, leukocyte IL-4 and IL-10 mRNA levels did not change with age, whereas IL-2, IL-2Rα, and IL-2Rγ mRNA levels decreased with age. These altered cytokine mRNA expression patterns may contribute to decreased naive T-cell function(s) with aging.

    DOI： 10.2147/VMRR.S32590

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  • cDNA cloning and mRNA expression of cat and dog Cdkal1. 国際誌

    Ichiro Yamamoto, Shingo Ishikawa, Li Gebin, Hiroshi Takemitsu, Megumi Fujiwara, Nobuko Mori, Yutaka Hatano, Tomoko Suzuki, Akihiro Mori, Nobuhiro Nakao, Koh Kawasumi, Toshinori Sako, Toshiro Arai

    Veterinary medicine (Auckland, N.Z.)   3   65 - 69   2012年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    The cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene encodes methylthiotransferase, and the gene contains risk variants for type 2 diabetes in humans. In this study, we performed complementary DNA cloning for Cdkal1 in the cat and dog and characterized the tissue expression profiles of its messenger RNA. Cat and dog Cdkal1 complementary DNA encoded 576 and 578 amino acids, showing very high sequence homology to mammalian CDKAL1 (>88.4%). Real-time polymerase chain reaction analyses revealed that Cdkal1 messenger RNA is highly expressed in smooth muscle and that tissue distribution of Cdkal1 is similar in cats and dogs. Genotyping analysis of single-nucleotide polymorphism for cat Cdkal1 revealed that obese cats had different tendencies from normal cats. These findings suggest that the cat and dog Cdkal1 gene is highly conserved among mammals and that cat Cdkal1 may be a candidate marker for genetic diagnosis of obesity.

    DOI： 10.2147/VMRR.S32540

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  • Water-soluble argatroban for antithrombogenic surface coating of tissue-engineered cardiovascular tissues. 国際誌

    Yasuhide Nakayama, Saori Yamaoka, Masashi Yamanami, Megumi Fujiwara, Masami Uechi, Keiichi Takamizawa, Hatsue Ishibashi-Ueda, Marie Nakamichi, Kingo Uchida, Taiji Watanabe, Keiichi Kanda, Hitoshi Yaku

    Journal of biomedical materials research. Part B, Applied biomaterials   99 ( 2 )   420 - 30   2011年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Argatroban is a powerful synthetic anticoagulant, but due to its water-insoluble nature, it is unsuitable for use as a coating material to reduce the thrombogenic potential of natural or tissue-engineered blood-contacting cardiovascular tissues. On the other hand, anionic compounds could adsorb firmly onto connective tissues. Therefore, in this study, an anionic form of argatroban was prepared by neutralization from its alkaline solution, dialysis, and freeze-drying. The subsequently obtained argatroban derivative could be easily dissolved in water. Analysis of the surface chemical composition showed that the water-soluble argatroban (WSA) could be adsorbed on the entire surface of tissue-engineered connective tissue sheets composed mainly of collagen. Adsorption was achieved on immersion of the tissue-engineered connective tissue sheet in a saline/WSA solution for only 30 s without any change in the mechanical properties of the tissue-engineered sheets. Complete surface adsorption (ca., 1 mg/cm(2) ) was obtained at WSA concentrations of over 5 mg/mL. WSA adsorption was maintained for at least 7 days with rinsing. Blood coagulation was significantly prevented on the WSA-adsorbed surfaces in acute in vitro experiments. The coating was applied to in vivo tissue-engineered vascular grafts (biotubes) or tri-leaflet tissues (biovalves) under development, ensuring a high likelihood of nonthrombogenicity of their blood-contacting surfaces with high patency, at least in the subchronic phase. It appears that WSA satisfies the initial requirements for a biocompatible aqueous coating material for use in natural or tissue-engineered tissues.

    DOI： 10.1002/jbm.b.31914

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  • Transcatheter Implantation of Autologous in vivo Tissue-Engineered, Valved Stents (BIOVALVED STENTs) in the Pulmonary Position in a Beagle Model 査読

    Masami Uechi, Marina Funayama, Yuichi Matsui, Takeshi Mizuno, Megumi Fujiwara, Tsutomu Tajikawa, Kenkichi Ohba, Masashi Yamanami, Taiji Watanabe, Keiichi Kanda, Hitoshi Yaku, Yasuhide Nakayama

    CIRCULATION   124 ( 21 )   2011年11月

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    記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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  • Successful Replacement of Beagle Pulmonary Valves by In Vivo Tissue-Engineered Valved-Conduits with the Sinus of Valsalva: Completely Autologous Tissue "BIOVALVEs" with No Synthetic Support Materials

    Masashi Yamanami, Masami Uechi, Megumi Fujiwara, Yuki Yahata, Hatsue Ishibashi-Ueda, Keiichi Kanda, Taiji Watanabe, Tomonori Oie, Tsutomu Tajikawa, Kenkichi Ohba, Hitoshi Yaku, Yasuhide Nakayama

    CIRCULATION   122 ( 21 )   2010年11月

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    記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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  • Development of a completely autologous valved conduit with the sinus of Valsalva using in-body tissue architecture technology: a pilot study in pulmonary valve replacement in a beagle model. 国際誌

    Masashi Yamanami, Yuki Yahata, Masami Uechi, Megumi Fujiwara, Hatsue Ishibashi-Ueda, Keiichi Kanda, Taiji Watanabe, Tsutomu Tajikawa, Kenkichi Ohba, Hitoshi Yaku, Yasuhide Nakayama

    Circulation   122 ( 11 Suppl )   S100-6   2010年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: We developed autologous prosthetic implants by simple and safe in-body tissue architecture technology. We present the first report on the development of autologous valved conduit with the sinus of Valsalva (BIOVALVE) by using this unique technology and its subsequent implantation in the pulmonary valves in a beagle model. METHODS AND RESULTS: A mold of BIOVALVE organization was assembled using 2 types of specially designed silicone rods with a small aperture in a trileaflet shape between them. The concave rods had 3 projections that resembled the protrusions of the sinus of Valsalva. The molds were placed in the dorsal subcutaneous spaces of beagle dogs for 4 weeks. The molds were covered with autologous connective tissues. BIOVALVEs with 3 leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds. These valves had adequate burst strength, similar to that of native valves. Tight valvular coaptation and sufficient open orifice area were observed in vitro. These BIOVALVEs were implanted to the main pulmonary arteries as allogenic conduit valves (n=3). Postoperative echocardiography demonstrated smooth movement of the leaflets with trivial regurgitation. Histological examination of specimens obtained at 84 days showed that the surface of the leaflet was covered by endothelial cells and neointima, including an elastin fiber network, and was formed at the anastomosis sides on the luminal surface of the conduit. CONCLUSIONS: We developed the first completely autologous BIOVALVE and successfully implanted these BIOVALVEs in a beagle model in a pilot study.

    DOI： 10.1161/CIRCULATIONAHA.109.922211

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  • Completely Autologous Valved-Conduit With the Sinus of Valsalva (BIOVALVEs) Constructed by in vivo-Tissue Engineering: Successful Pulmonary Valve Replacement in Beagle Model

    Masashi Yamanami, Yuki Yahata, Megumi Fujiwara, Tsutomu Tajikawa, Kenkichi Ohba, Taiji Watanabe, Keiichi Kanda, Hitoshi Yaku, Masami Uechi, Yasuhide Nakayama

    CIRCULATION   120 ( 18 )   S803 - S803   2009年11月

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    記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

    Web of Science

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MISC

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産業財産権

  • 皮膚障害の予防または治療のための医薬組成物

    藤原 めぐみ, 岡本 研, 佐藤 奈々, 岩永 崇, 芦澤 直樹

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    出願人：学校法人日本医科大学

    出願番号：特願2019-009351  出願日：2019年1月

    公開番号：特開2020-117455  公開日：2020年8月

    J-GLOBAL

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共同研究・競争的資金等の研究課題

  • XORのC末端領域は、血管内皮障害をもたらすXORの活性変換のトリガーとなるか

    研究課題/領域番号：18K15070  2018年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    藤原 めぐみ

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    配分額：4160000円 （ 直接経費：3200000円 、 間接経費：960000円 ）

    キサンチン酸化還元酵素(XOR)は活性変換(D/O変換)を起こして酸化酵素型（XO）をとると、H2O2とO2-を産生して血管内皮障害に寄与し得るが、その機序は細胞および組織レベルでは不明である。本研究では、C末端領域が関与すると思われるD/O変換について、局在変化との関連性およびプリン代謝変化の解析を行った。初年度は、ヒト臍帯静脈内皮細胞(HUVEC)にGFP fusion-XORを発現させ、D/O変換時における細胞内XORの局在変化および膜との相互作用について解析のために遺伝子導入による発現を試みたが、細胞イメージングによる発現と局在の確認に至ったものの、XORの発現自体が細胞に致死的に作用して同細胞での発現は確認できなかった。そのため、二年目はXOによる血管内皮障害の機序に着眼し、XOR阻害薬による内皮保護効果について解析した。皮膚の血管内皮障害に対するXOR阻害薬の効果を調査するために、障害範囲を厳密に局限しやすいことから電子線照射を採用した。放射線性皮膚炎モデルマウスへのXOR阻害薬の投薬は血中ヒポキサンチン(Hx)濃度を増加させ、重度皮膚炎を軽減した。この機序を探るため、細胞内アデニンヌクレオチドの分解で生じるHxの再利用(サルベージ経路)の賦活化を想定し、血中プリン代謝物の変化および細胞障害マーカーを測定した。放射線照射後にはDNA修復のために照射2時間後で最もATPが減少するが、Hx存在下ではATP減少率が軽減し、その後のDNA障害およびアポトーシスが有意に抑制され、かつ照射2日後の細胞生存性が増加した。このように、放射線照射時にXOR阻害剤により組織中Hxを高く保つことは、局所でのサルベージ経路を介したATP再合成を増加させ、DNA修復ひいては細胞生存率の増加につながることが明らかとなった。

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