研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Preclinical evaluation of an O-6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains 査読有り

Takashi Tsujiuchi, Atsushi Natsume, Kazuya Motomura, Goro Kondo, Melissa Ranjit, Rei Hachisu, Itsuro Sugimura, Shinpei Tomita, Isao Takehara, Max Woolley, Neil U. Barua, Steven S. Gill, Alison S. Bienemann, Yoriko Yamashita, Shinya Toyokuni, Toshihiko Wakabayashi

AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH 6 巻 ( 2 ) 頁： 169 - 178 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：E-CENTURY PUBLISHING CORP

The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O-6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O-6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

Web of Science

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脳梗塞発症前の運動はsuperoxide dismutase活性を増加させ脳梗塞障害を軽減する

野口泰司, 石田和人, 濱川みちる, 玉越敬悟, 高松泰行, 戸田拓弥, 加藤寛聡, 早稲田雄也, 赤塚慎也, 豊國伸哉

理学療法学Supplement 2013 巻 ( 0 ) 頁： 0007 - 0007 2014年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本理学療法士協会

【はじめに，目的】脳梗塞の後遺症に苦しむ患者数の増大から,脳梗塞の予防的介入が重要視されている。動物実験では,脳梗塞発症前に一定期間運動を行うことで,脳梗塞後の運動機能障害が軽減し,脳梗塞体積も減少するという報告がなされている（Wang RY. et al., 2001）。この作用機序について,我々の研究室では脳梗塞の二次的傷害の主要な要因である酸化ストレスに着目し,脳梗塞発症前に運動を行うことで酸化ストレス産物（8-OHdG，4-HNE修飾タンパク）の生成が軽減されることを報告し,酸化ストレス抑制の関連を示唆した（Hamakawa M. et al., 2013）。しかし,この酸化ストレス抑制の機序は明らかになっていない。そこで,本研究では脳内の主要な抗酸化ストレス物質の1つであるsuperoxide dismutase（SOD）に着目し,事前の運動による脳梗塞障害軽減効果の作用機序を検討することを目的とする。【方法】実験動物にはWistar系雄性ラット（5週齢）を用いた。無作為にSham群（n=6）,運動＋sham群（n=6）,脳梗塞群（n=8）,運動+脳梗塞群（n=12）の4群に分け,運動＋sham群と運動＋脳梗塞群は3週間のトレッドミル運動（15m/min，30分/日）を毎日行った。Sham群と脳梗塞群は走行させずにトレッドミル装置内に曝露させた。3週間後,脳梗塞群と運動＋脳梗塞群に対し,小泉法により90分間左中大脳動脈を閉塞することで脳梗塞モデル作成手術を施した。手術24時間後に,感覚-運動機能に関し,麻痺の重症度の評価としてneurological deficits（ND）を,前肢の感覚運動機能の評価としてlimb placing test（LP）を,前肢の協調運動機能の評価としてladder testを,歩行時のバランス能力の評価としてbeam walking test（BW）を行った。その直後に脳梗塞周囲の大脳皮質感覚運動野を採取し,SOD-Assay kit-WST（同仁化学研究所）を用いてSOD活性を測定した。また,SODの遺伝子発現について,real-time PCR法によりSOD1（Cu，Zn-SOD）,SOD2（Mn-SOD）,SOD3（EC-SOD）のmRNA発現量を定量化した。統計学的解析はSPSS ver. 16.0を用い,感覚－運動機能評価に関しND，LP，BWについてはMann-Whitney U testを,ladder testについてはStudent's t-testを行った。また,SOD活性,SOD1，2，3の遺伝子発現については一元配置分散分析にて比較し,事後検定としてTukey's testを行った。統計学的検定における有意水準は5%未満とした。【倫理的配慮，説明と同意】本研究における前処置は名古屋大学動物実験指針に従って実施した。【結果】運動＋脳梗塞群は脳梗塞群に比べて,ND，LP，ladder testにおいて有意に障害が軽度であった（p＜0.05）。一方でBWでは群間に有意差は認められなかった。またSOD活性は,運動＋脳梗塞群が脳梗塞群に比べ有意に高値を示した（p＜0.05）。さらにSOD1は,運動＋脳梗塞群が脳梗塞群に比べ有意に発現が高かった（p＜0.05）。SOD2，3は群間に有意差は認められなかった。【考察】脳梗塞モデル作成前に3週間のトレッドミル運動を行うことで,脳梗塞後の感覚－運動機能障害が軽減することが示された。またSOD活性およびSOD1発現量の増加が示された。これらの結果より,事前に運動を行うことは,脳梗塞時のSOD発現,活性が促進され,虚血/再灌流により生じる大量の活性酸素を迅速に消去し,酸化ストレスを抑制する作用があると考えられる。よって,脳梗塞発症前の運動が及ぼす障害軽減効果には,SODの抗酸化ストレス能に伴う神経保護作用が関与していることが示唆された。【理学療法学研究としての意義】脳梗塞発症前の運動による脳梗塞障害軽減効果の作用機序の一端を分子生物学的に示した。これらの結果は,脳梗塞の予防として推奨されている運動の効果を科学的に検討し,予防医療分野における理学療法のさらなる発展に寄与するものと考える。

DOI： 10.14900/cjpt.2013.0007

CiNii Research

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【職業・環境発がん:メカニズムと病理】繊維性ナノマテリアルの発がん機構

豊國伸哉

病理と臨床 32 巻頁： 632 - 637 2014年

Preclinical evaluation of an O-6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains

Tsujiuchi Takashi, Natsume Atsushi, Motomura Kazuya, Kondo Goro, Ranjit Melissa, Hachisu Rei, Sugimura Itsuro, Tomita Shinpei, Takehara Isao, Woolley Max, Barua Neil U., Gill Steven S., Bienemann Alison S., Yamashita Yoriko, Toyokuni Shinya, Wakabayashi Toshihiko

AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH 6 巻 ( 2 ) 頁： 169 - 178 2014年

Genotoxicity and carcinogenicity risk of carbon nanotubes. 査読有り国際誌

Toyokuni S

Advanced drug delivery reviews 65 巻 ( 15 ) 頁： 2098 - 110 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Advanced Drug Delivery Reviews

Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time-consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers. © 2013 Elsevier B.V.

DOI： 10.1016/j.addr.2013.05.011

Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats 国際誌

Toyokuni, S; Nagai, H; Okazaki, Y; Chew, SH; Yasui, H

FREE RADICAL BIOLOGY AND MEDICINE 65 巻頁： S25 - S25 2013年11月

Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelial carcinogenesis in rats. 査読有り国際誌

Nagai H, Okazaki Y, Chew SH, Misawa N, Yasui H, Toyokuni S

Cancer prevention research (Philadelphia, Pa.) 6 巻 ( 11 ) 頁： 1222 - 30 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Prevention Research

Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction. ©2013 AACR.

DOI： 10.1158/1940-6207.CAPR-13-0244

From nagoya to the world 査読有り国際誌 Open Access

Toyokuni S.

Nagoya Journal of Medical Science 75 巻 ( 1-2 ) 頁： 1 - 2 2013年9月

From nagoya to the world 国際誌 Open Access

Toyokuni S

Nagoya Journal of Medical Science 75 巻 ( 1-2 ) 頁： 1 - 2 2013年9月

Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats. 査読有り国際誌

Nagai H, Okazaki Y, Chew SH, Misawa N, Miyata Y, Shinohara H, Toyokuni S

Pathology international 63 巻 ( 9 ) 頁： 457 - 62 2013年9月

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

Multiwalled carbon nanotubes (MWCNTs) have attracted public attention not only for their potential applications in engineering and materials science but also for possible environmental risks. MWCNTs share similar properties with asbestos, a definite human carcinogen causing malignant mesothelioma (MM), in that they are both biopersistent thin fibers with a high aspect ratio. Certain types of MWCNTs do induce MM in animal experiments. Though there are many different types of MWCNTs awaiting use in industry, there is little evidence about what types of MWCNTs present a high risk for MMin vivo. We have previously shown that the diameter of MWCNTs is one of the critical factors for mesothelial injury, which eventually leads to MM. Because of the extensive commercial use of MWCNTs, the properties of MWCNTs that determine carcinogenic activity should be clarified. Here we report that a high dose (10mg) of a tangled form of pristine MWCNT (with a diameter of 15nm) did not induce MM after intraperitoneal administration in rats, which were followed for up to 3 years after injection. This observation strengthens our previous finding that the rigidity, diameter, length and surface properties of MWCNTs are important factors in MM induction in vivo. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/pin.12093

Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice (vol 23, pg 85, 2005) 査読有り国際誌

Naitoa, Y; Akagiri, S; Uchiyama, K; Kokura, S; Yoshida, N; Hasegawa, G; Nakamura, N; Ichikawa, H; Toyokuni, S; Ijichi, T; Yoshikawa, T

BIOFACTORS 39 巻 ( 5 ) 頁： 589 - 589 2013年9月

CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma. 査読有り国際誌 Open Access

Okazaki Y, Nagai H, Chew SH, Li J, Funahashi S, Tsujimura T, Toyokuni S

Cancer science 104 巻 ( 8 ) 頁： 989 - 95 2013年8月

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

Malignant mesothelioma (MM), which is associated with asbestos exposure, is one of the most deadly tumors in humans. Early MM is concealed in the serosal cavities and lacks specific clinical symptoms. For better treatment, early detection and prognostic markers are necessary. Recently, CD146 and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) were reported as possible positive markers of MM to distinguish from reactive mesothelia in humans. However, their application on MM of different species and its impact on survival remain to be elucidated. To disclose the utility of these molecules as early detection and prognostic markers of MM, we injected chrysotile or crocidolite intraperitoneally to rats, thus obtaining 26 peritoneal MM and establishing 11 cell lines. We immunostained CD146 and IMP3 using paraffin-embedded tissues and cell blocks and found CD146 and IMP3 expression in 58% (15/26) and 65% (17/26) of MM, respectively, but not in reactive mesothelia. There was no significant difference in both immunostainings for overexpression among the three histological subtypes of MM and the expression of CD146 and IMP3 was proportionally associated. Furthermore, the overexpression of CD146 and/or IMP3 was proportionally correlated with shortened survival. These results suggest that CD146 and IMP3 are useful diagnostic and prognostic markers of MM. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12185

Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x. 査読有り国際誌

Hotta H, Hamamura K, Yamashita K, Shibuya H, Tokuda N, Hashimoto N, Furukawa K, Yamamoto N, Hattori H, Toyokuni S, Ueda M, Furukawa K

Glycoconjugate journal 30 巻 ( 6 ) 頁： 585 - 97 2013年8月

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

Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs. © 2012 Springer Science+Business Media New York.

DOI： 10.1007/s10719-012-9458-2

Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells. 査読有り国際誌

Yamashita K, Nagai H, Kondo Y, Misawa N, Toyokuni S

Journal of clinical biochemistry and nutrition 53 巻 ( 1 ) 頁： 27 - 35 2013年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本酸化ストレス学会

Exposure to asbestos fibers increases the risk of mesothelioma in humans. One hypothetical carcinogenic mechanism is that asbestos fibers may directly induce mutations in mesothelial cells. Although the uptake of asbestos fibers by mesothelial cells is recognized, methods for the quantification of the uptake have not been well established. In the present study, we evaluated two distinct methods, using crocidolite fibers and MeT5A mesothelial cells. One method is histological evaluation using the cell-block technique, which allows for the direct cross-sectional observation of cells and fibers. We found the bright field observation with ×1000 magnification (oil-immersion) of the sample with Kemechtrot staining was most suitable for this purpose. The other method is flow cytometric analysis, which permits the evaluation of a much larger number of cells. We observed that the side scatter (SSC) increased with the intracellular fibers, and that the "mean SSC ratio (treated/control)" was useful for quantification. We could collect the cells with abundant internalized crocidolite fibers by sorting. Results of the two methodologies were correlated well in the experiments. The quantities of internalized fibers increased with incubation time and loaded dosage, but they were inversely associated with cellular density in culture. © 2013 JCBN.

DOI： 10.3164/jcbn.12-104

Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats. 査読有り

Hamakawa M, Ishida A, Tamakoshi K, Shimada H, Nakashima H, Noguchi T, Toyokuni S, Ishida K

Journal of clinical biochemistry and nutrition 53 巻 ( 1 ) 頁： 8 - 14 2013年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本酸化ストレス学会

Long-term exercise prior to brain ischemia enhances the activities of antioxidant enzymes and leads to a significant reduction in brain damage and neurological deficits in rats subjected to transient middle cerebral artery occlusion. However, it has not been established whether relatively short-term exercise generates similar results following middle cerebral artery occlusion. We aimed to determine whether short-term exercise could reduce oxidative damage and prevent sensori-motor dysfunction. Male Wistar rats were subjected to perform daily exercise on a treadmill for 30 min at a speed of 15 m/min for 3 weeks, followed by a 90-min middle cerebral artery occlusion. Animals were assessed after middle cerebral artery occlusion for neurological deficits and sensori-motor function. Brain tissues were processed to evaluate infarct volume and oxidative damage. Oxidative stress was assessed using immunohistochemistry for 4-hydroxy-2-nonenalmodified proteins and 8-hydroxy-2'-deoxyguanosine. Antioxidant enzymes were evaluated using immunohistochemistry for thioredoxin and activity assay for superoxide dismutase. Exercise for 3 weeks decreased the severity of paralysis and impairment in forelimb motor coordination. Furthermore, exercise had effect on superoxide dismutase and reduced the infarct volume and the number of cells immunopositive for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Our results suggest that pre-conditioning treadmill exercise for 3 weeks is useful for ameliorating ischemia-induced brain injury. © 2013 JCBN.

DOI： 10.3164/jcbn.12-72

Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens. 査読有り国際誌 Open Access

Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K

The Journal of biological chemistry 288 巻 ( 19 ) 頁： 13204 - 14 2013年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

Background: Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. Results: Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. Conclusion: There is a close relationship between the formation of AGEs and innate immune responses. Significance: Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies. Copyright © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M113.452177

DOI： 10.1074/jbc.m113.452177

CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION 国際誌

Toyokuni, S; Jiang, L; Okazaki, Y; Akatsuka, S

AMERICAN JOURNAL OF HEMATOLOGY 88 巻 ( 5 ) 頁： E168 - E169 2013年5月

Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. 査読有り国際誌 Open Access

Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T, Toyokuni S

PloS one 8 巻 ( 3 ) 頁： e57724 2013年3月

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

Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC. © 2013 Yamashita et al.

DOI： 10.1371/journal.pone.0057724

FROM NAGOYA TO THE WORLD 国際誌 Open Access

Toyokuni, S

NAGOYA JOURNAL OF MEDICAL SCIENCE 75 巻 ( 1-2 ) 頁： 1 - 2 2013年2月

Protective effect of cardioplegia with poly (ADP-ribose) polymerase-1 inhibitor against myocardial ischemia-reperfusion injury: in vitro study of isolated rat heart model. 査読有り国際誌

Yamazaki K, Tanaka S, Sakata R, Miwa S, Oriyanhan W, Takaba K, Minakata K, Marui A, Ikeda T, Toyokuni S, Komeda M, Ueda K

Journal of enzyme inhibition and medicinal chemistry 28 巻 ( 1 ) 頁： 143 - 7 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Enzyme Inhibition and Medicinal Chemistry

Poly(ADP-ribose) polymerase (PARP)-1 inhibitor has been suggested to attenuate the ischemia-reperfusion injury. We investigated the protective effect of the cardioplegia with a PARP-1 inhibitor, 4-hydoxyquinazoline (4-HQ), against myocardial ischemia-reperfusion injury. Isolated rat hearts were perfused on a Langendorff apparatus and cardioplegically arrested for 90 min by perfusion with St. Thomas' Hospital solution (ST-solution). In the Group ST (n = 8), the hearts were arrested with the ST-solution alone. The Group HQ (n = 8) were treated with the ST-solution containing 4-HQ (10 μM) for cardioplegia. During reperfusion, the Group HQ showed significantly greater functional recovery of +dp/dtmax (p = 0.005) and lower enzymatic leakage (p < 0.01). NAD+ levels were also preserved higher in the Group HQ (p < 0.01). Immunohistochemical study revealed lesser extents of oxidative stress and apoptosis, in the Group HQ. Thus, addition of 4-HQ in the cardioplegia may provide a new intervention for myocardial protection against ischemia-reperfusion injury by decreasing NAD+ consumption and suppressing oxidative stress. © 2013 Informa UK, Ltd.

DOI： 10.3109/14756366.2011.642373

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論文 - 豊國 伸哉

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論文 - 豊國　伸哉