研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Serum 4-hydroxy-2-nonenal-modified albumin is elevated in patients with type 2 diabetes mellitus 査読有り国際誌

Toyokuni S., Yamada S., Kashima M., Ihara Y., Yamada Y., Tanaka T., Hiai H., Seino Y., Uchida K.

Antioxidants and Redox Signaling 2 巻 ( 4 ) 頁： 681 - 685 2000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：Antioxidants and Redox Signaling

4-Hydroxy-2-nonenal (HNE) is one of the major lipid peroxidation products with cytotoxic and mutagenic activity. It further reacts with protein residues such as histidine to generate stable Michael adducts. To evaluate the status of oxidative stress in the serum of type 2 diabetes mellitus, we constructed a sandwich enzyme-linked immunosorbent assay to measure serum HNE-modified albumin by the use of a specific monoclonal antibody (HNEJ-2) against HNE-histidine adducts as well as an antibody against human serum albumin. Serum of type 2 diabetes outpatients revealed significantly higher levels of HNE-modified albumin (736.1 ± 34.2 pmol/ml, n = 54) than the matched nondiabetics (611.4 ± 39.1 pmol/ml, n = 30; means ± SEM; p = 0.018). However, no significant correlation was observed in diabetic outpatients between the levels of HNE-modified albumin and clinical parameters such as fasted blood glucose, HbA1c, diabetes duration, or complications. Our data demonstrated the increased formation of serum HNE-modified albumin in type 2 diabetic outpatients in the milieu between liver and vascular lumina, indicating the presence of oxidative stress.

DOI： 10.1089/ars.2000.2.4-681

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Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress

Tanaka T., Kondo S., Iwasa Y., Hiai H., Toyokuni S.

American Journal of Pathology 156 巻 ( 6 ) 頁： 2149 - 2157 2000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：American Journal of Pathology

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In search of genes specifically involved in oxystress-induced carcinogenesis, we have applied a modified fluorescent differential display technique to the tumors and an established cell line as well as their non- neoplastic counterparts. We screened approximately 84,000 products. Reverse Northern blotting confirmed differential expression of 20 transcripts, which showed either significant increase, decrease or lack of expression in the RCCs. Five cDNA clones encoded novel products of unknown function. Fifteen cDNA clones were identified by homology search, which included annexin II, Y- box binding protein, ribosomal proteins, heat shock proteins, DNA polymerase, nonmuscle caldesmon (increased); protein tyrosine phosphatase (decreased); selenoprotein P, stromal cell-derived factor 1, intestinal trefoil protein, nicotinamide adenine dinucleotide, reduced form (NADH) dehydrogenase, and insulin-like growth factor binding protein 7 (deleted). Most of the identified genes were associated with stress-response or cellular proliferation. These results suggest that multiple, interactive genetic pathways are involved in carcinogenesis induced by oxidative stress.

DOI： 10.1016/S0002-9440(10)65085-7

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Cytoprotective effects of nitroglycerin in ischemia-reperfusion-induced lung injury

Kawashima M., Bando T., Nakamura T., Isowa N., Liu M., Toyokuni S., Hitomi S., Wada H.

American Journal of Respiratory and Critical Care Medicine 161 巻 ( 3 I ) 頁： 935 - 943 2000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：American Journal of Respiratory and Critical Care Medicine

Prevention of ischemia-reperfusion (IR) injury is crucial for successful lung transplantation. We investigated whether a nitric oxide donor, nitroglycerin (NTG), could suppress the oxidative stress of IR injury and improve pulmonary function after reperfusion in an ex vivo rat lung perfusion model. In Fresh group of animals, the lungs were flushed with perfusate, followed immediately by reperfusion, and no lung injury was observed. In NTG- and NTG+ groups of animals, the lungs were flushed with perfusate alone or perfusate containing NTG, respectively. Harvested lung and heart blocks from these latter two groups were immersed in the corresponding perfusate at 4°C for 15 h, and were then reperfused for 60 min. Reperfusion induced pulmonary edema in the NTG- group, but not in the NTG + group. Shunt fractions in NTG+ group were significantly lower than in the NTG- group throughout reperfusion. NTG had no effect on pulmonary arterial pressure or myeloperoxidase activity. In contrast, oxidative DNA damage assessed immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly increased in the NTG- group, in the order alveolar epithelium > pulmonary endothelium > bronchial epithelium. NTG treatment significantly decreased staining with the anti-8-OHdG antibody in all three areas Of tissue. Therefore, administration of NTG attenuates the oxidative stress of IR injury, and may improve pulmonary function after reperfusion.

DOI： 10.1164/ajrccm.161.3.9905003

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Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers

Yamagami K., Yamamoto Y., Ishikawa Y., Yonezawa K., Toyokuni S., Yamaoka Y.

Journal of Laboratory and Clinical Medicine 135 巻 ( 6 ) 頁： 465 - 475 2000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：Journal of Laboratory and Clinical Medicine

The effect of geranyl-geranyl-acetone (GGA) administration before heat shock preconditioning on heat shock protein (HSP) 72 induction and on the acquisition of tolerance against ischemia-reperfusion injury was studied in rat livers. Male Wistar rats were divided into four groups: a control group (group C); a GGA group (group G); a simple heat shock group (group VH); and a heat shock with GGA premedication group (group GH). Five-, 10-, and 15-minute periods of heat shock preconditioning at 42°C were performed in groups VH and GH. Subgroups were determined according to the period of heat shock exposure. After a 48-hour recovery, rats in groups C, VH5, VH15, and GH5 received a 30-minute period of hepatic ischemia. Induction of HSP72, survival rates, and changes in biochemical and histologic parameters were compared among the groups. Five-minute heat shock preconditioning was not enough to induce HSP72. However, livers in group GH5 expressed approximately the same amount of HSP72 as those in group VH15. The expression of HSP72 in group GH15 was stronger than that found in group VH15. The degree and location of HSP72 expression were not different between groups GH5 and VH15. Seven-day survival was significantly better in groups GH5 (16/16) and VH15 (15/16) than in group C (8/16) or VH5 (9/16). The recovery of adenosine triphosphate in liver tissue was faster, and the release of liver-related enzymes during reperfusion was lower in groups GH5 and VH15 than in group C or VH5. Administration of GGA before heat shock preconditioning augmented the induction of HSP72 by decreasing the threshold for triggering the stress response.

DOI： 10.1067/mlc.2000.106806

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Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report

Shimizu K., Ogura S., Kobayashi T.K., Kushima R., Toyokuni S., Iwasa Y., Sakurai M.

Diagnostic Cytopathology 21 巻 ( 6 ) 頁： 398 - 401 1999年12月

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：Diagnostic Cytopathology

A 79-yr-old woman presented with a 5-yr history of swelling of the left cheek. The fine-needle aspiration (FNA) smear showed a spindle-cell neoplasm with capillaries and benign endothelial cells. The spindle cells possessed pleomorphic, hyperchromatic elongated nuclei and a moderate amount of ill- defined cytoplasm. They also showed papillary arcades surrounded and encased by relatively small ovoid to short spindle cells. Subsequent surgical excision confirmed the presence of malignant hemangiopericytoma (HP). Immunohistochemical studies on the histologic section using vimentin were strongly positive, consistent with HP. To the best of our knowledge, this is the second published report of FNA cellular features of malignant HP of the salivary gland. Besides delineating the FNA cellular features of HP of the salivary gland, the present case illustrates the value of using immunohistochemical approaches.

DOI： 10.1002/(SICI)1097-0339(199912)21:6<398::AID-DC6>3.0.CO;2-V

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Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report

Shimizu K, Ogura S, Kobayashi TK, Kushima R, Toyokuni S, Iwasa Y, Sakurai M

DIAGNOSTIC CYTOPATHOLOGY 21 巻 ( 6 ) 頁： 398 - 401 1999年12月

Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report 査読有り

K Shimizu, S Ogura, TK Kobayashi, R Kushima, S Toyokuni, Y Iwasa, M Sakurai

DIAGNOSTIC CYTOPATHOLOGY 21 巻 ( 6 ) 頁： 398 - 401 1999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：WILEY-LISS

A 79-yr-old woman presented with a 5-yr history of swelling of the left cheek. The fine-needle aspiration (FNA) smear show ed a spindle-cell neoplasm with capillaries and benign endothelial cells. The spindle cells possessed pleomorphic, hyperchromatic elongated nuclei and a moderate amount of ill-defined cytoplasm. They also showed papillary arcades surrounded and encased by relatively: small ovoid to short spindle cells. Subsequent surgical excision confirmed the presence of malignant hemangiopericytoma (HP). Immunohistochemical studies on the histologic section casing vimentin were strongly positive, consistent with HP To the best of our knowledge, this is the second published report of FNA cellular features of malignant HP of the salivary gland. Besides delineating the FNA cellular of HP of the salivary gland the present case illustrates the value of using immunohistochemical approaches.

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Heat-shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats

Yamamoto H., Yamamoto Y., Yamagami K., Kume M., Kimoto S., Toyokuni S., Uchida K., Fukumoto M., Yamaoka Y.

Research in Experimental Medicine 199 巻 ( 6 ) 頁： 309 - 318 1999年11月

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：Research in Experimental Medicine

Membrane lipids and cytosolic proteins are major targets of oxidative injury. This study examined the effect of heat-shock preconditioning associated with the induction of heat-shock protein 72 on liver injury, from the aspect of lipid peroxidation and protein denaturation after carbon tetrachloride (CCl4) administration in rats - one of the representative oxidative injuries. Male Wistar rats were divided into two groups, group HS (preconditioned by heat exposure) and group C (not preconditioned). Expression of HSP72 in the liver tissue was confirmed by Western blot analysis. After a 48-h recovery period, all rats were given CCl4 intragastrically. Liver damage was assessed by measuring serum liver-related enzyme levels and adenine nucleotide concentration in the liver tissue. Lipid peroxidation and protein denaturation were evaluated by measuring tiobarbituric acid reactive substances (TBARS) and by immunohistochemical staining of 4-hydroxy-2-nonenal(HNE)-modified proteins in the liver. Survival rates of the rats after CCl4 administration were also compared. Expression of HSP72 was clearly detected in group HS, but not in group C. Heat-shock preconditioning significantly improved the survival rate, suppressed the increase in liver-related enzyme levels and maintained adenosine triphosphate levels (P < 0.01 each). HNE-modified proteins - denatured proteins by free radical attack - were significantly less stained in group HS than in group C (P < 0.05). However, TBARS levels did not differ between groups. Because heat-shock preconditioning did not alter TBARS levels but reduced HNE-modified proteins in association with the expression of HSP72, it is suggested that HSP72 did not prevent lipid peroxidation but decreased the lipid peroxidation-induced denaturation of proteins. This seemed to be a mechanism of heat-shock preconditioning to ameliorate oxidative liver injury.

DOI： 10.1007/s004339900040

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Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis. 国際誌

Kawamura, K; Kageyama, F; Kobayashi, Y; Kawasaki, T; Toyokuni, S; Uchida, K

HEPATOLOGY 30 巻 ( 4 ) 頁： 543A - 543A 1999年10月

Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis. 国際誌

Kawamura, K, Kageyama, F, Kobayashi, Y, Kawasaki, T, Toyokuni, S, Uchida, K

HEPATOLOGY 30 巻 ( 4 ) 頁： 543A - 543A 1999年10月

P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

KOBAYASHI M., NAKAMURA H., YODOI J., TOYOKUNI S., SHIOTA K.

Congenital anomalies 39 巻 ( 3 ) 頁： 175 1999年9月

P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

KOBAYASHI M, NAKAMURA H, YODOI J, TOYOKUNI S, SHIOTA K

Congenital anomalies 39 巻 ( 3 ) 1999年9月

Iron chelators modulate the production of DNA strand breaks and 8-hydroxy-2'-deoxyguanosine

Toyokuni S., Sagripanti J.

Free Radical Research 31 巻 ( 2 ) 頁： 123 - 128 1999年9月

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：Free Radical Research

The interaction of chelators and reducing agents is of particular importance in understanding iron-associated pathology since catalytic iron undergoes cyclic reduction and oxidation in vivo. Therefore, we treated plasmid DNA with free or chelated Fe(III) in the presence of biological reductants, and simultaneously measured the number of single strand breaks (SSBs) and oxidative base modification (8-hydroxy-2'-deoxyguanosine; 8-OHdG) by quantitative gel electrophoresis and HPLC with electrochemical detection, respectively. Production of SSBs and 8-OHdG was linearly correlated suggesting that these true different lesions share a common chemical mechanism. The levels of both lesions were enhanced when Fe(III) was chelated to citrate or nitrilotriacetic acid. Reducing agents showed different potency in inducing DNA damage catalyzed by chelated iron (L-ascorbate > L-cysteine > H2O2). Chelation increased SSB formation by ~ 8-fold and 8-OHdG production by ~ 4-fold. The ratio of SSB/8-OHdG catalyzed by chelated iron, which is twice as high as by unchelated iron, indicates that chelation affects iron-catalyzed oxidative DNA damage in a specific way favoring strand breakage over base modification. Since iron is mostly chelated in biological systems, the production of genomic and mitochondrial DNA damage, particularly strand breaks, in diseases involving iron overload is likely to be higher than previously predicted from studies using unchelated iron.

DOI： 10.1080/10715769900301631

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Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers

Oberley TD, Toyokuni S, Szweda LI

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 5-6 ) 頁： 695 - 703 1999年9月

Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers 査読有り

TD Oberley, S Toyokuni, LI Szweda

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 5-6 ) 頁： 695 - 703 1999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：PERGAMON-ELSEVIER SCIENCE LTD

Both polyclonal and monoclonal antibodies to 4-hydroxy-2-nonenal (HNE) protein adducts were used to identify lipid peroxidation products in normal human kidney and in selected human kidney cancers using immunoperoxidase techniques at the light microscopic level and immunogold techniques at the ultrastructural level. HNE protein adducts were detected in most cell types in normal kidney, although in highly variable amounts. All six morphologic types of renal tumors examined showed some staining with antibodies to HNE protein adducts, although the intensity of staining Varied considerably depending on tumor type. Renal oncocytoma and the granular cell variant of renal adenocarcinoma both showed greater cytoplasmic staining for HNE protein adducts than the other tumors examined; these tumors both contain high numbers of mitochondria and suggest that mitochondria are a major source of lipid peroxidation products. To test this possibility, immunogold ultrastructural analysis was performed. HNE protein adducts were identified in nuclei and mitochondria in both normal proximal tubule and three types of renal carcinoma examined; these results localize oxidative damage at the subcellular level in both benign and malignant epithelium to nuclei and mitochondria. In conclusion, HNE protein adducts occur in kidneys in both normal and tumor cells, although immunomorphologic analyses suggest less HNE protein adducts in tumor cells. (C) 1999 Elsevier Science Inc.

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Association between M/L55-polymorphism of paraoxonase enzyme and oxidative DNA damage in patients with type 2 diabetes mellitus and in control subjects

Malin R., Rantalaiho V., Huang X.H., Wirta O., Pasternack A., Leinonen J.S., Alho H., Jokela H., Koivula T., Tanaka T., Okada K., Ochi H., Toyokuni S., Lehtimäki T.

Human Genetics 105 巻 ( 1-2 ) 頁： 179 - 180 1999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：Human Genetics

The paraoxonase enzyme (PON) gene polymorphism causes a change of methionine (M-allele) to leucine (L-allele). PON may reduce low density lipoprotein oxidation and prevent atherosclerosis. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a sensitive index of oxidative DNA damage. We have studied the association between the PON genotypes and the urinary excretion of 8-OHdG. The study population consisted of 93 Finnish type 2 diabetes patients and 106 non-diabetic control subjects. The 24-h excretion of 8-OHdG was significantly higher in diabetic patients than in control subjects (P < 0.001). In control subjects, the ratio of the 8-OHdG/glomerular filtration rate increased in order of genotype from MM to ML to LL (P < 0.0412). These results suggest that lipid peroxidation may have an effect on DNA oxidation.

DOI： 10.1007/s004399900074

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4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules 査読有り国際誌

Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY 274 巻 ( 34 ) 頁： 23787 - 23793 1999年8月

4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules

Okada K., Wangpoengtrakul C., Osawa T., Toyokuni S., Tanaka K., Uchida K.

Journal of Biological Chemistry 274 巻 ( 34 ) 頁： 23787 - 23793 1999年8月

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：Journal of Biological Chemistry

Oxidative stress is associated with important pathophysiological events in a variety of diseases. It has been postulated that free radicals and lipid peroxidation products generated during the process may be responsible for these effects because of their ability to damage cellular components such as membranes, proteins, and DNA. In the present study, we provide evidence that oxidative stress causes a transient impairment of intracellular proteolysis via covalent binding of 4-hydroxy-2-nonenal (HNE), a major end product of lipid peroxidation, to proteasomes. A single intraperitoneal treatment with the renal carcinogen, ferric nitrilotriacetate, caused oxidative stress, as monitored by accumulation of lipid peroxidation products and 8-hydroxy-2'- deoxyguanosine, in the kidney of mice. In addition, transient accumulation of HNE-modified proteins in the kidney was also found by competitive enzyme- linked immunosorbent assay and immunohistochemical analyses. This and the observation that the HNE-modified proteins were significantly ubiquitinated suggested a crucial role of proteasomes in the metabolism of HNE-modified proteins. In vitro incubation of the kidney homogenates with HNE indeed resulted in a transient accumulation of HNE-modified proteins, whereas the proteasome inhibitor significantly suppressed the time-dependent elimination of HNE-modified proteins. We found that, among three proteolytic activities (trypsin, chymotrypsin, and peptidylglutamyl peptide hydrolase activities) of proteasomes, both trypsin and peptidylglutamyl peptide hydrolase activities in the kidney were transiently diminished in accordance with the accumulation of HNE-modified proteins during oxidative stress. The loss of proteasome activities was partially ascribed to the direct attachment of HNE to the protein, based on the detection of HNE-proteasome conjugates by an immunoprecipitation technique. These results suggest that HNE may contribute to the enhanced accumulation of oxidatively modified proteins via an impairment of ubiquitin/proteasome-dependent intracellular proteolysis.

DOI： 10.1074/jbc.274.34.23787

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Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H, Imamura M

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 3-4 ) 頁： 401 - 410 1999年8月

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S., Toyokuni S., Iwasa Y., Tanaka T., Onodera H., Hiai H., Imamura M.

Free Radical Biology and Medicine 27 巻 ( 3-4 ) 頁： 401 - 410 1999年8月

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：Free Radical Biology and Medicine

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'- deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3- nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

DOI： 10.1016/S0891-5849(99)00087-8

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