研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C 国際誌

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

AMERICAN JOURNAL OF GASTROENTEROLOGY 95 巻 ( 4 ) 頁： 1041 - 1050 2000年4月

Overexpression of the hOGG1 gene and high 8-hydroxy-2 '-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism of the 8-OHdG level in DNA

Kondo S, Toyokuni S, Tanaka T, Hiai H, Onodera H, Kasai H, Imamura M

CLINICAL CANCER RESEARCH 6 巻 ( 4 ) 頁： 1394 - 1400 2000年4月

Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C 査読有り国際誌 Open Access

Kageyama F., Kobayashi Y., Kawasaki T., Toyokuni S., Uchida K., Nakamura H.

American Journal of Gastroenterology 95 巻 ( 4 ) 頁： 1041 - 1050 2000年4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：American Journal of Gastroenterology

OBJECTIVES: Hepatic iron deposition has been reported in chronic hepatitis C (CH-C), and iron-induced lipid peroxidation may be involved in the pathogenesis of CH-C. The aims of the present study were: 1) to determine whether patients with CH-C have evidence of enhanced hepatic lipid peroxidation and to evaluate its relation to iron status, compared with that in patients with chronic hepatitis B (CH-B); and 2) to assess the effect of interferon (IFN) therapy on hepatic iron and lipid peroxidation. METHODS: In the liver biopsies of 40 patients with CH-C and 26 patients with CH-B, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE)-protein adducts for evaluation of lipid peroxidation was performed, and hepatic iron status was biochemically and histologically assessed. In 16 CH-C patients with normal serum transaminases and undetectable serum HCV-RNA >6 months after the end of IFN treatment (responders) and in 11 nonresponders, hepatic HNE- protein adducts and siderosis were evaluated in pre- and posttreatment liver biopsies. RESULTS: Hepatocytic HNE-protein adducts and iron deposits were more abundant in the patients with CH-C than in those with CH-B. No correlation was found between the levels of hepatocytic HNE-protein adducts and hepatic iron status in either of the two groups. In the responders to IFN treatment for CH-C, hepatocytic HNE-protein adducts disappeared or attenuated with improvement of hepatic siderosis after the treatment, whereas IFN treatment did not improve hepatocytic expression of HNE-protein adducts and hepatic siderosis in the nonresponders. CONCLUSIONS: Patients with CH-C have evidence of enhanced hepatic iron accumulation and lipid peroxidation compared to those with CH-B. In CH-C, hepatic siderosis and lipid peroxidation are improved with successful IFN treatment. These results suggest that hepatic lipid peroxidation and iron may potentially play contributory roles in the pathogenesis of CH-C. (C) 2000 by Am. Coll. of Gastroenterology.

DOI： 10.1016/S0002-9270(00)00771-1

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Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C 国際誌

Kageyama, F, Kobayashi, Y, Kawasaki, T, Toyokuni, S, Uchida, K, Nakamura, H

AMERICAN JOURNAL OF GASTROENTEROLOGY 95 巻 ( 4 ) 頁： 1041 - 1050 2000年4月

Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism of the 8-OHdG level in DNA 査読有り国際誌

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

Clinical Cancer Research 6 巻 ( 4 ) 頁： 1394 - 1400 2000年4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：Clinical Cancer Research

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively modified lesions in DNA. Our previous study (Kondo et al., Free Radic. Biol. Med., 27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively stressed based on 8-OHdG determination. To elucidate 8-OHdG metabolism and its clinical significance in colorectal carcinoma, we studied the 8-OHdG repair system in DNA by measuring specific lyase activity and hOGG1 expression using quantitative-competitive reverse transcription-PCR. In addition, we searched for the presence of mutations and single nucleotide polymorphisms of the hOGG1 gene by single-strand conformational polymorphism and sequencing analyses. It was found that 8- OHdG-specific lyase activity and hOGG1 expression were significantly up- regulated in carcinoma, and a proportional association between 8-OHdG levels and either 8-OHdG lyase activity (r = 0.641, P < 0.05) or hOGG1 expression (r = 0.702, P < 0.05) was present. Whereas no difference was detected in the 8- OHdG level between early- and advanced-stage cancer, lyase activity (1.2- fold) and hOGG1 expression (1.6-fold) were significantly increased in advanced-stage cancer. No mutation was found in the 25 tumors examined. Three kinds of single nucleotide polymorphism were observed, including that of codon 326 (Ser/Cys) in exon 7. However, there was no correlation between any of the three polymorphic patterns and either 8-OHdG level or lyase activity. These results suggest that increased 8-OHdG levels in colorectal carcinoma are attributed to increased formation and are maintained by induced 8-OHdG repair activity at appropriate high levels. Our results may offer a unique approach in the development of preventive and therapeutic interventions as well as new insights into the pathogenesis of colorectal carcinoma.

DOI： 10.1093/carcin/19.5.897

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Overexpression of the hOGG1 gene and high 8-hydroxy-2 '-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism of the 8-OHdG level in DNA

Kondo S, Toyokuni S, Tanaka T, Hiai H, Onodera H, Kasai H, Imamura M

CLINICAL CANCER RESEARCH 6 巻 ( 4 ) 頁： 1394 - 1400 2000年4月

Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG level in DNA.

Kondo S, Toyokuni S, Tanaka T, Hiai H, Onodera H, Kasai H, Imamura M

Clinical cancer research : an official journal of the American Association for Cancer Research 6 巻 ( 4 ) 頁： 1394 - 400 2000年4月

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

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

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 161 巻 ( 3 ) 頁： 935 - 943 2000年3月

Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal- modified proteins in rat liver after ischemia-reperfusion: Distinct localization of the two oxidatively modified products

Yamagami K., Yamamoto Y., Kume M., Ishikawa Y., Yamaoka Y., Hiai H., Toyokuni S.

Antioxidants and Redox Signaling 2 巻 ( 1 ) 頁： 127 - 136 2000年1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：Antioxidants and Redox Signaling

Ischemia-reperfusion (IR) injury is an intractable process associated not only with therapeutic recanalization of vessels, but also with partial resection or transplantation of solid organs including liver. To develop methods for predicting the degree of hepatic IR injury and further to identify injured cells, we studied the formation of 8-hydroxy-2'-deoxy- guanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE)-modified proteins in the normothermic hepatic IR model of rats using immunohistochemistry, high- performance liquid chromatography (HPLC) determination and Western blot. The Pringle maneuver for either 15 or 30 min duration produced reversible or lethal damage, respectively. The levels of both products were significantly increased in proportion to ischemia duration 40 min after reperfusion, suggesting the involvement of hydroxyl radicals. Increased immunoreactivity of 8-OHdG was observed not only in the nuclei of hepatocytes but also in those of bile canalicular and endothelial cells. However, immunoreactivity of HNE-modified proteins was detected in the cytoplasm of hepatocytes, which was confirmed by Western blot, and in addition, in the nuclei of hepatocytes after severe injury. Thus, localization of the two oxidatively modified products was not identical. Our data suggest that these two products could be used for the assessment of hepatic IR injury in tissue, but that the biological significance of the two products might be different.

DOI： 10.1089/ars.2000.2.1-127

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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 Shinya, Yamada Satoshi, Kashima Minoru, Ihara Yu, Yamada Yuichiro, Tanaka Tomoyuki, Hiai Hiroshi, Seino Yutaka, Uchida Koji

ANTIOXIDANTS & REDOX SIGNALING 2 巻 ( 4 ) 頁： 681 - U65 2000年

Formation of 8-Hydroxy-2 '-Deoxyguanosine and 4-Hydroxy-2-Nonenal-Modified Proteins in Rat Liver after Ischemia-Reperfusion: Distinct Localization of the Two Oxidatively Modified Products

Yamagami Kazuhiko, Yamamoto Yuzo, Kume Makoto, Ishikawa Yasuhide, Yamaoka Yoshio, Hiai Hiroshi, Toyokuni Shinya

ANTIOXIDANTS & REDOX SIGNALING 2 巻 ( 1 ) 頁： 127 - 136 2000年

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

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

Open Access

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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

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