Papers by Shinya Toyokuni
Biochimica et biophysica acta, 2016
Essential metals, such as iron and copper, play a critical role in a plethora of cellular process... more Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metal compared to their normal counterparts. Interestingly, new anti-cancer agents have been developed that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS. These ligands can avidly bind metals ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis supp...
Helmut Sies established the concept of oxidative stress in 1985.
However, it took some time to in... more Helmut Sies established the concept of oxidative stress in 1985.
However, it took some time to introduce this concept into
pathology, where investigators count on formalin-fixed
paraffin-embedded tissue sections. I sought out antigens for
this purpose based on an oxidative stress-induced rat renal
carcinogenesis model, which revealed that 8-hydroxy-2′-
deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins
are ideal. These two monoclonal antibodies successfully
revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis.
Shigeru Okada established the aforementioned ferric
nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis
model, which thus far has answered many questions regarding
the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also inhuman carcinogenesis. Furthermore, excess iron is amajor pathology in asbestosinduced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.
Nihon eiseigaku zasshi. Japanese journal of hygiene, 2011
The research project entitled "Comprehensive approach on asbestos-related diseases" sup... more The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fuk...
Circulation Journal Official Journal of the Japanese Circulation Society, Mar 1, 2004
Free radical biology & medicine, Jan 17, 2015
Exposure to inflammation in utero is related to perinatal brain injury, which is itself associate... more Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microgli...
Bioscience Biotechnology and Biochemistry, 2009
The health promoting effects of a grapevine-shoot extract named Vineatrol30, which contains resve... more The health promoting effects of a grapevine-shoot extract named Vineatrol30, which contains resveratrol (Resv) as well as considerable amounts of Resv oligomers, have recently been investigated. In the present study, we analyzed the free radical scavenging capacity, the ability to inhibit lipid peroxidation, and the capacity to enhance the human glutathione peroxidase 1 (GPx) and the human superoxide dismutase 1 (SOD) gene promoter activities of Vineatrol30. Vineatrol30 was able to scavenge the 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical cation and led to concentration-dependent inhibition of lipid peroxidation, Vineatrol30 not being superior to Resv alone in both cases. Vineatrol30 also enhanced the gene promoter activities of human GPx and SOD expressed in V79 cells, whereas this effect could not be demonstrated for Resv. In summary, the results presented in this study show that the Vineatrol30 grapevine-shoot extract is a free radical scavenger and potent antioxidant at non-cytotoxic concentrations.
Journal of Clinical Biochemistry and Nutrition, 2015
Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effecti... more Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.
Fukuoka igaku zasshi = Hukuoka acta medica
Background—Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with he... more Background—Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. Methods and Results—Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor), or saline
Japanese Journal of Electrocardiology, 2004
SUMMARY We used immunofluorescence staining (monoclonal antibody N45.1) with cyto- logical imprin... more SUMMARY We used immunofluorescence staining (monoclonal antibody N45.1) with cyto- logical imprinting to study changes in the intranuclear distribution of 8-hydroxy-2 9 -deoxy- guanosine in renal cells of male Wistar rats after oxidative stress by ferric nitrilotriacetate. In the control proximal tubule cells, small spherical signals were uniformly distributed through- out the nuclei. Under oxidative stress, immunofluorescence intensity was increased,
Free radical biology & medicine, Jan 11, 2015
Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following ... more Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and...
Journal of clinical biochemistry and nutrition, 2015
Journal of Clinical Biochemistry and Nutrition, 2006
ABSTRACT Epidemiological studies have demonstrated that oxidative stress associated with a variet... more ABSTRACT Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.
Advances in DNA Damage and Repair, 1999
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Papers by Shinya Toyokuni
However, it took some time to introduce this concept into
pathology, where investigators count on formalin-fixed
paraffin-embedded tissue sections. I sought out antigens for
this purpose based on an oxidative stress-induced rat renal
carcinogenesis model, which revealed that 8-hydroxy-2′-
deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins
are ideal. These two monoclonal antibodies successfully
revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis.
Shigeru Okada established the aforementioned ferric
nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis
model, which thus far has answered many questions regarding
the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also inhuman carcinogenesis. Furthermore, excess iron is amajor pathology in asbestosinduced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.
However, it took some time to introduce this concept into
pathology, where investigators count on formalin-fixed
paraffin-embedded tissue sections. I sought out antigens for
this purpose based on an oxidative stress-induced rat renal
carcinogenesis model, which revealed that 8-hydroxy-2′-
deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins
are ideal. These two monoclonal antibodies successfully
revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis.
Shigeru Okada established the aforementioned ferric
nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis
model, which thus far has answered many questions regarding
the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also inhuman carcinogenesis. Furthermore, excess iron is amajor pathology in asbestosinduced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.