Keiko Nishio - Academia.edu (original) (raw)

Papers by Keiko Nishio

Research paper thumbnail of A Photo‐Thermal‐Electrical Converter Based On Carbon Nanotubes for Bioelectronic Applications

Angewandte Chemie International Edition, Dec 16, 2011

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Research paper thumbnail of In vitro evaluation of cellular influences induced by metal oxide nanoparticles

한국독성학회 심포지움 및 학술발표회, Nov 1, 2010

ABSTRACT Fullerene is one of the nanocarbons that is expected to have applications to life scienc... more ABSTRACT Fullerene is one of the nanocarbons that is expected to have applications to life science, such as nanomedicines. An understanding of the cellular influences of fullerene is essential for its application to life science. Although C60 and C70 are both known as major fullerenes, most previous reports about the cellular influences of fullerene are about C60. Thus we evaluated the cellular influences caused by C70. A stable and uniform C70-medium dispersion was prepared. The dispersion was stable for the experimental period. Mitochondrial activity (MTT assay), colony forming ability (clonogenic assay), induction of oxidative stress (intracellular ROS and lipid peroxidation levels) and cellular uptake (TEM observation) in human keratinocyte HaCaT and lung carcinoma A549 cells exposed to C70 were examined. C70 did not influence mitochondrial activity. On the other hand, C70 dispersion inhibited colony formation at the concentration of 25.2μgmL(-1). Exposure to C70 dispersion caused an increase in intracellular ROS and lipid peroxidation levels. The induction of intracellular ROS level was inhibited by pre-treatment of the cells by antioxidants. TEM observations of C70 exposed cells showed cellular uptake of C70. These results were similar to the cellular influences caused by C60 which were reported by us previously. Although C70 did not cause cell death, it caused the induction of intracellular oxidative stress.

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Research paper thumbnail of In vitro evaluation of cellular responses induced by stable fullerene C_ medium dispersion

The Journal of Biochemistry, Sep 1, 2010

Because of the expansion of the functionalities available for modification of fullerene C60 and i... more Because of the expansion of the functionalities available for modification of fullerene C60 and its derivatives, their uses are increasing. However, the consequences of fullerene exposure to human health have not been fully studied. In vitro experiments are useful for risk assessment and for understanding potential applications. However, the insolubility of pristine C60 in water makes the in vitro evaluation of cellular responses difficult. To overcome this problem, we prepared a stable and uniform C60-medium dispersion for in vitro examinations. In addition, we examined the effect of the C60-medium dispersion on human keratinocyte HaCaT cells and human lung carcinoma A549 cells to understand the cellular responses induced by exposure to C60. Results indicated that exposure to C60 did not affect cell viability; neither apoptosis nor necrosis were induced, while cell proliferation was inhibited. Furthermore, intracellular oxidative stress was induced by C60 exposure in both HaCaT and A549 cells. Transmission electron microscopy indicated the cellular uptake of C60 aggregates. The results obtained from this study indicate that C60 has oxidative stress induction potential. Further examinations including in vivo studies are necessary for a more accurate evaluation of biological influences by C60.

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Research paper thumbnail of Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients

Neuroscience Letters, Jun 11, 2009

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Research paper thumbnail of Identification and Characterization of Two Penta-EF-Hand Ca^ -Binding Proteins in Dictyostelium discoideum^1

The Journal of Biochemistry, Aug 1, 2001

Penta-EF-hand (PEF) proteins such as ALG-2 (apoptosis-linked gene 2 product) and the calpain smal... more Penta-EF-hand (PEF) proteins such as ALG-2 (apoptosis-linked gene 2 product) and the calpain small subunit are a newly classified family of Ca(2+)-binding proteins that possess five EF-hand-like motifs. We identified two mutually homologous PEF proteins, designated DdPEF-1 and DdPEF-2 (64% amino acid residue identities), in the cellular slime mold Dictyostelium discoideum. Both PEF proteins showed a higher similarity to mammalian ALG-2 and peflin (Group I PEF proteins) than to calpain and sorcin subfamily (Group II PEF proteins) in the first EF-hand (EF-1) regions. Northern blot analyses revealed that DdPEF-1 and DdPEF-2 were constitutively expressed throughout development of Dictyostelium, but their levels of expression were developmentally regulated. In situ hybridization analyses demonstrated that DdPEF-1 was expressed in both the anterior prestalk and the posterior prespore regions of the tipped aggregate, slugs and early culminants. On the other hand, DdPEF-2 was dominantly expressed in the anterior tip region of these multicellular structures. Both PEF proteins were detected as 22-23-kDa proteins in soluble fractions in the presence of EGTA but in particulate fractions in the presence of Ca(2+) by Western blotting using specific monoclonal antibodies. Together with the finding of PEF-like sequences in DNA databases of plants, fungi and protists, our results strongly suggest that Group I PEF proteins are ubiquitously present in all eukaryotes and play important roles in basic cellular functions.

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Research paper thumbnail of Acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles were prevented by vitamin C

Toxicology Letters, 2014

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Research paper thumbnail of Singlet-oxygen-derived products from linoleate activate Nrf2 signaling in skin cells

Free radical biology & medicine, 2015

Linoleates are required for normal mammalian health and development, but they are also prone to o... more Linoleates are required for normal mammalian health and development, but they are also prone to oxidation, resulting in biologically active metabolites such as hydroxyoctadecadienoic acids (HODEs). To investigate the biological activity of 9-EZ-HODE, 10-EZ-HODE, 12-ZE-HODE, and 13-ZE-HODE, the metabolites of singlet-oxygen-derived products from linoleates, we assessed adaptive cytoprotection in HaCaT skin cells. Treating HaCaT cells with sublethal concentrations of 10-EZ-HODE and 12-ZE-HODE, which are singlet-oxygen-mediated specific oxidation metabolites of linoleates, but not 9-EZ-HODE and 13-ZE-HODE, caused resistance to hydrogen peroxide-induced oxidative damage. Microarray analysis of HaCaT cells revealed that 10-EZ-HODE and 12-ZE-HODE induced cellular antioxidant genes that are responsive to nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), such as heme oxygenase-1 and glutathione synthesis enzymes. Although 10-EZ-HODE and 12-ZE-HODE did not induce Nrf2 mRNA, treatment w...

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Research paper thumbnail of Attenuation of lipopolysaccharide (LPS)-induced cytotoxicity by tocopherols and tocotrienols

Redox biology, 2013

Lipopolysaccharide (LPS) induces host inflammatory responses and tissue injury and has been impli... more Lipopolysaccharide (LPS) induces host inflammatory responses and tissue injury and has been implicated in the pathogenesis of various age-related diseases such as acute respiratory distress syndrome, vascular diseases, and periodontal disease. Antioxidants, particularly vitamin E, have been shown to suppress oxidative stress induced by LPS, but the previous studies with different vitamin E isoforms gave inconsistent results. In the present study, the protective effects of α- and γ-tocopherols and α- and γ-tocotrienols on the oxidative stress induced by LPS against human lung carcinoma A549 cells were studied. They suppressed intracellular reactive oxygen formation, lipid peroxidation, induction of inflammatory mediator cytokines, and cell death. Tocopherols were incorporated into cultured cells much slower than tocotrienols but could suppress LPS-induced oxidative stress at much lower intracellular concentration than tocotrienols. Considering the bioavailability, it was concluded th...

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Research paper thumbnail of Identification and characterization of novel calcium-binding proteins of Dictyostelium and their spatial expression patterns during development

Development, growth & differentiation

Five putative Ca2(+)-binding proteins, CBP5, 6, 7, 8 and 9, all having EF-hand motifs, were found... more Five putative Ca2(+)-binding proteins, CBP5, 6, 7, 8 and 9, all having EF-hand motifs, were found by searching the Dictyostelium cDNA database (http://www.csm.biol.tsukuba.ac.jp/cDNAproject.html). 45Ca2(+)-overlay experiments revealed that four of these (excluding CBP9) are real Ca2(+)-binding proteins. Northern blot analysis revealed that the genes encoding CBP5, 6, 7 and 8 are all developmentally regulated. In situ hybridization analyses revealed that spatial expression of these genes was regulated in several different ways. CBP1, 2, 3, 5, 6 and 7 are expressed in prespore cells in the slug stage. Transcripts of the genes for CBP1 and 5 are enriched in prestalk subtype PstO cells. In contrast, CBP4 is expressed predominantly in PstO cells. CBP8 is evenly expressed at a very low level throughout the whole slug. Such distinct spatial expression patterns suggest that the CBP might be involved in morphogenesis and might have their own roles either in prespore or in prestalk cell diffe...

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Research paper thumbnail of The Expression of Inflammatory Cytokine and Heme Oxygenase-1 Genes in THP-1 Cells Exposed to Metal Oxide Nanoparticles

Journal of Nano Research, 2015

ABSTRACT The effect of manufactured nanoparticles on the expression of proinflammatory cytokine g... more ABSTRACT The effect of manufactured nanoparticles on the expression of proinflammatory cytokine genes was examined. THP-1 cells differentiated into macrophage cells were exposed to TiO2 and NiO medium dispersions. After 2, 6, 12, or 24 hours exposure, the expression of IL-1 beta, IL-6, IL-8, TNF-alpha and HO-1 genes was determined by real-time PCR. TiO2 nanoparticles did not affect cytokine production. In addition, TiO2 nanoparticles did not dissolve in the dispersion. On the other hand, NiO nanoparticles enhanced the expression of all the genes tested. NiO dispersions were composed of 58.3 mu g/mL of NiO nanoparticles and 45.8 mu g/mL of Ni2+. The release of metal ions from the nanoparticles is associated with their cytotoxicity. Therefore, the effect of an NiCl2 solution containing 45.8 mu g/mL of Ni2+ on the expression of cytokine genes was also examined. The effects of NiCl2 were similar to those of the NiO nanoparticles. Furthermore, the effect of ZnO, SiO2-coated ZnO, Sb2O3, and Cr2O3 nanoparticles on the expression of IL-1 beta, IL-8 and TNF-alpha genes was examined. Soluble nanoparticles, such as ZnO, SiO2-coated ZnO, and Cr2O3 enhanced the gene expression of cytokines. Sb2O3 nanoparticles showed poor solubility and did not affect the expression of cytokine genes. In conclusion, these results suggest that nanoparticle solubility plays an important role in regulating the expression of proinflammatory cytokines.

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Research paper thumbnail of Cellular effects of industrial metal nanoparticles and hydrophilic carbon black dispersion

The Journal of Toxicological Sciences, 2014

The effects of five types of metal nanoparticles, gold (Au), silver (Ag), platinum (Pt), Au-polyv... more The effects of five types of metal nanoparticles, gold (Au), silver (Ag), platinum (Pt), Au-polyvinylpyrrolidone (PVP) colloid, and Pt-PVP colloid, and two types of hydrophilic carbon black on cell behavior were examined. Stable nanoparticle dispersions were prepared and applied to the culture medium of human keratinocyte (HaCaT) and human lung carcinoma (A549) cells for 6 and 24 hr. Then, the mitochondrial activity (MTT assay) and the induction of cellular oxidative stress were examined. The exposure to Au and Ag decreased mitochondrial activity. The exposure to Pt nanoparticles induced an increase in the intracellular reactive oxygen species (ROS) level. In contrast, Au-PVP, Pt-PVP, and hydrophilic carbon black did not exhibit any effects. The observed increase in the ROS level induced by the Pt nanoparticles in this study contradicted our previous findings, in which Pt did not produce chemically reactive molecules. Some nanoparticle dispersions included chemicals as the dispersant, which is used in industrial applications. In some cases, the dispersing agent may have caused some cellular effects. Adsorption of agents on the surface of the nanoparticles may be an important factor here. Hence, the cellular effects of industrial nanoparticles should be evaluated carefully.

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Research paper thumbnail of Ascorbic acid attenuates acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles

Journal of Occupational Health, 2015

Objectives: It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmo... more Objectives: It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmonary dysfunction, including oxidative stress, inflammation, and injury, but there are no reports on how to prevent these adverse effects. We have previously reported that the pulmonary symptoms caused by ZnO NPs were associated with oxidative stress; in the present study, we therefore investigated the use of ascorbic acid (AA), which is known as vitamin C, to prevent these toxic effects. Methods: A ZnO NP dispersion was introduced into rat lungs by intratracheal injection, and thereafter a 1% aqueous AA solution was given as drinking water. Bronchoalveolar lavage fluid was collected at 1 day and 1 week after injection, and lactate dehydrogenase (LDH) activity, heme oxygenase-1 (HO-1), and interleukin-6 (IL-6) levels were measured. In addition, expression of the chemokine cytokine-induced neutrophil chemoattractants (CINCs), HO-1, and metallothionein-1 (MT-1) genes in the lungs were determined. Results: Acute oxidative stress induced by ZnO NPs was suppressed by supplying AA. Increases in LDH activity and IL-6 concentration were also suppressed by AA, as was the expression of the CINC-1, CINC-3, and HO-1 genes. Conclusions: Oral intake of AA prevents acute pulmonary oxidative stress and inflammation caused by ZnO NPs. Intake of AA after unanticipated exposure to ZnO NPs is possibly the first effective treatment for the acute pulmonary dysfunction they cause.

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Research paper thumbnail of Evaluation of cellular effects of silicon dioxide nanoparticles

Toxicology Mechanisms and Methods, 2014

Silica nanoparticles (nSiO2s) are an important type of manufactured nanoparticles. Although there... more Silica nanoparticles (nSiO2s) are an important type of manufactured nanoparticles. Although there are some reports about the cytotoxicity of nSiO2, the association between physical and chemical properties of nSiO2s and their cellular effects is still unclear. In this study, we examined the correlation between the physiochemical properties and cellular effects of three kinds of amorphous nSiO2s; sub-micro-scale amorphous SiO2, and micro-scale amorphous and crystalline SiO2 particles. The SiO2 particles were dispersed in culture medium and applied to HaCaT human keratinocytes and A549 human lung carcinoma cells. nSiO2s showed stronger protein adsorption than larger SiO2 particles. Moreover, the cellular effects of SiO2 particles were independent of the particle size and crystalline phase. The extent of cell membrane damage and intracellular ROS levels were different among nSiO2s. Upon exposure to nSiO2s, some cells released lactate dehydrogenase (LDH), whereas another nSiO2 did not induce LDH release. nSiO2s caused a slight increase in intracellular ROS levels. These cellular effects were independent of the specific surface area and primary particle size of the nSiO2s. Additionally, association of solubility and protein adsorption ability of nSiO2 to its cellular effects seemed to be small. Taken together, our data suggest that nSiO2s do not exert potent cytotoxic effects on cells in culture, especially compared to the effects of micro-scale SiO2 particles. Further studies are needed to address the role of surface properties of nSiO2s on cellular processes and cytotoxicity.

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Research paper thumbnail of Effects of ultrafine TiO2 particles on gene expression profile in human keratinocytes without illumination: Involvement of extracellular matrix and cell adhesion

Toxicology Letters, 2009

Assessing in vitro cellular responses to molecular events is an effective mean to elucidate the t... more Assessing in vitro cellular responses to molecular events is an effective mean to elucidate the toxicological behavior of the ultrafine nanoparticles. In this study, we utilized the DNA microarray analysis technique to determine the gene expression profiles of the human keratinocyte HaCaT cells exposed to anatase titanium dioxide (TiO(2)) particles of different (7 nm, 20 nm and 200 nm) average diameters without illumination. Cells were incubated for 24 h with TiO(2) particles, which were dispersed in the culture medium and size-fractionated such that the concentration of titanium in all the fractionated samples was nearly equivalent. According to the cluster analysis, only genes involved in the 'inflammatory response' and 'cell adhesion', but not the genes involved in 'oxidative stress' and 'apoptosis', were over-represented among the genes that were up-regulated in HaCaT cells. After 24 h exposure to ultrafine 7 nm TiO(2) particles, we observed altered expression levels of genes involved in matrix metalloproteinase activity (MMP-9 and MMP-10) and cell adhesion (fibronectin FN-1, integrin ITGB-6, and mucin MUC-4). These results suggest that the ultrafine TiO(2) particles without illumination have no significant impact on ROS-associated oxidative damage, but affect the cell-matrix adhesion in keratinocytes for extracellular matrix remodeling.

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Research paper thumbnail of Cellular responses by stable and uniform ultrafine titanium dioxide particles in culture-medium dispersions when secondary particle size was 100nm or less

Toxicology in Vitro, 2010

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Research paper thumbnail of Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species

Toxicology, 2005

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Research paper thumbnail of Elevation of oxidized DJ-1 in the brain and erythrocytes of Parkinson disease model animals

Neuroscience Letters, 2010

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Research paper thumbnail of Evaluation of cellular influences of platinum nanoparticles by stable medium dispersion

Metallomics, 2011

Platinum nanoparticles have industrial application, for example in catalysis, and are used in con... more Platinum nanoparticles have industrial application, for example in catalysis, and are used in consumer products such as cosmetics and supplements. Therefore, among the many nanoparticles, platinum is one of the more accessible nanoparticles for consumers. Most platinum nanoparticles that are used in cosmetics and supplements which have an anti-oxidant activity are modified particles. However, the cellular influences of pristine platinum nanoparticles are still unclear, although it has been reported that platinum nanoparticles induce oxidative stress. In this study, we investigated the cellular influences induced by pure pristine platinum nanoparticles. Platinum nanoparticles of 100% purity were dispersed in a cell culture medium and stable medium dispersion was obtained. The platinum nanoparticle medium dispersion was applied to two kinds of cultured cells, A549 and HaCaT cells, and the cellular influences were examined. Cell viability (MTT assay), cell proliferation (clonogenic assay), apoptosis induction (caspase-3 activity), intracellular ROS level (DCFH assay), and lipid peroxidation level (DPPP assay) were measured as markers of cellular influences. Transmission electron microscope observation showed cellular uptake of platinum nanoparticles. However, the platinum nanoparticles did not drive any markers. It is known that some metal oxide nanoparticles such as NiO and CuO show severe cytotoxicity via metal ion release. Compared with these toxic nanoparticles, the platinum nanoparticles used in this study did not release platinum ions into the culture media. These results suggest that the physically and chemically inactive cellular influences of platinum nanoparticles are small.

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Research paper thumbnail of Association of the physical and chemical properties and the cytotoxicity of metal oxide nanoparticles: metal ion release, adsorption ability and specific surface area

Metallomics, 2012

Association of cellular influences and physical and chemical properties were examined for 24 kind... more Association of cellular influences and physical and chemical properties were examined for 24 kinds of industrial metal oxide nanoparticles: ZnO, CuO, NiO, Sb(2)O(3), CoO, MoO(3), Y(2)O(3), MgO, Gd(2)O(3), SnO(2), WO(3), ZrO(2), Fe(2)O(3), TiO(2), CeO(2), Al(2)O(3), Bi(2)O(3), La(2)O(3), ITO, and cobalt blue pigments. We prepared a stable medium dispersion for each nanoparticle and examined the influence on cell viability and oxidative stress together with physical and chemical characterizations. ZnO, CuO, NiO, MgO, and WO(3) showed a large amount of metal ion release in the culture medium. The cellular influences of these soluble nanoparticles were larger than insoluble nanoparticles. TiO(2), SnO(2), and CeO(2) nanoparticles showed strong protein adsorption ability; however, cellular influences of these nanoparticles were small. The primary particle size and the specific surface area seemed unrelated to cellular influences. Cellular influences of metal oxide nanoparticles depended on the kind and concentrations of released metals in the solution. For insoluble nanoparticles, the adsorption property was involved in cellular influences. The primary particle size and specific surface area of metal oxide nanoparticles did not affect directly cellular influences. In conclusion the most important cytotoxic factor of metal oxide nanoparticles was metal ion release.

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Research paper thumbnail of Extracellular matrix family proteins that are potential targets of Dd-STATa in Dictyostelium discoideum

Journal of Plant Research, 2004

Dd-STATa is a functional Dictyostelium homologue of metazoan STAT (signal transducers and activat... more Dd-STATa is a functional Dictyostelium homologue of metazoan STAT (signal transducers and activators of transcription) proteins, which is activated by cAMP and is thereby translocated into the nuclei of anterior tip cells of the prestalk region of the slug. By using in situ hybridization analyses, we found that the SLF308 cDNA clone, which contains the ecmF gene that encodes a putative extracellular matrix protein and is expressed in the anterior tip cells, was greatly down-regulated in the Dd-STATa-null mutant. Disruption of the ecmF gene, however, resulted in almost no phenotypic change. The absence of any obvious mutant phenotype in the ecmF-null mutant could be due to a redundancy of similar genes. In fact, a search of the Dictyostelium whole genome database demonstrates the existence of an additional 16 homologues, all of which contain a cellulose-binding module. Among these homologues, four genes show Dd-STATa-dependent expression, while the others are Dd-STATa-independent. We discuss the potential role of Dd-STATa in morphogenesis via its effect on the interaction between cellulose and these extracellular matrix family proteins.

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Research paper thumbnail of A Photo‐Thermal‐Electrical Converter Based On Carbon Nanotubes for Bioelectronic Applications

Angewandte Chemie International Edition, Dec 16, 2011

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Research paper thumbnail of In vitro evaluation of cellular influences induced by metal oxide nanoparticles

한국독성학회 심포지움 및 학술발표회, Nov 1, 2010

ABSTRACT Fullerene is one of the nanocarbons that is expected to have applications to life scienc... more ABSTRACT Fullerene is one of the nanocarbons that is expected to have applications to life science, such as nanomedicines. An understanding of the cellular influences of fullerene is essential for its application to life science. Although C60 and C70 are both known as major fullerenes, most previous reports about the cellular influences of fullerene are about C60. Thus we evaluated the cellular influences caused by C70. A stable and uniform C70-medium dispersion was prepared. The dispersion was stable for the experimental period. Mitochondrial activity (MTT assay), colony forming ability (clonogenic assay), induction of oxidative stress (intracellular ROS and lipid peroxidation levels) and cellular uptake (TEM observation) in human keratinocyte HaCaT and lung carcinoma A549 cells exposed to C70 were examined. C70 did not influence mitochondrial activity. On the other hand, C70 dispersion inhibited colony formation at the concentration of 25.2μgmL(-1). Exposure to C70 dispersion caused an increase in intracellular ROS and lipid peroxidation levels. The induction of intracellular ROS level was inhibited by pre-treatment of the cells by antioxidants. TEM observations of C70 exposed cells showed cellular uptake of C70. These results were similar to the cellular influences caused by C60 which were reported by us previously. Although C70 did not cause cell death, it caused the induction of intracellular oxidative stress.

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Research paper thumbnail of In vitro evaluation of cellular responses induced by stable fullerene C_ medium dispersion

The Journal of Biochemistry, Sep 1, 2010

Because of the expansion of the functionalities available for modification of fullerene C60 and i... more Because of the expansion of the functionalities available for modification of fullerene C60 and its derivatives, their uses are increasing. However, the consequences of fullerene exposure to human health have not been fully studied. In vitro experiments are useful for risk assessment and for understanding potential applications. However, the insolubility of pristine C60 in water makes the in vitro evaluation of cellular responses difficult. To overcome this problem, we prepared a stable and uniform C60-medium dispersion for in vitro examinations. In addition, we examined the effect of the C60-medium dispersion on human keratinocyte HaCaT cells and human lung carcinoma A549 cells to understand the cellular responses induced by exposure to C60. Results indicated that exposure to C60 did not affect cell viability; neither apoptosis nor necrosis were induced, while cell proliferation was inhibited. Furthermore, intracellular oxidative stress was induced by C60 exposure in both HaCaT and A549 cells. Transmission electron microscopy indicated the cellular uptake of C60 aggregates. The results obtained from this study indicate that C60 has oxidative stress induction potential. Further examinations including in vivo studies are necessary for a more accurate evaluation of biological influences by C60.

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Research paper thumbnail of Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients

Neuroscience Letters, Jun 11, 2009

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Research paper thumbnail of Identification and Characterization of Two Penta-EF-Hand Ca^ -Binding Proteins in Dictyostelium discoideum^1

The Journal of Biochemistry, Aug 1, 2001

Penta-EF-hand (PEF) proteins such as ALG-2 (apoptosis-linked gene 2 product) and the calpain smal... more Penta-EF-hand (PEF) proteins such as ALG-2 (apoptosis-linked gene 2 product) and the calpain small subunit are a newly classified family of Ca(2+)-binding proteins that possess five EF-hand-like motifs. We identified two mutually homologous PEF proteins, designated DdPEF-1 and DdPEF-2 (64% amino acid residue identities), in the cellular slime mold Dictyostelium discoideum. Both PEF proteins showed a higher similarity to mammalian ALG-2 and peflin (Group I PEF proteins) than to calpain and sorcin subfamily (Group II PEF proteins) in the first EF-hand (EF-1) regions. Northern blot analyses revealed that DdPEF-1 and DdPEF-2 were constitutively expressed throughout development of Dictyostelium, but their levels of expression were developmentally regulated. In situ hybridization analyses demonstrated that DdPEF-1 was expressed in both the anterior prestalk and the posterior prespore regions of the tipped aggregate, slugs and early culminants. On the other hand, DdPEF-2 was dominantly expressed in the anterior tip region of these multicellular structures. Both PEF proteins were detected as 22-23-kDa proteins in soluble fractions in the presence of EGTA but in particulate fractions in the presence of Ca(2+) by Western blotting using specific monoclonal antibodies. Together with the finding of PEF-like sequences in DNA databases of plants, fungi and protists, our results strongly suggest that Group I PEF proteins are ubiquitously present in all eukaryotes and play important roles in basic cellular functions.

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Research paper thumbnail of Acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles were prevented by vitamin C

Toxicology Letters, 2014

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Research paper thumbnail of Singlet-oxygen-derived products from linoleate activate Nrf2 signaling in skin cells

Free radical biology & medicine, 2015

Linoleates are required for normal mammalian health and development, but they are also prone to o... more Linoleates are required for normal mammalian health and development, but they are also prone to oxidation, resulting in biologically active metabolites such as hydroxyoctadecadienoic acids (HODEs). To investigate the biological activity of 9-EZ-HODE, 10-EZ-HODE, 12-ZE-HODE, and 13-ZE-HODE, the metabolites of singlet-oxygen-derived products from linoleates, we assessed adaptive cytoprotection in HaCaT skin cells. Treating HaCaT cells with sublethal concentrations of 10-EZ-HODE and 12-ZE-HODE, which are singlet-oxygen-mediated specific oxidation metabolites of linoleates, but not 9-EZ-HODE and 13-ZE-HODE, caused resistance to hydrogen peroxide-induced oxidative damage. Microarray analysis of HaCaT cells revealed that 10-EZ-HODE and 12-ZE-HODE induced cellular antioxidant genes that are responsive to nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), such as heme oxygenase-1 and glutathione synthesis enzymes. Although 10-EZ-HODE and 12-ZE-HODE did not induce Nrf2 mRNA, treatment w...

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Research paper thumbnail of Attenuation of lipopolysaccharide (LPS)-induced cytotoxicity by tocopherols and tocotrienols

Redox biology, 2013

Lipopolysaccharide (LPS) induces host inflammatory responses and tissue injury and has been impli... more Lipopolysaccharide (LPS) induces host inflammatory responses and tissue injury and has been implicated in the pathogenesis of various age-related diseases such as acute respiratory distress syndrome, vascular diseases, and periodontal disease. Antioxidants, particularly vitamin E, have been shown to suppress oxidative stress induced by LPS, but the previous studies with different vitamin E isoforms gave inconsistent results. In the present study, the protective effects of α- and γ-tocopherols and α- and γ-tocotrienols on the oxidative stress induced by LPS against human lung carcinoma A549 cells were studied. They suppressed intracellular reactive oxygen formation, lipid peroxidation, induction of inflammatory mediator cytokines, and cell death. Tocopherols were incorporated into cultured cells much slower than tocotrienols but could suppress LPS-induced oxidative stress at much lower intracellular concentration than tocotrienols. Considering the bioavailability, it was concluded th...

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Research paper thumbnail of Identification and characterization of novel calcium-binding proteins of Dictyostelium and their spatial expression patterns during development

Development, growth & differentiation

Five putative Ca2(+)-binding proteins, CBP5, 6, 7, 8 and 9, all having EF-hand motifs, were found... more Five putative Ca2(+)-binding proteins, CBP5, 6, 7, 8 and 9, all having EF-hand motifs, were found by searching the Dictyostelium cDNA database (http://www.csm.biol.tsukuba.ac.jp/cDNAproject.html). 45Ca2(+)-overlay experiments revealed that four of these (excluding CBP9) are real Ca2(+)-binding proteins. Northern blot analysis revealed that the genes encoding CBP5, 6, 7 and 8 are all developmentally regulated. In situ hybridization analyses revealed that spatial expression of these genes was regulated in several different ways. CBP1, 2, 3, 5, 6 and 7 are expressed in prespore cells in the slug stage. Transcripts of the genes for CBP1 and 5 are enriched in prestalk subtype PstO cells. In contrast, CBP4 is expressed predominantly in PstO cells. CBP8 is evenly expressed at a very low level throughout the whole slug. Such distinct spatial expression patterns suggest that the CBP might be involved in morphogenesis and might have their own roles either in prespore or in prestalk cell diffe...

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Research paper thumbnail of The Expression of Inflammatory Cytokine and Heme Oxygenase-1 Genes in THP-1 Cells Exposed to Metal Oxide Nanoparticles

Journal of Nano Research, 2015

ABSTRACT The effect of manufactured nanoparticles on the expression of proinflammatory cytokine g... more ABSTRACT The effect of manufactured nanoparticles on the expression of proinflammatory cytokine genes was examined. THP-1 cells differentiated into macrophage cells were exposed to TiO2 and NiO medium dispersions. After 2, 6, 12, or 24 hours exposure, the expression of IL-1 beta, IL-6, IL-8, TNF-alpha and HO-1 genes was determined by real-time PCR. TiO2 nanoparticles did not affect cytokine production. In addition, TiO2 nanoparticles did not dissolve in the dispersion. On the other hand, NiO nanoparticles enhanced the expression of all the genes tested. NiO dispersions were composed of 58.3 mu g/mL of NiO nanoparticles and 45.8 mu g/mL of Ni2+. The release of metal ions from the nanoparticles is associated with their cytotoxicity. Therefore, the effect of an NiCl2 solution containing 45.8 mu g/mL of Ni2+ on the expression of cytokine genes was also examined. The effects of NiCl2 were similar to those of the NiO nanoparticles. Furthermore, the effect of ZnO, SiO2-coated ZnO, Sb2O3, and Cr2O3 nanoparticles on the expression of IL-1 beta, IL-8 and TNF-alpha genes was examined. Soluble nanoparticles, such as ZnO, SiO2-coated ZnO, and Cr2O3 enhanced the gene expression of cytokines. Sb2O3 nanoparticles showed poor solubility and did not affect the expression of cytokine genes. In conclusion, these results suggest that nanoparticle solubility plays an important role in regulating the expression of proinflammatory cytokines.

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Research paper thumbnail of Cellular effects of industrial metal nanoparticles and hydrophilic carbon black dispersion

The Journal of Toxicological Sciences, 2014

The effects of five types of metal nanoparticles, gold (Au), silver (Ag), platinum (Pt), Au-polyv... more The effects of five types of metal nanoparticles, gold (Au), silver (Ag), platinum (Pt), Au-polyvinylpyrrolidone (PVP) colloid, and Pt-PVP colloid, and two types of hydrophilic carbon black on cell behavior were examined. Stable nanoparticle dispersions were prepared and applied to the culture medium of human keratinocyte (HaCaT) and human lung carcinoma (A549) cells for 6 and 24 hr. Then, the mitochondrial activity (MTT assay) and the induction of cellular oxidative stress were examined. The exposure to Au and Ag decreased mitochondrial activity. The exposure to Pt nanoparticles induced an increase in the intracellular reactive oxygen species (ROS) level. In contrast, Au-PVP, Pt-PVP, and hydrophilic carbon black did not exhibit any effects. The observed increase in the ROS level induced by the Pt nanoparticles in this study contradicted our previous findings, in which Pt did not produce chemically reactive molecules. Some nanoparticle dispersions included chemicals as the dispersant, which is used in industrial applications. In some cases, the dispersing agent may have caused some cellular effects. Adsorption of agents on the surface of the nanoparticles may be an important factor here. Hence, the cellular effects of industrial nanoparticles should be evaluated carefully.

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Research paper thumbnail of Ascorbic acid attenuates acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles

Journal of Occupational Health, 2015

Objectives: It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmo... more Objectives: It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmonary dysfunction, including oxidative stress, inflammation, and injury, but there are no reports on how to prevent these adverse effects. We have previously reported that the pulmonary symptoms caused by ZnO NPs were associated with oxidative stress; in the present study, we therefore investigated the use of ascorbic acid (AA), which is known as vitamin C, to prevent these toxic effects. Methods: A ZnO NP dispersion was introduced into rat lungs by intratracheal injection, and thereafter a 1% aqueous AA solution was given as drinking water. Bronchoalveolar lavage fluid was collected at 1 day and 1 week after injection, and lactate dehydrogenase (LDH) activity, heme oxygenase-1 (HO-1), and interleukin-6 (IL-6) levels were measured. In addition, expression of the chemokine cytokine-induced neutrophil chemoattractants (CINCs), HO-1, and metallothionein-1 (MT-1) genes in the lungs were determined. Results: Acute oxidative stress induced by ZnO NPs was suppressed by supplying AA. Increases in LDH activity and IL-6 concentration were also suppressed by AA, as was the expression of the CINC-1, CINC-3, and HO-1 genes. Conclusions: Oral intake of AA prevents acute pulmonary oxidative stress and inflammation caused by ZnO NPs. Intake of AA after unanticipated exposure to ZnO NPs is possibly the first effective treatment for the acute pulmonary dysfunction they cause.

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Research paper thumbnail of Evaluation of cellular effects of silicon dioxide nanoparticles

Toxicology Mechanisms and Methods, 2014

Silica nanoparticles (nSiO2s) are an important type of manufactured nanoparticles. Although there... more Silica nanoparticles (nSiO2s) are an important type of manufactured nanoparticles. Although there are some reports about the cytotoxicity of nSiO2, the association between physical and chemical properties of nSiO2s and their cellular effects is still unclear. In this study, we examined the correlation between the physiochemical properties and cellular effects of three kinds of amorphous nSiO2s; sub-micro-scale amorphous SiO2, and micro-scale amorphous and crystalline SiO2 particles. The SiO2 particles were dispersed in culture medium and applied to HaCaT human keratinocytes and A549 human lung carcinoma cells. nSiO2s showed stronger protein adsorption than larger SiO2 particles. Moreover, the cellular effects of SiO2 particles were independent of the particle size and crystalline phase. The extent of cell membrane damage and intracellular ROS levels were different among nSiO2s. Upon exposure to nSiO2s, some cells released lactate dehydrogenase (LDH), whereas another nSiO2 did not induce LDH release. nSiO2s caused a slight increase in intracellular ROS levels. These cellular effects were independent of the specific surface area and primary particle size of the nSiO2s. Additionally, association of solubility and protein adsorption ability of nSiO2 to its cellular effects seemed to be small. Taken together, our data suggest that nSiO2s do not exert potent cytotoxic effects on cells in culture, especially compared to the effects of micro-scale SiO2 particles. Further studies are needed to address the role of surface properties of nSiO2s on cellular processes and cytotoxicity.

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Research paper thumbnail of Effects of ultrafine TiO2 particles on gene expression profile in human keratinocytes without illumination: Involvement of extracellular matrix and cell adhesion

Toxicology Letters, 2009

Assessing in vitro cellular responses to molecular events is an effective mean to elucidate the t... more Assessing in vitro cellular responses to molecular events is an effective mean to elucidate the toxicological behavior of the ultrafine nanoparticles. In this study, we utilized the DNA microarray analysis technique to determine the gene expression profiles of the human keratinocyte HaCaT cells exposed to anatase titanium dioxide (TiO(2)) particles of different (7 nm, 20 nm and 200 nm) average diameters without illumination. Cells were incubated for 24 h with TiO(2) particles, which were dispersed in the culture medium and size-fractionated such that the concentration of titanium in all the fractionated samples was nearly equivalent. According to the cluster analysis, only genes involved in the 'inflammatory response' and 'cell adhesion', but not the genes involved in 'oxidative stress' and 'apoptosis', were over-represented among the genes that were up-regulated in HaCaT cells. After 24 h exposure to ultrafine 7 nm TiO(2) particles, we observed altered expression levels of genes involved in matrix metalloproteinase activity (MMP-9 and MMP-10) and cell adhesion (fibronectin FN-1, integrin ITGB-6, and mucin MUC-4). These results suggest that the ultrafine TiO(2) particles without illumination have no significant impact on ROS-associated oxidative damage, but affect the cell-matrix adhesion in keratinocytes for extracellular matrix remodeling.

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Research paper thumbnail of Cellular responses by stable and uniform ultrafine titanium dioxide particles in culture-medium dispersions when secondary particle size was 100nm or less

Toxicology in Vitro, 2010

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Research paper thumbnail of Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species

Toxicology, 2005

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Research paper thumbnail of Elevation of oxidized DJ-1 in the brain and erythrocytes of Parkinson disease model animals

Neuroscience Letters, 2010

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Research paper thumbnail of Evaluation of cellular influences of platinum nanoparticles by stable medium dispersion

Metallomics, 2011

Platinum nanoparticles have industrial application, for example in catalysis, and are used in con... more Platinum nanoparticles have industrial application, for example in catalysis, and are used in consumer products such as cosmetics and supplements. Therefore, among the many nanoparticles, platinum is one of the more accessible nanoparticles for consumers. Most platinum nanoparticles that are used in cosmetics and supplements which have an anti-oxidant activity are modified particles. However, the cellular influences of pristine platinum nanoparticles are still unclear, although it has been reported that platinum nanoparticles induce oxidative stress. In this study, we investigated the cellular influences induced by pure pristine platinum nanoparticles. Platinum nanoparticles of 100% purity were dispersed in a cell culture medium and stable medium dispersion was obtained. The platinum nanoparticle medium dispersion was applied to two kinds of cultured cells, A549 and HaCaT cells, and the cellular influences were examined. Cell viability (MTT assay), cell proliferation (clonogenic assay), apoptosis induction (caspase-3 activity), intracellular ROS level (DCFH assay), and lipid peroxidation level (DPPP assay) were measured as markers of cellular influences. Transmission electron microscope observation showed cellular uptake of platinum nanoparticles. However, the platinum nanoparticles did not drive any markers. It is known that some metal oxide nanoparticles such as NiO and CuO show severe cytotoxicity via metal ion release. Compared with these toxic nanoparticles, the platinum nanoparticles used in this study did not release platinum ions into the culture media. These results suggest that the physically and chemically inactive cellular influences of platinum nanoparticles are small.

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Research paper thumbnail of Association of the physical and chemical properties and the cytotoxicity of metal oxide nanoparticles: metal ion release, adsorption ability and specific surface area

Metallomics, 2012

Association of cellular influences and physical and chemical properties were examined for 24 kind... more Association of cellular influences and physical and chemical properties were examined for 24 kinds of industrial metal oxide nanoparticles: ZnO, CuO, NiO, Sb(2)O(3), CoO, MoO(3), Y(2)O(3), MgO, Gd(2)O(3), SnO(2), WO(3), ZrO(2), Fe(2)O(3), TiO(2), CeO(2), Al(2)O(3), Bi(2)O(3), La(2)O(3), ITO, and cobalt blue pigments. We prepared a stable medium dispersion for each nanoparticle and examined the influence on cell viability and oxidative stress together with physical and chemical characterizations. ZnO, CuO, NiO, MgO, and WO(3) showed a large amount of metal ion release in the culture medium. The cellular influences of these soluble nanoparticles were larger than insoluble nanoparticles. TiO(2), SnO(2), and CeO(2) nanoparticles showed strong protein adsorption ability; however, cellular influences of these nanoparticles were small. The primary particle size and the specific surface area seemed unrelated to cellular influences. Cellular influences of metal oxide nanoparticles depended on the kind and concentrations of released metals in the solution. For insoluble nanoparticles, the adsorption property was involved in cellular influences. The primary particle size and specific surface area of metal oxide nanoparticles did not affect directly cellular influences. In conclusion the most important cytotoxic factor of metal oxide nanoparticles was metal ion release.

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Research paper thumbnail of Extracellular matrix family proteins that are potential targets of Dd-STATa in Dictyostelium discoideum

Journal of Plant Research, 2004

Dd-STATa is a functional Dictyostelium homologue of metazoan STAT (signal transducers and activat... more Dd-STATa is a functional Dictyostelium homologue of metazoan STAT (signal transducers and activators of transcription) proteins, which is activated by cAMP and is thereby translocated into the nuclei of anterior tip cells of the prestalk region of the slug. By using in situ hybridization analyses, we found that the SLF308 cDNA clone, which contains the ecmF gene that encodes a putative extracellular matrix protein and is expressed in the anterior tip cells, was greatly down-regulated in the Dd-STATa-null mutant. Disruption of the ecmF gene, however, resulted in almost no phenotypic change. The absence of any obvious mutant phenotype in the ecmF-null mutant could be due to a redundancy of similar genes. In fact, a search of the Dictyostelium whole genome database demonstrates the existence of an additional 16 homologues, all of which contain a cellulose-binding module. Among these homologues, four genes show Dd-STATa-dependent expression, while the others are Dd-STATa-independent. We discuss the potential role of Dd-STATa in morphogenesis via its effect on the interaction between cellulose and these extracellular matrix family proteins.

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