Faculty Profiles - NAKAMURA Yoshimasa

Papers - NAKAMURA Yoshimasa

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Cycloartenyl Ferulate from Rice as a Biologically Active Antioxidant Invited Reviewed

NAKAMURA Yoshimasa

Oleoscience 25 ( 5 ) 199 - 204 2025

Authorship：Lead author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Oil Chemists' Society

Rice serves as an excellent source of antioxidants such as vitamin Es, ferulic acid, and γ-oryzanols as well as starch. Since these antioxidants are abundant in the rice bran layer and germ parts, it has been considered that brown rice is more physiologically active than white rice. However, it remains unclear how much the chemical or biological antioxidant activity of brown rice differs from that of white rice in terms of quality and quantity. Our research group has shown that, at the level of extracts, white rice exhibits chemical or biological antioxidant activity comparable to that of brown rice. In addition, the contribution of cycloartenyl ferulate (CAF), a major molecular species of γ-oryzanols, to the biological antioxidant activity of rice was found to be much greater than that of vitamin Es. Based on these results, this review highlights the potential of CAF for health functions based on their antioxidant properties.

DOI： 10.5650/oleoscience.25.199

Quercetin Attenuates Acetaldehyde-Induced Cytotoxicity via the Heme Oxygenase-1-Dependent Antioxidant Mechanism in Hepatocytes Invited Reviewed International journal

Kexin Li, Minori Kidawara, Qiguang Chen, Shintaro Munemasa, Yoshiyuki Murata, Toshiyuki Nakamura, Yoshimasa Nakamura

International Journal of Molecular Sciences 25 ( 16 ) 2024.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

It is still unclear whether or how quercetin influences the toxic events induced by acetaldehyde in hepatocytes, though quercetin has been reported to mitigate alcohol-induced mouse liver injury. In this study, we evaluated the modulating effect of quercetin on the cytotoxicity induced by acetaldehyde in mouse hepatoma Hepa1c1c7 cells, the frequently used cellular hepatocyte model. The pretreatment with quercetin significantly inhibited the cytotoxicity induced by acetaldehyde. The treatment with quercetin itself had an ability to enhance the total ALDH activity, as well as the ALDH1A1 and ALDH3A1 gene expressions. The acetaldehyde treatment significantly enhanced the intracellular reactive oxygen species (ROS) level, whereas the quercetin pretreatment dose-dependently inhibited it. Accordingly, the treatment with quercetin itself significantly up-regulated the representative intracellular antioxidant-related gene expressions, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase, catalytic subunit (GCLC), and cystine/glutamate exchanger (xCT), that coincided with the enhancement of the total intracellular glutathione (GSH) level. Tin protoporphyrin IX (SNPP), a typical HO-1 inhibitor, restored the quercetin-induced reduction in the intracellular ROS level, whereas buthionine sulphoximine, a representative GSH biosynthesis inhibitor, did not. SNPP also cancelled the quercetin-induced cytoprotection against acetaldehyde. These results suggest that the low-molecular-weight antioxidants produced by the HO-1 enzymatic reaction are mainly attributable to quercetin-induced cytoprotection.

DOI： 10.3390/ijms25169038

Evaluation of quercetin as a potential cytoprotector against acetaldehyde using the cultured hepatocyte model with aldehyde dehydrogenase isozyme deficiency. Reviewed International journal

Yuhang Xu, Takeshi Sawamoto, Ruitong Sun, Aki Ishikura, Shintaro Munemasa, Yoshiyuki Murata, Ayano Satoh, Akiko Matsumoto, Toshiyuki Nakamura, Yoshimasa Nakamura

Bioscience, biotechnology, and biochemistry 2024.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Protective effect of quercetin against acetaldehyde was evaluated using the cultured hepatocyte models with aldehyde dehydrogenase (ALDH) isozyme deficiency (aldh2-kd and aldh1a1-kd). The quercetin-induced cytoprotection against acetaldehyde in the ALDH1A1-deficient mutant (aldh1a1-kd) was weaker than that in wild type. Furthermore, quercetin did not enhance the ALDH activity in aldh1a1-kd cells, suggesting that ALDH1A1 is involved in the quercetin-induced cytoprotection.

DOI： 10.1093/bbb/zbae100

Cycloartenyl Ferulate Is the Predominant Compound in Brown Rice Conferring Cytoprotective Potential against Oxidative Stress-Induced Cytotoxicity Invited Reviewed

Hongyan Wu, Toshiyuki Nakamura, Yingnan Guo, Riho Matsumoto, Shintaro Munemasa, Yoshiyuki Murata, Yoshimasa Nakamura

International Journal of Molecular Sciences 24 ( 1 ) 822 - 822 2023.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Since brown rice extract is a rich source of biologically active compounds, the present study is aimed to quantify the major compounds in brown rice and to compare their cytoprotective potential against oxidative stress. The content of the main hydrophobic compounds in brown rice followed the order of cycloartenyl ferulate (CAF) (89.00 ± 8.07 nmol/g) >> α-tocopherol (αT) (19.73 ± 2.28 nmol/g) > γ-tocotrienol (γT3) (18.24 ± 1.41 nmol/g) > α-tocotrienol (αT3) (16.02 ± 1.29 nmol/g) > γ-tocopherol (γT) (3.81 ± 0.40 nmol/g). However, the percent contribution of CAF to the radical scavenging activity of one gram of whole brown rice was similar to those of αT, αT3, and γT3 because of its weaker antioxidant activity. The CAF pretreatment displayed a significant cytoprotective effect on the hydrogen peroxide-induced cytotoxicity from 10 µM, which is lower than the minimal concentrations of αT and γT required for a significant protection. CAF also enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation coincided with the enhancement of the heme oxygenase-1 (HO-1) mRNA level. An HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly impaired the cytoprotection of CAF. The cytoprotective potential of CAF is attributable to its cycloartenyl moiety besides the ferulyl moiety. These results suggested that CAF is the predominant cytoprotector in brown rice against hydrogen peroxide-induced cytotoxicity.

DOI： 10.3390/ijms24010822

The microbiota catabolites of quercetin glycosides concertedly enhance the resistance against acetaldehyde-induced oxidative stress. Reviewed International journal

Kexin Li, Hongyan Wu, Minori Kidawara, Yun Lin, Ayano Satoh, Gongliang Zhang, Shintaro Munemasa, Yoshiyuki Murata, Toshiyuki Nakamura, Yoshimasa Nakamura

Free radical research 56 ( 9-10 ) 1 - 14 2022.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

3,4-Dihydroxyphenylacetic acid (DOPAC) and 3-hydroxyphenylacetic acid (OPAC) are the predominant catabolites of quercetin glycosides, such as quercetin 4'-O-β-glucoside from the onion, produced by intestinal microbiota. Although each catabolite has been reported to protect the cells from acetaldehyde-induced cytotoxicity, the effect of their combination remains to be clarified. The purpose of this study was to determine whether the combination of DOPAC and OPAC enhances the resistance against the acetaldehyde-induced oxidative stress in the cultured hepatocytes. The pretreatment of the combination of DOPAC (5 μM) and OPAC (5 μM) showed the significant protection against the acetaldehyde- and hydrogen peroxide-induced cytotoxicity, even though each compound at the same concentration did not. This combination also significantly inhibited the intracellular dichlorofluorescin diacetate-detectable reactive oxygen species (ROS) level, whereas the solo treatment did slightly, suggesting that reducing mechanisms of ROS or compounds that enhance ROS production are involved in the cytoprotective effect. The combinatory treatment significantly enhanced the gene expression of not only the aldehyde dehydrogenases (ALDHs), but also glutamate-cysteine ligase, catalytic subunit, the first rate-limiting enzyme of glutathione (GSH) synthesis. Accordingly, both the intracellular GSH level and the total ALDH activity were enhanced by DOPAC plus OPAC. Involvement of GSH in the cytoprotection as well as ALDH up-regulation by the combination were confirmed by the experiments using a GSH biosynthesis inhibitor, buthionine sulfoximine. Taken together, the present results suggested that the quercetin microbiota catabolites concertedly protect the cells from acetaldehyde through a pre-enhanced resistance against oxidative stress by the GSH-dependent up-regulation of ALDHs.

DOI： 10.1080/10715762.2022.2159820

Benzyl isothiocyanate and its metabolites inhibit cell proliferation through protein modification in mouse preosteoclast RAW264.7 cells. Reviewed International journal

Toshiyuki Nakamura, Chiharu Tsutsui, Yu Okuda, Naomi Abe-Kanoh, Saori Okazawa, Shintaro Munemasa, Yoshiyuki Murata, Yoji Kato, Yoshimasa Nakamura

Journal of biochemical and molecular toxicology e23184 2022.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Benzyl isothiocyanate (BITC), derived from cruciferous vegetables, is an organosulfur compound exerting antiproliferative effects in several human cancer cells. In this study, we assessed BITC as a potential osteoclastogenesis inhibitor and investigated its underlying mechanism. BITC at 5 μM significantly decreased the viability of the osteoclast-like differentiating RAW264.7 cells, coinciding with the downregulation of the primary biomarkers for osteoclast differentiation, such as the tartrate-resistant acid phosphatase activity and nuclear factor of activated T-cells gene expression. Not only BITC but also its metabolites, inhibited cell proliferation in the normal RAW264.7 cells, suggesting that BITC shows an anti-osteoclastogenesis effect in vivo after its ingestion and metabolism, possibly through an antiproliferative action. Both BITC and its metabolites also enhanced the DNA fragmentation and the caspase-3 activity, whereas their higher concentrations tended to suppress these effects. BITC was intracellularly accumulated when the cells were treated with its metabolites via their degradation into the free form. A quantitative experiment using the proteolysis/high performance liquid chromatography technique showed that the amount of BITC-lysine thiourea in the cells was also increased in a time-dependent manner, suggesting that lysine modification of the cellular proteins actually took place in the cells treated by BITC. Among the cellular proteins, the cleaved caspase-3 was identified as a potential target for lysine modification by BITC. Taken together, BITC dissociated from its metabolites as well as its free form might modulate osteoclastogenesis, possibly through inhibition of cell proliferation by protein modification.

DOI： 10.1002/jbt.23184

A Major Intestinal Catabolite of Quercetin Glycosides, 3-Hydroxyphenylacetic Acid, Protects the Hepatocytes from the Acetaldehyde-Induced Cytotoxicity through the Enhancement of the Total Aldehyde Dehydrogenase Activity Invited Reviewed International journal

Yujia Liu, Takumi Myojin, Kexin Li, Ayuki Kurita, Masayuki Seto, Ayano Motoyama, Xiaoyang Liu, Ayano SATOH, Shintaro Munemasa, Yoshiyuki Murata, Toshiyuki Nakamura, Yoshimasa Nakamura

International Journal of Molecular Sciences 23 ( 3 ) 2022.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aldehyde dehydrogenases (ALDHs) are the major enzyme superfamily for the aldehyde metabolism. Since the ALDH polymorphism leads to the accumulation of acetaldehyde, we considered that the enhancement of the liver ALDH activity by certain food ingredients could help prevent alcohol-induced chronic diseases. Here, we evaluated the modulating effects of 3-hydroxyphenylacetic acid (OPAC), the major metabolite of quercetin glycosides, on the ALDH activity and acetaldehyde-induced cytotoxicity in the cultured cell models. OPAC significantly enhanced the total ALDH activity not only in mouse hepatoma Hepa1c1c7 cells, but also in human hepatoma HepG2 cells. OPAC significantly increased not only the nuclear level of aryl hydrocarbon receptor (AhR), but also the AhR-dependent reporter gene expression, though not the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent one. The pretreatment of OPAC at the concentration required for the ALDH upregulation completely inhibited the acetaldehyde-induced cytotoxicity. Silencing AhR impaired the resistant effect of OPAC against acetaldehyde. These results strongly suggested that OPAC protects the cells from the acetaldehyde-induced cytotoxicity, mainly through the AhR-dependent and Nrf2-independent enhancement of the total ALDH activity. Our findings suggest that OPAC has a protective potential in hepatocyte models and could offer a new preventive possibility of quercetin glycosides for targeting alcohol-induced chronic diseases.

DOI： 10.3390/ijms23031762

Characterization of benzyl isothiocyanate extracted from mashed green papaya by distillation. Reviewed International journal

Nakamura T, Murata Y, Nakamura Y

Food chemistry 299 125118 - 125118 2019.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The aim of this study was to extract benzyl isothiocyanate (BITC) from green papaya by distillation apparatus without using organic solvents, and to improve the stability of BITC in aqueous solution. The distillation of mashed green papaya successfully yielded BITC as a water solution with more than 80% purity with good reproducibility. The amount of BITC in the distilled water gradually decreased during its storage at 4 °C, whereas it was not significantly changed at -20 °C for a few months. Moreover, the addition of l-cysteine ameliorated the BITC decomposition by the 4 °C-storage, but not affected by N-acetyl-cysteine and glutathione. These results suggested that the combination of BITC extraction by distillation and cysteine supplementation as well as frozen storage might be a useful method for the preparation and storage of the safer grade of BITC-containing extract.

DOI： 10.1016/j.foodchem.2019.125118

Yeast screening system reveals the inhibitory mechanism of cancer cell proliferation by benzyl isothiocyanate through down-regulation of Mis12. Reviewed International journal

Naomi Abe-Kanoh, Narumi Kunisue, Takumi Myojin, Ayako Chino, Shintaro Munemasa, Yoshiyuki Murata, Ayano Satoh, Hisao Moriya, Yoshimasa Nakamura

Scientific reports 9 ( 1 ) 8866 - 8866 2019.6

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Benzyl isothiocyanate (BITC) is a naturally-occurring isothiocyanate derived from cruciferous vegetables. BITC has been reported to inhibit the proliferation of various cancer cells, which is believed to be important for the inhibition of tumorigenesis. However, the detailed mechanisms of action remain unclear. In this study, we employed a budding yeast Saccharomyces cerevisiae as a model organism for screening. Twelve genes including MTW1 were identified as the overexpression suppressors for the antiproliferative effect of BITC using the genome-wide multi-copy plasmid collection for S. cerevisiae. Overexpression of the kinetochore protein Mtw1 counteracts the antiproliferative effect of BITC in yeast. The inhibitory effect of BITC on the proliferation of human colon cancer HCT-116 cells was consistently suppressed by the overexpression of Mis12, a human orthologue of Mtw1, and enhanced by the knockdown of Mis12. We also found that BITC increased the phosphorylated and ubiquitinated Mis12 level with consequent reduction of Mis12, suggesting that BITC degrades Mis12 through an ubiquitin-proteasome system. Furthermore, cell cycle analysis showed that the change in the Mis12 level affected the cell cycle distribution and the sensitivity to the BITC-induced apoptosis. These results provide evidence that BITC suppresses cell proliferation through the post-transcriptional regulation of the kinetochore protein Mis12.

DOI： 10.1038/s41598-019-45248-2

Physiological relevance of covalent protein modification by dietary isothiocyanates Reviewed

Toshiyuki Nakamura, Naomi AbeKanoh, Yoshimasa Nakamura

Journal of Clinical Biochemistry and Nutrition 62 ( 1 ) 11 - 19 2018.1

Authorship：Last author,　Corresponding author Language：English Publisher：The Society for Free Radical Research Japan

Isothiocyanates (ITCs), naturally occurring in abundance in crucif erous vegetables, are the most wellstudied organosulfur com pounds having an electrophilic reactivity. ITCs have been accepted as major ingredients of these vegetables that afford their health promoting potentials. ITCs are able to modulate protein functions related to drugmetabolizing enzymes, transporters, kinases and phosphatases, etc. One of the most important questions about the molecular basis for the health promoting effects of ITCs is how they modulate cellular target proteins. Although the molec ular targets of ITCs remains to be validated, dietary modulation of the target proteins via covalent modification by ITCs should be one of the promising strategies for the protection of cells against oxidative and inflammatory damage. This review discusses the plausible target proteins of dietary ITCs with an emphasis on pos sible involvement of protein modification in their health promot ing effects. The fundamental knowledge of ITCs is also included with consideration of the chemistry, intracellular behavior, and metabolism.

DOI： 10.3164/jcbn.17-91

Flavonoid metabolism: the interaction of metabolites and gut microbiota Reviewed

Kaeko Murota, Yoshimasa Nakamura, Mariko Uehara

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 82 ( 4 ) 600 - 610 2018

Authorship：Lead author Language：English Publisher：TAYLOR & FRANCIS LTD

Several dietary flavonoids exhibit anti-oxidative, anti-inflammatory, and anti-osteoporotic activities relevant to prevention of chronic diseases, including lifestyle-related diseases. Dietary flavonoids (glycoside forms) are enzymatically hydrolyzed and absorbed in the intestine, and are conjugated to their glucuronide/sulfate forms by phase II enzymes in epithelial cells and the liver. The intestinal microbiota plays an important role in the metabolism of flavonoids found in foods. Some specific products of bacterial transformation, such as ring-fission products and reduced metabolites, exhibit enhanced properties. Studies on the metabolism of flavonoids by the intestinal microbiota are crucial for understanding the role of these compounds and their impact on our health. This review focused on the metabolic pathways, bioavailability, and physiological role of flavonoids, especially metabolites of quercetin and isoflavone produced by the intestinal microbiota.

DOI： 10.1080/09168451.2018.1444467

Benzyl isothiocyanate ameliorates acetaldehyde-induced cytotoxicity by enhancing aldehyde dehydrogenase activity in murine hepatoma Hepa1c1c7 cells Reviewed

Yujia Liu, Momoko Yamanaka, Naomi Abe-Kanoh, Xiaoyang Liu, Beiwei Zhu, Shintaro Munemasa, Toshiyuki Nakamura, Yoshiyuki Murata, Yoshimasa Nakamura

FOOD AND CHEMICAL TOXICOLOGY 108 305 - 313 2017.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

In the present study, we assessed benzyl isothiocyanate (BITC), an organosulfur compound from cruciferous vegetables, as a potential inducer of aldehyde dehydrogenase (ALDH) activity using murine hepatoma Hepa1c1c7 cells. BITC was shown to enhance not only the total ALDH activity, but also the ALDH activity of the cytosolic/microsomal and mitochondrial fraction. BITC also significantly increased the gene and protein expression of ALDH1A1, ALDH2 and ALDH3A1 in a concentration-dependent manner. Simultaneously, the gene expression of phase 2 drug-metabolizing enzymes, such as NAD(P)H: quinone oxidoreductase 1 and heme oxygenase-1, was increased by the BITC treatment. Western blot experiments revealed that BITC not only up-regulated the Nrf2 protein expression, but also stimulated the nuclear translocation of Nrf2. Furthermore, silencing Nrf2 reduced the basal and BITC-enhanced levels of the total activity and gene expression of ALDHs. The pretreatment of BITC completely mitigated the acetaldehyde-induced cytotoxicity, which was impaired by silencing Nrf2. The present study demonstrated that BITC has been identified as a potential inducer of the total ALDH activity to prevent the acetaldehyde-induced cytotoxicity. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.fct.2017.08.016

3,4-Dihydroxyphenylacetic acid is a predominant biologically-active catabolite of quercetin glycosides Reviewed

Yue Tang, Sayaka Nakashima, Shunya Saiki, Yui Myoi, Naomi Abe, Shoko Kuwazuru, Beiwei Zhu, Hitoshi Ashida, Yoshiyuki Murata, Yoshimasa Nakamura

FOOD RESEARCH INTERNATIONAL 89 716 - 723 2016.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Since dietary flavonoid glycosides, including quercetin 4'-glucoside from onion, are poorly absorbed from the gastrointestinal tract, they are converted into smaller phenolic acids, which can be absorbed into the circulation. The purpose of this study was to compare the effects of the major phenolic acid catabolites of quercetin 4'-glucoside, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-hydroxyphenylacetic acid, 3,4-dihydroxybenzoic acid (protocatechuic acid) and hippuric acid, on the antioxidant activity and phase II cytoprotective enzyme induction in vitro. Both DOPAC and protocatechuic acid, having a catechol moiety, exhibited both DPPH radical scavenging and superoxide dismutase-like activities, whereas 3-hydroxyphenyl acetic acid and hippuric acid did not. DOPAC also more potently enhanced the gene expression of several phase II drug-metabolizing enzymes than the other phenolic acid catabolites. DOPAC significantly inhibited the hydrogen peroxide-induced cytotoxicity in hepatocytes with the enhancement of the total glutathione S-transferase activity. In conclusion, DOPAC may play a key role in the antioxidative potential of the colonic lumen after the ingestion of the quercetin glycoside-rich onion. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.foodres.2016.09.034

Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells Reviewed

N. Abe, D-X Hou, S. Munemasa, Y. Murata, Y. Nakamura

CELL DEATH & DISEASE 5 2014.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Benzyl isothiocyanate (BITC), a dietary isothiocyanate derived from cruciferous vegetables, inhibits the proliferation of colorectal cancer cells, most of which overexpress beta-catenin as a result of mutations in the genes for adenomatous polyposis coli or mutations in beta-catenin itself. Because nuclear factor-kappa B (NF-kappa B) is a plausible target of BITC signaling in inflammatory cell models, we hypothesized that it is also involved in BITC-inhibited proliferation of colorectal cancer cells. siRNA-mediated knockdown of the NF-kappa B p65 subunit significantly decreased the BITC sensitivity of human colorectal cancer HT-29 cells with mutated p53 tumor suppressor protein. Treating HT-29 cells with BITC induced the phosphorylation of I kappa B kinase, I kappa B-alpha and p65, the degradation of I kappa B-a, the translocation of p65 to the nucleus and the upregulation of NF-kappa B transcriptional activity. BITC also decreased alpha-catenin binding to a positive cis element of the cyclin D1 promoter and thus inhibited beta-catenin-dependent cyclin D1 transcription, possibly through a direct interaction between p65 and alpha-catenin. siRNA-mediated knockdown of p65 confirmed that p65 negatively affects cyclin D1 expression. On the other hand, when human colorectal cancer HCT-116 cells with wild-type p53 were treated with BITC, translocation of p65 to the nucleus was inhibited rather than enhanced. p53 knockout increased the BITC sensitivity of HCT-116 cells in a p65-dependent manner, suggesting that p53 negatively regulates p65-dependent effects. Together, these results identify BITC as a novel type of antiproliferative agent that regulates the NF-kappa B pathway in p53-deficient colorectal cancer cells.

DOI： 10.1038/cddis.2014.495

Electrophiles in Foods: The Current Status of Isothiocyanates and Their Chemical Biology Invited Reviewed

Yoshimasa Nakamura, Noriyuki Miyoshi

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 74 ( 2 ) 242 - 255 2010.2

Authorship：Lead author,　Corresponding author Language：English Publisher：TAYLOR & FRANCIS LTD

Unlike many classical signals and hormones, exposure of the cells to electrophilic molecules potentially induces a series of characteristic and wide-ranging biological responses by covalently attaching with macromolecules such as proteins as well as small cellular reductants. In addition to chemicals originated from xenobiotics or lipid peroxidation, electrophiles in foods have recently attracted much attention. These compounds have recently been found to induce expression of cytoprotective proteins that are involved in the elimination or inactivation of oxidative stress and carcinogenic electrophiles implicated in several pathogeneses. The redox-sensitive regulating systems such as Keap1/Nrf2/ARE play a key role in this induction and thus are considered to be the most important target of electrophiles in foods. This review highlights the food-derived electrophiles as promising protectors against various diseases, with an emphasis on possible molecular mechanisms. Current knowledge of isothiocyanates (ITCs), representative electrophile compounds from cruciferous vegetables, is discussed also, with consideration of the chemistry, metabolism, absorption, and factors influencing the biological activities of ITCs. In addition, this review attempts to provide a balanced perspective on the relative beneficial and harmful effects of the food electrophiles.

DOI： 10.1271/bbb.90731

JNK-dependent NFATc1 pathway positively regulates IL-13 gene expression induced by (-)-epigallocatechin-3-gallate in human basophilic KU812 cells Reviewed

Haitao Wu, Hang Qi, Dai Iwasaki, Beiwei Zhu, Yasuaki Shimoishi, Yoshiyuki Murata, Yoshimasa Nakamura

FREE RADICAL BIOLOGY AND MEDICINE 47 ( 7 ) 1028 - 1038 2009.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

(-)-Epigallocatechin-3-gallate (EGCG) has been reported to possess a wide range of biological and pharmacological properties. In this study, we investigated the effects of EGCG on IL-13 gene expression in human basophilic KU812 cells. The IL-13 mRNA expression level was dose-dependently increased by treatment with EGCG (5-20 mu M) for 1 h and additional incubation in a medium for 23 h. EGCG significantly increased the intracellular peroxide level as detected by the peroxide-sensitive probe 2',7'-dichlorodihydro-fluorescein diacetate. A pharmacological experiment using catalase and a structure-activity relationship study revealed that the exogenously produced H(2)O(2) significantly, but partially, contributed to the IL-13 expression as well as the intracellular oxidative status. Furthermore, EGCG at the concentration required for IL-13 up-regulation activated c-Jun NH(2)-terminal kinase (JNK), but not extracellular signal-regulated protein kinase or p38 mitogen-activated protein kinase in KU812 cells. Transfection of a JNK-specific siRNA as well as treatment with a JNK-specific inhibitor, SP600125, significantly reduced the EGCG-induced IL-13 mRNA expression, by 47.1 and 44.6%, respectively. In addition, we observed the nuclear translocation, mRNA up-regulation, and activation of DNA binding with the IL-13 promoter of nuclear factor of activated T cells (NFATc1) in the EGCG-treated cells. These data provide biological evidence that EGCG induces IL-13 mRNA expression via the JNK-dependent NFATc1 pathway in KU812 cells. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2009.07.011

Docosahexaenoic acid induces ERK1/2 activation and neuritogenesis via intracellular reactive oxygen species production in human neuroblastoma SH-SY5Y cells Reviewed

Haitao Wu, Sanae Ichikawa, Chiharu Tani, Beiwei Zhu, Mikiro Tada, Yasuaki Shimoishi, Yoshiyuki Murata, Yoshimasa Nakamura

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS 1791 ( 1 ) 8 - 16 2009.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Docosahexaenoic acid (22: 6n-3: DHA) is a long chain polyunsaturated fatty acid that exists highly enriched in fish oil, and it is one of the low molecular weight food chemicals which can pass a blood brain barrier. A preliminary survey of several fatty acids for expression of growth-associated protein-43 (GAP-43), a marker of axonal growth, identified DHA as one of the most potent inducers. The human neuroblastoma SH-SY5Y cells exposed to DHA showed significant and dose-dependent increases in the percentage of cells with longer neurites. To elucidate signaling mechanisms involved in DHA-enhanced basal neuritogenesis, we examined the role of extracellular signal-regulated kinase (ERK)1/2 and intracellular reactive oxygen species (ROS) production using SH-SY5Y cells. From immunoblotting experiments, we observed that DHA induced the ROS production, protein tyrosine phosphatase inhibition, mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) phosphorylation, and sequentially ERK1/2 phosphorylation, the last of which was significantly reduced by MEK inhibitor U0126. Both antioxidants and MEK inhibitor affected DHA-induced GAP-43 expression, whereas the specific PI3K inhibitor LY294002 did not. We found that total protein tyrosine phosphatase activity was also downregulated by DHA treatment. which was counteracted by antioxidant pretreatment. These results suggest that the ROS-dependent ERK pathway, rather than PI3K, plays an important role during DHA-enhanced neurite outgrowth. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbalip.2008.10.004

ATP depletion alters the mode of cell death induced by benzyl isothiocyanate Reviewed

Noriyuki Miyoshi, Etsuko Watanabe, Toshihiko Osawa, Masashi Okuhira, Yoshiyuki Murata, Hiroshi Ohshima, Yoshimasa Nakamura

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1782 ( 10 ) 566 - 573 2008.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Pro-inflammatory death is presumably an undesirable event in cancer prevention process, thus biochemical comprehension and molecular definition of this process could have important clinical implications. In the present study, we examined the cytophysiological conversion of cell death mode by benzyl isothiocyanate (BITC) in human cervical cancer HeLa cells. The detailed studies using flow cytometric and morphological analyses demonstrated that the cells treated with appropriate concentration (25 mu M) of BITC showed apoptotic feature, such as chromatin condensation, DNA fragmentation, and preserved plasma membrane integrity, whereas these features were disappeared by treatment with higher concentration (100 mu M). The treatment with 2-deoxyglucose, an inhibitor of ATP synthesis, drastically increased in the ratio of necrotic dead cells, while it influences little that of apoptotic cells. Moreover, an analysis using the mitochondrial DNA-deficient HeLa cells demonstrated that the rho degrees cells were more susceptible to the BITC-induced necrosis-like cell death compared to the wild-type (rho(+)) cells, whereas the ROS production was significantly inhibited in the rho degrees cells. It is likely that the BITC-induced ROS is derived from mitochondrial respiratory chain and ruled out the contribution to the mechanism of cell death mode switching. In addition, the BITC treatment resulted in a more rapid depletion of ATP in the rho degrees cells than in the rho(+) cells. Furthermore. a caspase inhibitor, Z-VAD-fmk counteracted not only apoptosis, but also necrosis-like cell death induced by BITC, suggesting that increment in this cell death pattern might be due to the interruption of events downstream of a caspase-dependent pathway. The obtained data suggested that the decline in the intracellular ATP level plays an important role in tuning the mode of cell death by BITC. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbadis.2008.07.002

Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy Invited Reviewed

Masuko Ushio-Fukai, Yoshimasa Nakamura

CANCER LETTERS 266 ( 1 ) 37 - 52 2008.7

Authorship：Last author Language：English Publisher：ELSEVIER IRELAND LTD

Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H(2)O(2) are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22(phox), p47 (phox) and the small G-protein Rac1. NADPH oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2008.02.044

Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells Reviewed

Yoshimasa Nakamura, Nikolay Patrushev, Hyoe Inomata, Dolly Mehta, Norifumi Urao, Ha Won Kim, Masooma Razvi, Vidisha Kini, Kalyankar Mahadev, Barry J. Goldstein, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai

CIRCULATION RESEARCH 102 ( 10 ) 1182 - 1191 2008.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR) 2 in tyrosine, which is followed by disruption of VE-cadherin-mediated cell-cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin-mediated cell-cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell-cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo.

DOI： 10.1161/CIRCRESAHA.107.167080

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