Hiroshi Nishioka

Kyorin University, Edo, Tōkyō, Japan

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Publications (26)50.82 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to evaluate the effects of active hexose correlated compound intake on the immune competence in healthy volunteers. Thirty-four subjects were randomized to receive placebo or active hexose correlated compound at 1.0 g/d for 4 weeks in early winter. Natural killer cell activity was significantly increased in both groups during the study period, the natural killer cell number, however, was not altered in the active hexose correlated compound group while placebo group showed remarkable decline. In addition, the score of immunological vigor, an index of total immune competence, was maintained in the active hexose correlated compound group although that of placebo group lowered during the test period. These results suggested that the continuous active hexose correlated compound intake maintained the immune competence against the seasonal change.
    11/2014; 20(1). DOI:10.1177/2156587214555573
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    ABSTRACT: A novel enzyme-treated asparagus extract (ETAS) has been developed as a functional material produced from asparagus stem. Studies were conducted to determine the effect of ETAS on heat shock protein 70 (HSP70) expression and alleviation of stress. HeLa cells were treated with ETAS, and HSP70 mRNA and protein levels were measured using a reverse transcription-polymerase chain reaction (RT-PCR) assay and an enzyme-linked immunosorbent assay (ELISA), respectively. ETAS showed significant increases in HSP70 mRNA at more than 0.125 mg/mL and the protein at more than 1.0 mg/mL. The antistress effect was evaluated in a murine sleep-deprivation model. A sleep-deprivation stress load resulted in elevation of blood corticosterone and lipid peroxide concentrations, while supplementation with ETAS at 200 and 1000 mg/kg body weight was associated with significantly reduced levels of both stress markers, which were in the normal range. The HSP70 protein expression level in mice subjected to sleep-deprivation stress and supplemented with ETAS was significantly enhanced in stomach, liver, and kidney, compared to ETAS-untreated mice. A preliminary and small-sized human study was conducted among healthy volunteers consuming up to 150 mg/d of ETAS daily for 7 d. The mRNA expression of HSP70 in peripheral leukocytes was significantly elevated at intakes of 100 or 150 mg/d, compared to their baseline levels. Since HSP70 is known to be a stress-related protein and its induction leads to cytoprotection, the present results suggest that ETAS might exert antistress effects under stressful conditions, resulting from enhancement of HSP70 expression.
    Journal of Food Science 02/2014; 79(3). DOI:10.1111/1750-3841.12371 · 1.79 Impact Factor
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    ABSTRACT: The safety of enzyme-treated asparagus extract (ETAS) developed as a novel anti-stress functional material was assessed in acute and subchronic studies and genotoxicity assays. In the acute oral dose toxicity study, all rats survived during the test period and ETAS did not influence clinical appearance, body weight gain and necropsy findings at a dosage of 2,000 mg/kg body weight. Thus, the 50% lethal dose (LD50) of ETAS was determined to be greater than 2,000 mg/kg. The 90-day subchronic study (500, 1,000 and 2,000 mg/kg body weight, delivered by gavage) in rats reported no significant adverse effects in food consumption, body weight, mortality, urinalysis, hematology, biochemistry, necropsy, organ weight and histopathology. In the micronucleus test of mice, the incidence of micronuclei in ETAS-administered groups (500, 1,000 and 2,000 mg/kg/day, injected twice) was equivalent to that of the negative control group, while the positive control group receiving mitomycin C showed a high incidence. The potential of ETAS to induce gene mutation was tested using four Salmonella typhimurium strains and Escherichia coli WP2uvrA. The test sample was not mutagenic to the test strains. These results support the safety of ETAS as food and dietary supplement.
    Regulatory Toxicology and Pharmacology 01/2014; 68(2). DOI:10.1016/j.yrtph.2013.12.011 · 2.14 Impact Factor
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    ABSTRACT: Enzyme-treated asparagus extract (ETAS) has been developed as a novel anti-stress functional food ingredient that is produced from asparagus. Two human intervention trials with ETAS were conducted in healthy adult male volunteers. Study 1 was a randomized, double-blind, placebo-controlled study to assess the effects of ETAS on expression of heat shock protein 70 (HSP70) mRNA in blood and the autonomic nervous system (ANS). The ETAS group showed a tendency to enhance HSP70 mRNA expression level compared to the placebo group. Several ANS condition parameters were significantly improved in the ETAS group when compared to the placebo group. In Study 2, a randomized, double-blind, placebo-controlled, crossover trial investigated the influence on stress-related hormones and sleep. Serum and salivary cortisol levels were significantly elevated compared to baseline during the placebo period, but remained unchanged during the ETAS period. The salivary chromogranin A level was significantly decreased in the ETAS-treated subjects compared to their baseline levels. The actual sleep time was not significantly different between ETAS and placebo. However, when the subjects were divided into two categories based on sleep efficiency or the average of night sleeping time, ETAS intake was effective to modulate the sleep state among those with low sleep efficiency or excess sleep time.
    Journal of Nutritional Science and Vitaminology 01/2014; 60(4):283-90. DOI:10.3177/jnsv.60.283 · 0.87 Impact Factor
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    ABSTRACT: A novel 5-hydroxymethyl-2-furfural (HMF; 1) derivative, which is named as asfural (compound 2), was isolated from enzyme-treated asparagus extract (ETAS) along with HMF (1) as a heat shock protein 70 (HSP70) inducible compound. The structure of compound 2 was elucidated on the basis of its spectroscopic data from HREIMS and NMR, while the absolute configuration was determined using chiral HPLC analysis, compared to two synthesized compounds, (S)- and (R)-asfural. As a result, compound 2 derived from ETAS was assigned as (S)-(2-formylfuran-5-yl)methyl 5-oxopyrrolidine-2-carboxylate. When compound 2, synthesized (S)- and (R)-asfural, and HMF (1) were evaluated in terms of HSP70 mRNA expression-enhancing activity in HL-60 cells, compound 2 and (S)-asfural significantly increased the expression level in a concentration dependent manner. HMF (1) also showed significant activity at 0.25 mg/mL.
    Journal of Agricultural and Food Chemistry 09/2013; 61(38). DOI:10.1021/jf402010c · 3.11 Impact Factor
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    ABSTRACT: Recently, the ability of polyphenols to reduce the risk of dementia and Alzheimer's disease (AD) has attracted a great deal of interest. In the present study, we investigated the attenuating effects of oligomerised lychee fruit-derived polyphenol (OLFP, also called Oligonol) on early cognitive impairment. Male senescence-accelerated mouse prone 8 (SAMP8) mice (4 months old) were given OLFP (100 mg/kg per d) for 2 months, and then conditioned fear memory testing was conducted. Contextual fear memory, which is considered hippocampus-dependent memory, was significantly impaired in SAMP8 mice compared with non-senescence-accelerated mice. OLFP attenuated cognitive impairment in SAMP8 mice. Moreover, the results of real-time PCR analysis that followed DNA array analysis in the hippocampus revealed that, compared with SAMP8 mice, the mRNA expression of Wolfram syndrome 1 (Wfs1) was significantly higher in SAMP8 mice administered with OLFP. Wfs1 reportedly helps to protect against endoplasmic reticulum (ER) stress, which is thought to be one of the causes for AD. The expression of Wfs1 was significantly up-regulated in NG108-15 neuronal cells by the treatment with OLFP, and the up-regulation was inhibited by the treatment of the cells with a c-Jun N-terminal kinase-specific inhibitor rather than with an extracellular signal-regulated kinase inhibitor. Moreover, OLFP significantly attenuated the tunicamycin-induced expression of the ER stress marker BiP (immunoglobulin heavy chain-binding protein) in the cells. These results suggest that OLFP has an attenuating effect on early cognitive impairment in SAMP8 mice, and diminishes ER stress in neuronal cells.
    The British journal of nutrition 03/2013; DOI:10.1017/S000711451300086X · 3.34 Impact Factor
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    ABSTRACT: The results obtained from our previous study showed that the addition of a lychee fruit-derived low molecular form of polyphenol, Oligonol, provoked higher levels of lipolytic activity via the degradation of perilipin 1 in primary rat adipocytes. In the current study, we investigated the possible mechanisms by which Oligonol could promote the degradation of perilipin 1 protein. The addition of Oligonol caused the degradation of GFP-tagged perilipin 1 in a time-dependent manner. Meanwhile, the co-addition of Oligonol and NH4CI, a lysosome inhibitor, failed to promote the degradation of perilipin 1, while the co-addition of Oligonol and MG132, a proteasome inhibitor, induced a reduction in the levels of perilipin 1. These results suggest that the Oligonol-induced degradation of perilipin 1 is regulated via a lysosome-dependent mechanism.
    Natural product communications 09/2012; 7(9):1193-6. · 0.92 Impact Factor
  • Daisuke Nakamoto · Kota Shigama · Hiroshi Nishioka · Hajime Fujii
    International Journal of Clinical Medicine 01/2012; 03(05):361-367. DOI:10.4236/ijcm.2012.35069
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    ABSTRACT: Oligonol is a lychee fruit-derived low-molecular form of polyphenol. In this study, the effect of Oligonol on the mitogen activated-protein kinase (MAPK) signaling pathway in primary adipocytes was investigated to examine the mechanism underlying the enhanced levels of phosphorylated extracellular-signaling regulatory kinase1/2 (ERK1/2) that accompany an in vitro increase in lipolysis. Oligonol significantly elevated the levels of activated Ras and the phosphorylation of Raf-1 and MAPK/ERK kinase1/2 (MEK1/2) with no increase in pan-Raf-1 and -MEK1/2 proteins. The increase in phosphorylation of Raf-1 and MEK1/2 with Oligonol was inhibited completely by pretreatment with GW5074, a selective Raf-1 inhibitor, or PD98059, a selective MEK1/2 inhibitor. IL-6 also activated the MAPK signaling pathway in adipocytes through the association with its receptor. IL-6-induced phosphorylation of Raf-1 and MEK1/2 was significantly inhibited by pretreatment with the IL-6 receptor antibody. Under such a condition, however, the levels of phosphorylated Raf-1 and MEK1/2 with Oligonol still remained significantly higher, and there was a significant decrease in secretion of IL-6 from adipocytes, compared with untreated control cells. These results suggest that Oligonol activates the Ras/Raf-1/MEK1/2 signaling pathway, independent of the IL-6 signaling pathway, leading to activation of ERK1/2 proteins in primary adipocytes.
    Biochemical and Biophysical Research Communications 10/2010; 402(3):554-9. DOI:10.1016/j.bbrc.2010.10.082 · 2.28 Impact Factor
  • Takehito Miura · Kentaro Kitadate · Hiroshi Nishioka · Koji Wakame
    Biotechnology in Functional Foods and Nutraceuticals, 04/2010: pages 51-60; , ISBN: 978-1-4200-8711-6
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    ABSTRACT: Hyperglycaemia is known to reduce nitric oxide (NO) bioavailability by modulating endothelial NO synthase (eNOS) activity, and polyphenols are believed to have cardiovascular benefit. One possible mechanism could be through interaction with eNOS. The effects of the oligomerized polyphenol oligonol on eNOS phosphorylation status and activity were examined in porcine aortic endothelial cells cultured in high glucose concentrations. Key results: Exposure to high glucose concentrations strongly inhibited eNOS phosphorylation at Ser-1177 and dephosphorylation at Thr-495 in bradykinin (BK)-stimulated cells. These inhibitory effects of high glucose were significantly prevented by treatment with oligonol. Akt and p38 mitogen-activated protein kinase (MAPK) were activated in BK-stimulated cells. High glucose inhibited Akt activation but enhanced p38 MAPK activation, both of which were reversed by oligonol treatment. The phosphatidylinositol 3-kinase inhibitor wortmannin blocked the reversal by oligonol of phosphorylation at Ser-1177, but not dephosphorylation at Thr-495, in BK-stimulated cells exposed to high glucose. The effect of oligonol on BK dephosphorylation under high glucose was mimicked by protein kinase C (PKC) epsilon-neutralizing peptides. These data suggest that the effects of oligonol on high glucose-induced attenuation of eNOS Ser-1177 phosphorylation and Thr-495 dephosphorylation may be regulated by Akt activation and PKCepsilon inhibition respectively. Oligonol also prevented high glucose-induced attenuation of BK-stimulated NO production. Oligonol prevented the impairment of eNOS activity induced by high glucose through reversing altered eNOS phosphorylation status. This mechanism may underlie the beneficial cardiovascular health effects of this oligomerized polyphenol.
    British Journal of Pharmacology 02/2010; 159(4):928-38. DOI:10.1111/j.1476-5381.2009.00594.x · 4.99 Impact Factor
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    ABSTRACT: Several polyphenols have been shown to be beneficial in preventing the accumulation of body fat in mammals. This paper reports that adding oligonol, a lychee fruit-derived low-molecular form of polyphenol mixture, has a greater effect on lipolysis in primary adipocytes compared with tea (-)-epigallocatechin-3-gallate (EGCG) alone, accompanied by a significant increase in activation of extracellular signalling-related kinase 1/2 (ERK1/2). However, neither phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), a molecule upstream of ERK1/2, nor the level of heme oxygenase-1 (HO-1), a molecule downstream of ERK1/2 was significantly changed between oligonol and EGCG, although the addition of oligonol and EGCG significantly increased the levels of phosphorylated MEK1/2 and HO-1 compared with the non-treated control cells. These results suggest that the coordinated direct effect of mixed polyphenol, which comprises oligonol, on ERK1/2 plays a key role in a greater lipolytic response to oligonol than EGCG alone.
    Phytotherapy Research 01/2010; 25(3):467-71. DOI:10.1002/ptr.3296 · 2.40 Impact Factor
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    ABSTRACT: Many polyphenolic compounds are poorly digested, and have low bioavailability due to their long chain lengths and chemical composition. A processed, flavanol-rich lychee fruit extract (FRLFE) that is higher in flavanol monomers, dimer and trimers than its unprocessed counterpart, was tested in a variety of models. First, mature visceral adipocytes were treated with 0, 3, 10 or 30 microg/mL FRLFE (day 6-8). Compared with the controls, the treated cells had lower triglyceride concentrations, less lipid accumulation and a smaller lipid droplet size. Adiponectin release was significantly greater in cells receiving 3 or 10 microg/mL FRLFE than in the controls. Second, rats given a single dose of 50 or 100 mg/kg FRLFE had significant increases in plasma (-)-epicatechin, 3'-O-methyl-(-)-epicatechin, and (+)-catechin levels, peak values were at approximately 2 h and appreciable concentrations were still detected at 6 h. Rats supplemented daily for 1 week with 50 or 100 mg/kg FRLFE had significantly elevated metabolite concentrations. In response to an oxidative stress, erythrocyte membrane integrity was significantly improved in the 100 mg/kg FRLFE group. Third, 7-month-old mice fed a 200 mg/kg FRLFE diet for 10 months showed a significant decrease in glucose, triglyceride and lipid peroxide levels compared with mice fed a control diet. Collectively, these results support the concept that the flavanols present in FRLFE are well absorbed and bioactive.
    Phytotherapy Research 01/2010; 24(8):1223-8. DOI:10.1002/ptr.3137 · 2.40 Impact Factor
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    ABSTRACT: The effect of Oligonol, a phenolic product from lychee fruit polyphenol (LFP) containing catechin-type monomers and lower oligomers of proanthocyanidin, on lipolysis in primary adipocytes was investigated in order to examine the possible mechanism underlying the regulation of in vivo metabolism in fat. Oligonol significantly increased lipolysis, which was accompanied by both activation of extracellular signaling-related kinase 1/2 (ERK1/2) and down-regulation of perilipin protein expression, without an increase in intracellular cAMP production. The increase in lipolysis with Oligonol was prevented completely by pretreatment with either PD98059 or U0126, selective ERK1/2 inhibitors, which also prevented the reduction in the expression of perilipin protein. Tumor necrosis factor-alpha also down-regulated the expression of perilipin protein. However, there was no significant alteration in the expression of Galphai protein with Oligonol. These findings indicate that Oligonol enhances lipolysis in primary adipocytes, independent of cAMP production, but its effect is dependent on activation of the ERK1/2 pathway, leading to down-regulation of perilipin protein expression.
    Phytotherapy Research 11/2009; 23(11):1626-33. DOI:10.1002/ptr.2846 · 2.40 Impact Factor
  • Buxiang Sun · Koji Wakame · Eri Sato · Hiroshi Nishioka · Okezie I Aruoma · Hajime Fujii
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    ABSTRACT: Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.
    09/2009; 33(3-4):293-9. DOI:10.1016/j.canep.2009.07.006
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    ABSTRACT: Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. In addition, inflammatory changes through dysregulated expression of inflammation-related adipokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in WAT are considered to be one of the causes of insulin resistance. Recently, enhanced oxidative stress in adipocytes has been reported to be implicated in dysregulated expression of inflammation-related adipokines. Polyphenols are well known as potent natural antioxidants in the diet. In the present study, we investigated the antioxidative effects of an oligomerized grape seed polyphenol (OGSP) on inflammatory changes in coculture of adipocytes and macrophages. Coculture of HW mouse white adipocytes and RAW264 mouse macrophages markedly increased the production of TNF-alpha, MCP-1 and plasminogen activator inhibitor-1 compared with control culture. Treatment of HW cells with OGSP significantly attenuated the dysregulated production of adipokines. Moreover, OGSP significantly suppressed coculture-induced production of reactive oxygen species (ROS). Although enhanced release of free fatty acids (FFAs) by coculture was not altered by OGSP, FFA-induced ROS production in HW cells was significantly attenuated by OGSP. Furthermore, OGSP significantly reduced increases in the transcriptional activity of nuclear factor-kappaB and activation of extracellular signal-regulated kinase by coculture. Thus, these results suggest that the antioxidative properties of OGSP attenuate inflammatory changes induced by the coculture of adipocytes and macrophages.
    The Journal of nutritional biochemistry 02/2009; 21(1):47-54. DOI:10.1016/j.jnutbio.2008.10.003 · 4.59 Impact Factor
  • Kota Shigama · Akihiro Nakaya · Koji Wakame · Hiroshi Nishioka · Hajime Fujii
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    ABSTRACT: Active hexose correlated compound (AHCC) is an extract of a basidiomycete mushroom that is used as a supplement by some cancer patients undergoing chemotherapy; it is thought to enhance the therapeutic effects and reduce the side effects of select anticarcinogenic agents. AHCC has been reported to strengthen the anticancer effects of cisplatin (CDDP) and ameliorate its side effects in female BALB/cA mice inoculated with Colon-26 tumor cells. In this study, the role of AHCC in alleviating the side effects induced by several other anticancer drugs was explored in non-tumor-bearing mice receiving monotherapy with paclitaxel (TAX), or multi-drug chemotherapy with TAX plus CDDP, 5-fluorouracil (5FU) plus irinotecan, CDDP plus 5FU, or doxorubicin plus cyclophosphamide. Outcomes from the drug treatment groups with and without AHCC supplementation were compared to controls that received vehicle alone. The multi-drug treatments significantly reduced bone marrow cell viability in all groups and leukocyte count in all groups except for TAX+CDDP; these myelosuppresive effects were generally alleviated by AHCC. Hepatotoxicity and nephrotoxicity caused by the treatments that included TAX and CDDP were also significantly improved by AHCC. The death rate was 20 to 30 percent in all treatment groups except TAX+CDDP, and supplementation with AHCC greatly reduced or eliminated mortality. These results support the concept that AHCC can be beneficial for cancer patients receiving chemotherapy.
    Journal of Experimental Therapeutics and Oncology 01/2009; 8(1):43-51.
  • Takehito MIURA · Kentaro KITADATE · Hiroshi NISHIOKA
    Japanese Journal of Complementary and Alternative Medicine 01/2009; 6(1):1-7. DOI:10.1625/jcam.6.1
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    ABSTRACT: Oligonol is a phenolic product derived from lychee fruit extract and green tea extract, containing catechin-type monomers and oligomers of proanthocyanidins, produced by a manufacturing process which converts polyphenol polymers into oligomers. The safety of Oligonol was assessed in acute and subchronic studies and genotoxicity assays. In a single dose acute study of Oligonol, male and female rats were administered 2000mg/kg body weight (bw) Oligonol in water by gavage. Oligonol caused no adverse effects and body weight gain and food consumption were within normal range, thus the LD(50) of Oligonol was determined to be greater than 2000mg/kg. A 90 day subchronic study (100, 300 and 1000mg/kgbw/day, oral gavage) in male and female rats reported no significant adverse effects in food consumption, body weight, mortality, clinical chemistry, haematology, gross pathology and histopathology. Similarly, no adverse effects were observed in mice fed diets providing 2, 20 or 200mg/kgbw Oligonol or 200mg/kgbw lychee polyphenol for 90 days. Oligonol did not show any potential to induce gene mutations in reverse mutation tests using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA strains. Oligonol did not induce chromosomal aberrations in cultured Chinese hamster lung cells, but it showed increased polyploidy. In a micronucleus assay in mice, Oligonol did not induce any micronuclei or suppress bone marrow, indicating it does not cause chromosome aberrations. The results from these safety studies and previous reports support the safety of Oligonol for human consumption.
    Food and Chemical Toxicology 07/2008; 46(12):3553-62. DOI:10.1016/j.fct.2008.06.005 · 2.90 Impact Factor
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    ABSTRACT: In this study we investigated the antioxidative effects of Oligonol (Amino Up Chemical Co., Ltd., Sapporo, Japan), a new polyphenol, in adipocytes. The levels of reactive oxygen species (ROS) and the expression of adipokine genes decreased in HW mouse white adipocytes upon treatment with Oligonol as compared to control cells. The transcriptional activity of nuclear factor-kappaB (NF-kappaB) and the activation of extracellular signal-regulated kinase (ERK) 1/2 were also down-regulated by Oligonol. In addition, when C57BL/6J mice were fed a high fat diet (HFD) for 5 weeks, the levels of epididymal white adipose tissue (WAT) mass and lipid peroxidation in WAT both increased, but Oligonol intake clearly inhibited such HFD-induced increases. Furthermore, dysregulated expression of genes for adipokines in WAT of mice fed solely a HFD was attenuated by Oligonol intake. These results suggest that Oligonol has antioxidative effects and that it attenuates HFD-induced dysregulated expression of genes for adipokines in adipocytes.
    Bioscience Biotechnology and Biochemistry 03/2008; 72(2):463-76. DOI:10.1271/bbb.70567 · 1.21 Impact Factor