芦田 均 | ![]() |
アシダ ヒトシ | |
大学院農学研究科 生命機能科学専攻 | |
教授 | |
農芸化学関係 |
2019年 飯島藤十郎財団, 飯島藤十郎食品科学賞, 学術研究
国内外の国際的学術賞
2018年 兵庫県, 兵庫県科学賞, 科学研究
国内外の国際的学術賞
2017年 Royal Society of Chemistry, Food & Function優秀審査員賞, 論文審査員賞
学会誌・学術雑誌による顕彰
2016年 日本栄養・食糧学会, 日本栄養・食糧学会賞, 学会賞
国内外の国際的学術賞
2016年 American Society of Chemistry, Journal of Agricultural and Food Chemistry優秀審査員賞, 論文審査員賞
学会誌・学術雑誌による顕彰
2014年12月 一般財団法人大阪科学技術センター, 第3回ネイチャー・インダストリー・アワード特別賞, メタボリックシンドロームの予防・改善に寄与する機能性成分の網羅的探索法と作用機構解明,ならびにそれを高含有する農作物生産のための環境創造型農業の開発
国内学会・会議・シンポジウム等の賞
2014年 John Wiley & Sons, Inc., Molecular Nutrition and Food Research優秀審査員賞, 審査員賞
出版社・新聞社・財団等の賞
2013年 日本薬学会生薬天然物部会, 第5回食品薬学シンポジウム 優秀発表賞, カカオポリフェノールの高血糖・肥満抑制効果とその作用機構
日本国国内学会・会議・シンポジウム等の賞
2010年10月 日本生物工学会, 第18回生物工学論文賞, パン酵母β-グルカンのラットにおける脂質異常症予防効果
国内学会・会議・シンポジウム等の賞
2009年03月 日本農芸化学会, 日本農芸化学会英文誌Bioscience, Biotechnology, and Biochemistry論文賞, Identification of Two Major Ammonia-Releasing Reactions Involved in Secondary Natto Fermentation
日本国学会誌・学術雑誌による顕彰
It is generally recognized that the main function of α-tocopherol (αToc), which is the most active form of vitamin E, is its antioxidant effect, while non-antioxidant effects have also been reported. We previously found that αToc ameliorates diabetic nephropathy via diacylglycerol kinase alpha (DGKα) activation in vivo, and the activation was not related to the antioxidant effect. However, the underlying mechanism of how αToc activates DGKα have been enigmatic. We report that the membrane-bound 67 kDa laminin receptor (67LR), which has previously been shown to serve as a receptor for epigallocatechin gallate (EGCG), also contains a novel binding site for vitamin E, and its association with Vitamin E mediates DGKα activation by αToc. We employed hydrogen-deuterium exchange mass spectrometry (HDX/MS) and molecular dynamics (MD) simulations to identify the specific binding site of αToc on the 67LR and discovered the conformation of the specific hydrophobic pocket that accommodates αToc. Also, HDX/MS and MD simulations demonstrated the detailed binding of EGCG to a water-exposed hydrophilic site on 67LR, while in contrast αToc binds to a distinct hydrophobic site. We demonstrated that 67LR triggers an important signaling pathway mediating non-antioxidant effects of αToc, such as DGKα activation. This is the first evidence demonstrating a membrane receptor for αToc and one of the underlying mechanisms of a non-antioxidant function for αToc.
2022年12月, The Journal of nutritional biochemistry, 110, 109129 - 109129, 英語, 国際誌研究論文(学術雑誌)
Pectolinarigenin (PG) and its glycoside pectolinarin (PN) were reported to have various health beneficial functions such as anti-inflammatory and anti-carcinogenic activities. It has also been reported that PG and PN have radical scavenging ability as direct antioxidant activity. However, the indirect antioxidant activity of PG and PN by inducing antioxidant enzymes in hepatocytes is not fully understood yet. In this study, we investigated whether PG and PN increase expression of antioxidant enzymes through the nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated pathway in human hepatoma HepG2 cells and the liver of male ICR mice. PG, but not PN, induced antioxidant enzymes, namely heme oxigenase-1, NAD(P)H:quinone oxidoreductase 1, and aldo-keto reductase family 1 member B10, in HepG2 cells. As for the induction mechanism of these enzymes, PG-induced nuclear accumulation of Nrf2 increased antioxidant response element (ARE)-mediated transcriptional activity and suppressed degradation of Nrf2 through modification of Kelch-like EXH-associated protein 1. Oral administration of PG also induced nuclear accumulation Nrf2 and expression of antioxidant enzymes in the liver of mice. Therefore, PG, but not PN, exhibits the indirect antioxidant activity by inducing antioxidant enzymes through the Nrf2/ARE pathway and may protect liver from oxidative stress.
2022年03月30日, Antioxidants (Basel, Switzerland), 11 (4), 英語, 国際誌研究論文(学術雑誌)
Nutmeg is the seed of Myristica fragrans or its powder and is used as a spice and a traditional medicine. The antidiabetic effect of nutmeg is not fully understood yet. In this study, we examine the isolation and identification of the active compounds of Myristica fragrans with regards to glucose uptake and elucidate their mechanism in L6 myotubes. Myrisiticin, licarin B, erythro-2-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol (ADDP) and (7S,8R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-propan-1-ol (ADTP) were isolated and identified as the active compounds. Myristicin or a mixture of ADDP and ADTP promoted the translocation of glucose transporter 4 (GLUT4) through phosphorylation of AMP-activated protein kinase in L6 myotubes 15 min after treatment, while licarin B promoted it 240 min after treatment. Oral administration of the fraction from Myristica fragrans containing these active compounds to ICR mice suppressed post-prandial hyperglycemia. Thus, Myristica fragrans is a promising functional food to prevent post-prandial hyperglycemia and type 2 diabetes mellitus by promoting glucose uptake in muscle.
2022年03月11日, Food & function, 英語, 国際誌研究論文(学術雑誌)
The adipocytes play an important role in driving the obese-state-white adipose tissue (WAT) stores the excess energy as fat, wherein brown adipose tissue (BAT) is responsible for energy expenditure via the thermoregulatory function of uncoupling protein 1 (UCP1)-the imbalance between these two onsets obesity. Moreover, the anti-obesity effects of brown-like-adipocytes (beige) in WAT are well documented. Browning, the process of transformation of energy-storing into energy-dissipating adipocytes, is a potential preventive strategy against obesity and its related diseases. In the present study, to explore an alternative source of natural products in the regulation of adipocyte transformation, we assessed the potential of theobromine (TB), a bitter alkaloid of the cacao plant, inducing browning in mice (in vivo) and primary adipocytes (in vitro). Dietary supplementation of TB significantly increased skin temperature of the inguinal region in mice and induced the expression of UCP1 protein. It also increased the expression levels of mitochondrial marker proteins in subcutaneous adipose tissues but not in visceral adipose tissues. The microarray analysis showed that TB supplementation upregulated multiple thermogenic and beige adipocyte marker genes in subcutaneous adipose tissue. Furthermore, in mouse-derived primary adipocytes, TB upregulated the expression of the UCP1 protein and mitochondrial mass in a PPARγ ligand-dependent manner. It also increased the phosphorylation levels of PPARγ coactivator 1α without affecting its protein expression. These results indicate that dietary supplementation of TB induces browning in subcutaneous WAT and enhances PPARγ-induced UCP1 expression in vitro, suggesting its potential to treat obesity.
2022年02月, The Journal of nutritional biochemistry, 100, 108898 - 108898, 英語, 国際誌研究論文(学術雑誌)
Non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), are a major health issue throughout the world. Certain food components such as polyphenols are expected to possess preventive effects on NAFLD and NASH. In this study, the preventive effects of black soybean polyphenols were examined by using three NAFLD/NASH animal models. In a choline-deficient and L-amino acid-defined high-fat diet-induced NASH model, the intake of black soybean polyphenols decreased oxidative stress, but failed in attenuating liver injury and decreasing the expression of alpha-smooth muscle actin (α-SMA). In a Western diet with sucrose and fructose containing sweetened water-induced NAFLD model, black soybean polyphenols suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, inflammatory cytokine expression, and α-SMA expression accompanied by modulation of lipid metabolism. In a combination of Western diet and carbon tetrachloride model, black soybean polyphenols also suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, and α-SMA expression. In conclusion, black soybean is an attractive food for the prevention of NAFLD and NASH due to its strong antioxidant activity.
2022年01月24日, Food & function, 13 (2), 1000 - 1014, 英語, 国際誌研究論文(学術雑誌)
Decreased mitochondrial metabolism suppresses glucose metabolism, resulting in obesity and diabetes. The present study aimed to investigate mechanisms underlying the 5-aminolevulinic acid (5-ALA) hydrochloride-mediated increase in glucose uptake in high-fat diet (HFD)-fed mice in vivo and C2C12 myotube cells in vitro. C57BL/6N male mice (20 weeks old) were fed either HFD or normal diet (ND) for 4 weeks. A total of five HFD-fed mice were orally administered with 300 mg/kg 5-ALA hydrochloride and 47.1 mg/kg sodium ferrous citrate (SFC; HFD + 5-ALA/SFC), whereas ND and other HFD-fed mice were orally administered with saline. After 4 weeks, these mice were intraperitoneally administered with 2 g/kg glucose and 3.2 mg/kg 2-deoxyglucose (2DG) for intraperitoneal glucose tolerance test (IPGTT) and glucose uptake test. Body weights, plasma glucose levels and the area under the curve of IPGTT were lower in mice treated with HFD + 5-ALA/SFC compared with in those treated with HFD alone. 2DG uptake in the gastrocnemius muscle and heart were more significantly improved in the HFD + 5-ALA/SFC mice compared with the HFD-fed mice. Furthermore, 5-ALA/SFC increased 2DG uptake in C2C12 cells to a similar level to the insulin-treated group. Moreover, it increased glucose transport (GLUT)1 translocation in the plasma membrane by 2.5-fold relative to the controls without affecting GLUT1 expression; however, it had no effect on GLUT4 translocation. Therefore, 5-ALA/SFC enhanced gastrocnemius and cardiac glucose uptake in HFD-fed mice, and upregulated GLUT1 translocation to the plasma membrane, but not GLUT4 in C2C12 myotube cells. Therefore, it could potentially be used as a novel drug for the treatment of diabetes.
2021年12月, Experimental and therapeutic medicine, 22 (6), 1454 - 1454, 英語, 国際誌研究論文(学術雑誌)
研究論文(学術雑誌)
Kaempferol possesses various health-promoting functions including antihyperglycemic activity, but its underlying molecular mechanism is poorly understood. Glucose transporter 4 (GLUT4) plays an important role in the uptake of blood glucose into muscle cells after its translocation to the plasma membrane. In this study, we demonstrated that kaempferol at 1.0 nM or more significantly increased the uptake of 2-[3H]- deoxy-d-glucose by 1.3-1.4-fold in L6 myotubes. Kaempferol at 10 pM or more also significantly increased GLUT4 translocation by 1.3-1.6-fold. Kaempferol at 1.0 nM significantly increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) by 2.9-fold, liver kinase B1 and Janus kinase 2 (JAK2) by 1.9-fold, and signal transducer and activator of transcription 3 by 3.7-fold. In addition, kaempferol increased phosphorylation of phosphoinositide 3-kinase (PI3K) by 1.8-fold but not the insulin receptor. Small interfering RNA (siRNA) for AMPK, JAK2, or PI3K canceled kaempferol-induced glucose uptake and GLUT4 translocation. Furthermore, siRNA for JAK2 canceled kaempferol-induced phosphorylation of AMPK and PI3K. These results indicate that a JAK2-depdendent pathway regulates kaempferol-induced glucose uptake and GLUT4 translocation in L6 myotubes and that kaempferol may be an effective compound for the prevention of hyperglycemia.
2020年11月25日, Journal of agricultural and food chemistry, 68 (47), 13720 - 13729, 英語, 国際誌研究論文(学術雑誌)
Black soybean (Glycine max L.), a cultivar containing abundant polyphenols in its seed coat such as anthocyanins and flavan-3-ols, has been reported to possess various health benefits toward lifestyle diseases. In this review article, the safety evaluation of polyphenol-rich black soybean seed coat extract (BE) and absorption of BE polyphenols are summarized. Additionally, we describe the antioxidant activity of BE polyphenols and their ability to induce antioxidant enzymes. The health benefits of BE and its polyphenols, such as anti-obesity and anti-hyperglycemic activities through the activation of AMP-activated protein kinase and translocation of glucose transporter 4, respectively, are also discussed. Furthermore, we found that black soybean polyphenols were involved in the improvement of vascular function. These emerging data require further investigation in scientific studies and human trials to evaluate the prevention of lifestyle diseases using black soybean polyphenols.
2020年09月23日, Food & function, 11 (9), 7321 - 7339, 英語, 国際誌研究論文(学術雑誌)
Vascular dysfunction and injurious stimuli such as oxidative stress are closely related to the risk of cardiovascular diseases (CVD). Dietary polyphenols are reported to exert beneficial effects in reducing the risk of CVD. Black soybean has been used as a nutritionally rich food and contains abundant polyphenols in its seed coat and grain. Black soybean has many beneficial physiological activities, and its prevention effects on CVD risk were reported mainly in animal experiments. In this study, we performed a randomized, single blind, placebo controlled, crossover trial to investigate the effect of black soybean consumption on the vascular function in healthy humans. Twenty-two healthy adults aged from 30 to 60 completed the four week trial with daily consumption of about a 40 g test material cookie containing 20 g roasted black soybean powder. Body composition, vascular function, biomarkers for oxidative stress, and polyphenol contents in the urine and the plasma were measured. After ingestion of the black soybean cookie, vascular function, which was evaluated by plethysmogram using a Pulse Analyzer®, was improved and systolic blood pressure was decreased. Moreover, nitric oxide levels in plasma and urine were increased, while an oxidative stress biomarker, 8-hydroxy-2'-deoxyguanosine level, in the plasma was decreased accompanied by an increase in the concentration of polyphenols derived from black soybean in plasma and urine. These results suggest that the antioxidant activity of black soybean polyphenols and an increase in the nitric oxide level may contribute to the improvement of vascular function. Thus, black soybean is an attractive food material for improvement of vascular function through decreasing oxidative stress by its potent antioxidant activity and increasing the nitric oxide level in healthy humans.
2020年09月10日, Nutrients, 12 (9), 英語, 国際誌研究論文(学術雑誌)
研究論文(学術雑誌)
Vascular dysfunction and injurious stimuli such as oxidative stress is closely related to the risk of cardiovascular diseases (CVD). Dietary polyphenols is reported to exert the beneficial effects on reducing the risk of CVD. Black soybean is rich in polyphenols, including isoflavones, anthocyanidins and flavan-3-ols, and its prevention effects on CVD risk were reported in the animal experiments. In this study, we investigated the effect of black soybean consumption on the vascular function and oxidative stress associating with the polyphenol concentrations in healthy women. Lowered vascular age was observed in 33 out of 44 volunteers who completed the 8-week trial. It was observed that improvement of the vascular stiffness, increasing in the urinary NO2 and NO3 level, and decreasing in the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine, hexanoyl-lysine and myeloperoxidase. In addition, concentration of 12 polyphenols in black soybean increased in the plasma and urine. Increased concentration of polyphenols would be involved in the decreased oxidative stress. Thus, black soybean consumption improved the vascular function through an increase in nitric oxide and a decrease in oxidative stress accompanied by increasing the polyphenol concentrations in healthy women.
2020年07月30日, Archives of biochemistry and biophysics, 688, 108408 - 108408, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Mammals have the biological clocks with approximately 24 h-rhythm. Energy metabolism including glucose metabolism is regulated by the biological clocks. Glucose metabolism is affected by not only meal volume and its energy but also meal timing. We have reported that cacao liquor procyanidin-rich extract (CLPr) ameliorated the postprandial hyperglycemia through AMP-activated protein kinase pathway. However, the effect of administration timing of CLPr on the postprandial hyperglycemia and its signaling pathway are still unclear. In the present study, we compared the effect of CLPr-administration at the rest-phase (light-period) and active-phase (dark-period) on glucose metabolism. Single oral administration of CLPr to ICR mice at the rest-phase, but not at the active-phase, promoted phosphorylation of AMP-activated protein kinase and its upstream liver kinase B1 and translocation of glucose transporter 4 to the plasma membrane in the skeletal muscle, resulting in reduced postprandial hyperglycemia. These results indicated that the intake of CLPr at the rest-phase more effectively suppressed postprandial hyperglycemia.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 61 - 66, 英語, 国内誌研究論文(学術雑誌)
Energy metabolism and circadian rhythms are closely related together, i.e., the timing of nutrient intake affects metabolism under the regulation of circadian rhythms. Previously, we have reported that cacao liquor procyanidin (CLPr) promotes energy metabolism, resulting in preventing obesity and hyperglycemia. However, it is not unclear whether CLPr regulates clock gene expression. In this study, we investigated whether the administration timing of CLPr affected clock gene expression and found that CLPr regulated the circadian clock gene expression through the glucagon-like peptide-1 (GLP-1) signaling pathway. CLPr administration at Zeitgeber time 3 increased the expression level of Per family and Dbp in the liver. At the same administration timing, CLPr increased GLP-1 and insulin concentration in the plasma and phosphorylation of AMPK in the liver. It was noteworthy that an antagonist for GLP-1 receptor Exendin (9-39) canceled CLPr-increased expression of Per family and Dbp and phosphorylation of AMPK in the liver, in addition to insulin secretion. These results strongly suggest that CLPr-induced GLP-1 regulates the changes in clock gene expression in the liver through increased insulin. Thus, CLPr is a possible functional food material for prevention and/or amelioration of metabolic disorders through preventing circadian disruption through GLP-1 and AMPK pathways.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 53 - 60, 英語, 国内誌研究論文(学術雑誌)
Urban particulate matters (PM) exposure is significantly correlated with extrinsic skin aging signs and skin cancer incidence. PM contains polycyclic aromatic hydrocarbons, and they act as the agonists of aryl hydrocarbon receptor (AhR). Activation of AhR promotes generation of intracellular reactive oxygen species (ROS) and inflammation. Enzymatically synthesized glycogen (ESG), which is synthesized from starch, possesses various functions, such as anti-tumor, anti-obesity and antioxidant. However, the effects of ESG on PM-induced skin inflammation remain unclear. In this study, we investigated whether ESG has a protective effect on PM-induced oxidative stress and inflammation in human epidermal keratinocytes. ESG inhibited PM-induced expression of inflammatory cytokines IL6, TNFA and PTGS2. ESG also inhibited PM-induced phosphorylation of MAPKs and ROS accumulation. However, ESG had no effect on PM-induced expression of CYP1A1, one of the target proteins of AhR. On the other hand, ESG increased nuclear translocation of Nrf2 and expression of antioxidant proteins, HO-1 and NQO1. These results suggest that ESG suppressed PM-induced inflammation by decreasing ROS accumulation through the Nrf2 pathway.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 29 - 35, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Enzymatically synthesized glycogen is a product from starch. Enzymatically synthesized glycogen has been reported to possess various health beneficial effects such as anti-oxidative and anti-inflammatory effects. In this study, we investigated the effect of enzymatically synthesized glycogen on ultraviolet B-induced oxidative stress and apoptosis in normal human epidermal keratinocytes. Treatment with enzymatically synthesized glycogen suppressed ultraviolet B-induced reactive oxygen species, caspase-3 activity, and DNA fragmentation in normal human epidermal keratinocytes. Furthermore, enzymatically synthesized glycogen increased in the expression level of heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, and NF-E2-related factor 2, a transcriptional factor for heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1. Although enzymatically synthesized glycogen did not increase in its mRNA expression level of NF-E2-related factor 2, enzymatically synthesized glycogen retained its protein degradation. Knockdown of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 canceled enzymatically synthesized glycogen-suppressed reactive oxygen species accumulation in normal human epidermal keratinocytes. It is, therefore, concluded that enzymatically synthesized glycogen inhibited ultraviolet B-induced oxidative stress through increasing the expression level of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 through the NF-E2-related factor 2 pathway in normal human epidermal keratinocytes.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 36 - 42, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Turmeric and its components have various health beneficial functions. However, little is known about function of bisacurone, which is one of the sesquiterpenes in turmeric, at the compound level. In this study, we investigated the preventive effect of bisacurone on hepatic lipid accumulation and its mechanism in HepG2 cells and ICR mice. In HepG2 cells, bisacurone significantly inhibited fatty acid-induced intracellular lipid accumulation in a dose-dependent manner. Bisacurone at 10 µM increased protein expression of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1A accompanied by phosphorylation of AMP-activated protein kinase. In the liver of ICR mice, bisacurone decreased total lipids, triglyceride, and cholesterol contents. Bisacurone at 10 mg/kg body weight increased phosphorylation of AMP-activated protein kinase, and its downstream acetyl-CoA carboxylase as a rate-limiting enzyme for lipogenesis, while it decreased the nuclear translocation level of sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein as the major transcription factors for lipogenesis. On the other hand, bisacurone promoted lipolysis by up-expression of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1A. Thus, bisacurone might be a valuable food factor for preventing hepatic lipid accumulation by inhibiting lipogenesis and promoting lipolysis through phosphorylation of AMP-activated protein kinase.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 43 - 52, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Quercetin and its glycosides possess various health beneficial functions, but comparative study of them on energy metabolism in different tissues are not well studied. In this study, we investigated AMP-activated protein kinase regulated glucose metabolism in the skeletal muscle and lipid metabolism in the white adipose tissue and liver to compare the effectiveness of quercetin and its glycosides, namely isoquercitrin, rutin, and enzymatically modified isoquercitrin, in male ICR mice. The mice were fed a standard or high-fat diet supplemented with 0.1% quercetin and its glycosides for 13 weeks. Quercetin glycosides, but not quercetin, decreased body weight gain and fat accumulation in the mesenteric adipose tissue in high-fat groups. All compounds decreased high-fat diet-increased plasma glucose and insulin levels. Moreover, all compounds significantly increased AMP-activated protein kinase phosphorylation in either standard or high-fat diet-fed mice in all tissues tested. As its downstream events, all compounds induced glucose transporter 4 translocation in the muscle. In the white adipose tissue and liver, all compounds increased lipogenesis while decreased lipolysis. Moreover, all compounds increased browning markers and decreased differentiation markers in adipose tissue. Therefore, quercetin and its glycosides are promising food components for prevention of adiposity and hyperglycemia through modulating AMP-activated protein kinase-driven pathways.
2020年07月, Journal of clinical biochemistry and nutrition, 67 (1), 74 - 83, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Since a decrease in muscle mass leads to an increased risk of mortality, the prevention of muscle wasting contributes to maintaining the quality of life. Recently, we reported that glabridin, a prenylated flavonoid in licorice, prevents dexamethasone-induced muscle loss. In this study, we focused on the other prenylated chalcones 4-hydroxyderricin and xanthoangelol in Ashitaba (Angelica keiskei) and investigated their prevention effect on dexamethasone-induced muscle loss. It was found that 4-hydroxyderricin and xanthoangelol significantly prevented dexamethasone-induced protein degradation in C2C12 myotubes by suppressing the expression of ubiquitin ligases, Cbl-b and MuRF-1. These prenylated chalcones acted as the antagonists of the glucocorticoid receptor and inhibited the binding of dexamethasone to this receptor and its subsequent nuclear translocation. In addition, the chalcones suppressed the phosphorylation of p38 and FoxO3a as the upstream factors for ubiquitin ligases. Dexamethasone-induced protein degradation and upregulation of Cbl-b were attenuated by the knockdown of the glucocorticoid receptor but not by the knockdown of p38. In male C57BL/6J mice, the Ashitaba extract, containing 4-hydroxyderricin and xanthoangelol, suppressed dexamethasone-induced muscle mass wasting accompanied by a decrease in the expression of ubiquitin ligases by inhibiting the nuclear translocation of the glucocorticoid receptor and phosphorylation of FoxO3a. In conclusion, 4-hydroxyderricin and xanthoangelol are effective compounds to inhibit steroid-induced muscle loss.
2020年06月24日, Food & function, 11 (6), 5498 - 5512, 英語, 国際誌研究論文(学術雑誌)
In the body, alcohol dehydrogenase rapidly converts ethanol to its toxic metabolite, acetaldehyde, which is further metabolized to non-toxic acetic acid by aldehyde dehydrogenase (ALDH). 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi (Wasabia japonica) has various physiological effects such as anti-oxidative, anti-inflammatory and anti-cancer effects. However, the effect of 6-MSITC on alcohol metabolism has not been studied. In this study, we investigated the effects of 6-MSITC on hepatic ALDH activity and protein expression both in vitro and in vivo. 6-MSITC inhibited ethanol- and acetaldehyde-induced cytotoxicity. Treatment with 6-MSITC to HepG2 cells enhanced ALDH activity through the induction of mitochondrial ALDH2 expression, but not cytosolic ALDH1A1. Knockdown of Nrf2 canceled the 6-MSITC-induced ALDH2 expression, indicating that Nrf2 regulated ALDH2 expression. Moreover, 6-MSITC increased the nuclear translocation of Nrf2 and the expression levels of HO-1 and SOD2, Nrf2-regulated phase II drug-metabolizing enzymes. Oral administration of 6-MSITC increased the mitochondrial ALDH2 activity and its expression in the liver of C57BL/6J mice. These results suggested that 6-MSITC is possible to protect acetaldehyde toxicity in hepatocytes by induction of mitochondrial ALDH2 expression through Nrf2/ARE pathway.
2020年03月07日, Archives of biochemistry and biophysics, 686, 108329 - 108329, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Skeletal muscle secretes biologically active proteins that contribute to muscle hypertrophy in response to either exercise or dietary intake. The identification of skeletal muscle-secreted proteins that induces hypertrophy can provide critical information regarding skeletal muscle health. Dietary provitamin A, β-carotene, induces hypertrophy of the soleus muscle in mice. Here, we hypothesized that skeletal muscle produces hypertrophy-inducible secretory proteins via dietary β-carotene. Knockdown of retinoic acid receptor (RAR) γ inhibited the β-carotene-induced increase soleus muscle mass in mice. Using RNA sequencing, bioinformatic analyses, and literature searching, we predicted transglutaminase 2 (TG2) to be an all-trans retinoic acid (ATRA)-induced secretory protein in cultured C2C12 myotubes. Tg2 mRNA expression increased in ATRA- or β-carotene-stimulated myotubes and in the soleus muscle of β-carotene-treated mice. Knockdown of RARγ inhibited β-carotene-increased mRNA expression of Tg2 in the soleus muscle. ATRA increased endogenous TG2 levels in conditioned medium from myotubes. Extracellular TG2 promoted the phosphorylation of Akt, mechanistic target of rapamycin (mTOR), and ribosomal p70 S6 kinase (p70S6K), and inhibitors of mTOR, phosphatidylinositol 3-kinase, and Src (rapamycin, LY294002, and Src I1, respectively) inhibited TG2-increased phosphorylation of mTOR and p70S6K. Furthermore, extracellular TG2 promoted protein synthesis and hypertrophy in myotubes. TG2 mutant lacking transglutaminase activity exerted the same effects as wild-type TG2. Knockdown of G protein-coupled receptor 56 (GPR56) inhibited the effects of TG2 on mTOR signaling, protein synthesis, and hypertrophy. These results indicated that TG2 expression was upregulated through ATRA-mediated RARγ and that extracellular TG2 induced myotube hypertrophy by activating mTOR signaling-mediated protein synthesis through GPR56, independent of transglutaminase activity.
2020年02月, Biochimica et biophysica acta. Molecular cell research, 1867 (2), 118563 - 118563, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Black soybean seed coat polyphenols were reported to possess various bioregulatory functions. However, the effects of black soybean seed coat polyphenols on vascular functions are unknown. Vascular dysfunction caused by aging and vascular stiffness is associated with a risk of cardiovascular disease (CVD), and a reduction in nitric oxide (NO) levels can trigger the onset of CVD. In the present study, we investigated the effect of polyphenol-rich black soybean seed coat extract (BE) on vascular functions and the underlying mechanisms involved. The oral administration of BE at 50 mg per kg body weight to Wistar rats increased NO levels as determined by eNOS phosphorylation. The administration of BE also increased GLP-1 and cAMP levels. Furthermore, the effects of BE were inhibited in the presence of a GLP-1 receptor antagonist. This suggests that GLP-1 is strongly involved in the underlying mechanism of NO production in vivo. In conclusion, BE contributes to the improvement of vascular functions by promoting NO production. Regarding the putative underlying mechanism, GLP-1 secreted from intestinal cells by the polyphenols in BE activates eNOS in vascular endothelial cells.
2019年12月11日, Food & function, 10 (12), 7875 - 7882, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
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研究論文(学術雑誌)
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研究論文(学術雑誌)
Quercetin possesses various health beneficial functions, but its poor bioavailability limits these functions. Enzymatically modified isoquercitrin (EMIQ) is a quercetin glycoside with a greater bioavailability than quercetin. In this study, we investigated whether EMIQ regulates energy metabolism in mice and its underlying molecular mechanism. Male C57BL/6 mice were fed a normal diet with different doses of EMIQ or quercetin (0.02%, 0.1% and 0.5%) for two weeks. Supplementation with 0.1% EMIQ significantly decreased white adipose tissue (WAT) weight. Supplementation with 0.02% and 0.1% EMIQ promoted phosphorylation of adenosine monophosphate activated protein kinase (AMPK) in the WAT, liver, and muscle. In the WAT, 0.1% EMIQ downregulated peroxisome proliferator-activated receptor (PPAR)γ, CCAAT-enhancer-binding protein (C/EBP)α, C/EBPβ, and sterol regulatory element-binding protein 1 expression, as well as upregulated mitochondrial uncoupling protein (UCP) 2 and carnitine palmitoyltransferase-1 expression. Supplementation with 0.1% EMIQ also promoted the expression of thermogenesis-associated factors including PPARγ coactivator α (PGC-1α), UCP1, PR-domain containing protein 16, and sirtuin 1 in the WAT. In the liver, EMIQ promoted the phosphorylation of acetyl-CoA carboxylase, and increased the expression of PPARα, constitutive androstane-receptor, and farnesoid X receptor. Furthermore, supplementation with 0.02% or 0.1% EMIQ suppressed the plasma glucose level accompanied by the translocation of glucose transporter 4 to the plasma membrane of the muscle. Our results suggest that EMIQ is a potential food additive for the regulation of energy metabolism through AMPK phosphorylation.
2019年08月01日, Food & function, 10 (8), 5188 - 5202, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
For over 4000 years, liquorice has been one of the most frequently employed botanicals as a traditional herbal medicine. Although previous reports have found that liquorice flavonoids possess various health beneficial effects, the underlying mechanism responsible for the anti-diabetic effect of liquorice flavonoids remains unclear. The present study demonstrates that liquorice flavonoid oil (LFO) improves type 2 diabetes mellitus through GLUT4 translocation to the plasma membrane by activating both the adenosine monophosphate-activated protein kinase (AMPK) pathway and Akt pathway in muscle of KK-A y mice. Furthermore, LFO lowered postprandial hyperglycaemia in a human study. These results indicate that LFO may exert a therapeutic effect on metabolic disorders, such as diabetes and hyperglycaemia, by modulating glucose metabolism through AMPK- and insulin-dependent pathways in skeletal muscle.
2019年04月, International Journal of Food Sciences and Nutrition, 70 (3), 294 - 302研究論文(学術雑誌)
The flavon luteolin has various health-promoting activities including cardiovascular protection, anti-inflammatory activity and anticancer activity. A serum concentration of about 100 nM luteolin is reached by dietary habit. However, little is known about the function of luteolin over its physiological concentration range. In this study, we investigated whether a physiological concentration of luteolin could activate nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated expression of phase II drug-metabolizing enzymes in human hepatoma HepG2 cells. Interestingly, less than 1 nM of luteolin could induce phase II drug-metabolizing enzymes, such as GSTs, HO-1, and NQO1. Both 1 and 100 nM luteolin increased expression and activity of ALDH2, which metabolized toxic acetaldehyde into nontoxic acetic acid. Luteolin increased nuclear accumulation of Nrf2 and enhanced the ARE-binding complex through increasing the stability of the Nrf2 protein. Luteolin increased phosphorylation of Nrf2 at Ser40, and MEK inhibitors (U0126 and PD98059) canceled luteolin-induced phosphorylation of Nrf2. Furthermore, luteolin increased modified Keap1. In conclusion, a physiological concentration of luteolin induces the expression of phase II drug-metabolizing enzymes by enhancement of Nrf2 nuclear accumulation through MEK1/2-ERK1/2-mediated phosphorylation of Nrf2, increasing Nrf2 stability and inducing a conformational change of Keap1.
2019年03月15日, Archives of biochemistry and biophysics, 663, 151 - 159, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Quercetin and its metabolite isorhamnetin elicit various beneficial effects on human health. However, their bioavailability is low. In this study, we investigated whether low concentrations in the physiological range could promote glucose uptake in L6 myotubes, as well as the underlying molecular mechanisms. We found that 0.1 nM and 1 nM quercetin or 1 nM isorhamnetin significantly increased glucose uptake via translocation of glucose transporter type 4 (GLUT4) to the plasma membrane of L6 myotubes. Quercetin principally activated the CaMKKβ/AMPK signalling pathway at these concentrations, but also activated IRS1/PI3K/Akt signalling at 10 nM. In contrast, 1 nM and 10 nM isorhamnetin principally activated the JAK/STAT pathway. Treatment with siAMPKα and siJAK2 abolished quercetin- and isorhamnetin-induced GLUT4 translocation, respectively. However, treatment with siJAK3 did not affect isorhamnetin-induced GLUT4 translocation, indicating that isorhamnetin induced GLUT4 translocation mainly through JAK2, but not JAK3, signalling. Thus, quercetin preferably activated the AMPK pathway and, accordingly, stimulated IRS1/PI3K/Akt signalling, while isorhamnetin activated the JAK2/STAT pathway. Furthermore, after oral administration of quercetin glycoside at 10 and 100 mg/kg body weight significantly induced GLUT4 translocation to the plasma membrane of skeletal muscles in mice. In the same animals, plasma concentrations of quercetin aglycone form were 4.95 and 6.80 nM, respectively. In conclusion, at low-concentration ranges, quercetin and isorhamnetin promote glucose uptake by increasing GLUT4 translocation via different signalling pathways in skeletal muscle cells; thus, these compounds may possess beneficial functions for maintaining glucose homeostasis by preventing hyperglycaemia at physiological concentrations.
2019年, Scientific Reports, 9 (1), 2690 - 2690, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Glucose uptake ability into L6 skeletal muscle cell was examined with eleven kinds of ring fission metabolites of (-)-epigallocatechin gallate (EGCG) produced by intestinal bacteria. The metabolites 5-(3,5-dihydroxyphenyl)-γ-valerolactone (EGC-M5), 4-hydroxy-5-(3,4,5-trihydroxyphenyl)valeric acid (EGC-M6), 5-(3,4,5-trihydroxyphenyl)-γ-valerolactone (EGC-M7) and 5-(3-hydroxyphenyl)valeric acid (EGC-M11) have been found to promote uptake of glucose into L6 myotubes significantly. EGC-M5, which is one of the major ring fission metabolites of EGCG, was also found to have a promotive effect on glucose transporter 4 (GLUT4) translocation accompanied by phosphorylation of AMP-activated protein kinase (AMPK) signaling pathway in skeletal muscle both in vivo and in vitro. Furthermore, the effect of oral single dosage of EGC-M5 on glucose tolerance test with ICR mice was examined and significant suppression of hyperglycemia was observed. These data suggested that EGC-M5 has an antidiabetic effect in vivo.
2019年, Biological and Pharmaceutical Bulletin, 42 (2), 212 - 221, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Aims: Muscle mass is regulated by the balance between the synthesis and degradation of muscle proteins. Loss of skeletal muscle mass is associated with an increased risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. The aim of this study was to clarify the effects of licorice flavonoid oil on muscle mass in KK-Ay/Ta mice. Main methods: Male genetically type II diabetic KK-Ay/Ta mice received 0, 1, or 1.5 g/kg BW of licorice flavonoid oil by mouth once daily for 4 weeks. After 4 weeks, the femoral and soleus muscles were collected for western blotting for evaluation of the mTOR/p70 S6K, p38/FoxO3a, and Akt/FoxO3a signaling pathways. Key findings: Ingestion of licorice flavonoid oil significantly enhanced femoral muscle mass without affecting body weight in KK-Ay/Ta mice. Licorice flavonoid oil also decreased expression of MuRF1 and atrogin-1, which are both markers of muscle atrophy. The mechanisms by which licorice flavonoid oil enhances muscle mass include activation of mTOR and p70 S6K, and regulation of phosphorylation of FoxO3a. Significance: Ingestion of licorice flavonoids may help to prevent muscle atrophy.
Elsevier Inc., 2018年07月15日, Life Sciences, 205, 91 - 96, 英語[査読有り]
研究論文(学術雑誌)
Adipose tissues in obese individuals are characterized by a state of chronic low-grade inflammation. Pre-adipocytes and adipocytes in this state secrete pro-inflammatory adipokines, such as interleukin 6 (IL-6), which induce insulin resistance and hyperglycemia. Theophylline (1,3-dimethylxanthine) exerts anti-inflammatory effects, but its effects on pro-inflammatory adipokine secretion by pre-adipocytes and adipocytes have not been examined. In this study, we found that theophylline decreased IL-6 secretion by 3T3-L1 pre-adipocytes and mouse-derived primary pre-adipocytes. The synthetic glucocorticoid dexamethasone (DEX) induced IL-6 expression in 3T3-L1 pre-adipocytes, and this effect was suppressed by theophylline at the mRNA level. Knockdown of CCAAT/enhancer binding protein (C/EBP) δ inhibited DEX-induced IL-6 expression, and theophylline suppressed C/EBPδ expression. Furthermore, theophylline suppressed transcriptional activity of the glucocorticoid receptor (GR) through suppression of nuclear localization of GR. In vivo, glucocorticoid corticosterone treatment (100 μg/mL) increased fasting blood glucose and plasma IL-6 levels in C57BL/6 N mice. Theophylline administration (0.1% diet) reduced corticosterone-increased fasting blood glucose, plasma IL-6 levels, and Il6 gene expression in adipose tissues. These results show that theophylline administration attenuated glucocorticoid-induced hyperglycemia and IL-6 production by inhibiting GR activity. The present findings indicate the potential of theophylline as a candidate therapeutic agent to treat insulin resistance and hyperglycemia.
Academic Press Inc., 2018年05月15日, Archives of Biochemistry and Biophysics, 646, 98 - 106, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
[査読有り]
研究論文(学術雑誌)
The potential health benefits of phenolic acids found in food and beverages has been suggested from a number of large population studies. However, the mechanism of how these compounds may exert biological effects is less well established. It is also now recognised that many complex polyphenols in the diet are metabolised to simple phenolic acids which can be taken up in the circulation. In this paper a number of selected phenolic compounds have been tested for their bioactivity in two cell culture models. The expression and activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells and the uptake of glucose in muscle cells. Our data indicate that while none of the compounds tested had a significant effect on eNOS expression or activation in endothelial cells, several of the compounds increased glucose uptake in muscle cells. These compounds also enhanced the translocation of the glucose transporter GLUT4 to the plasma membrane, which may explain the observed increase in cellular glucose uptake. These results indicate that simple cell culture models may be useful to help understand the bioactivity of phenolic compounds in relation to cardiovascular protection.
2018年, Fitoterapia, 82, 22 - 28, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
SCOPE: The prevalence of type 2 diabetes mellitus (T2DM) is increasing yearly worldwide. Glycemic control is the basis for the treatment of T2DM, as it can prevent the progress of associated complications. Spices possess various health beneficial effects on humans. The aim of this study is to search for spices that can promote glucose uptake and to elucidate the underlying molecular mechanism(s). METHODS AND RESULTS: Among 24 spice extracts, the extracts from black pepper and white pepper significantly increase glucose uptake in L6 myotubes. Piperine is found to be the active compound in these extracts. Treatment of myotubes with piperine induces the translocation of glucose transporter 4 (GLUT4) to the plasma membrane by phosphorylation of AMP-activated protein kinase (AMPK). Piperine increases the intracellular Ca2+ level and reactive oxygen species (ROS) generation through transient receptor potential vanilloid channel 1 (TRPV1), followed by activation of Ca2+ /calmodulin-dependent protein kinase kinase-beta (CaMKKβ) as the upstream events for AMPK phosphorylation. Furthermore, oral administration of piperine to Wistar rats at 0.01 and 0.1 mg kg-1 body weight decreases postprandial hyperglycemia accompanied by GLUT4 translocation and AMPK phosphorylation. CONCLUSION: Piperine in pepper prevents hyperglycemia by GLUT4 translocation through CaMKKβ/AMPK signaling via TRPV1-dependent increase in the intracellular Ca2+ level and ROS generation.
2018年, Molecular Nutrition and Food Research., 62 (11), e1800086, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Cacao extract (CE) consumption has beneficial effects on human health, such as lowering the risk of obesity. However, the underlying molecular mechanism for the anti-obesity effect of CE remains incompletely understood. Here, we used a 50% aqueous alcohol extract of cacao mass, which is rich in methylxanthine derivatives (about 11%) and poor in flavan-3-ols (less than 1%), and assessed the suppression effects of this extract on adipocyte differentiation to investigate the anti-obesity mechanism. CE dose-dependently decreased fat accumulation in 3T3-L1 cells without affecting cell viability. CE also dose-dependently decreased the protein and gene expression levels of two adipogenesis-related transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs). Moreover, CE decreased protein expression levels of sterol regulatory element-binding protein 1 (SREBP1) and its downstream fatty acid synthase (FAS), which was accompanied by the retained localization of SREBP1 in the cytoplasm of 3T3-L1 cells. After ICR mice were fed a diet containing 1% CE for 1 wk, their white adipose tissue weight was lower, whereas their brown adipose tissue weight was higher compared with those of control animals. Additionally, the protein expression levels of PPARγ, C/EBPs, SREBP1, and FAS in the white adipose tissue of these mice were also lower than those in control animals. In contrast, diet supplementation with CE induced higher levels of phos-phorylated AMP-activated protein kinase (AMPK) and its downstream acetyl-CoA carboxylase. In conclusion, methylxanthine derivative-rich CE decreases fat accumulation in adipocytes by downregulating the expression of the adipocyte differentiation master regulators through the activation of AMPK.
Center for Academic Publications Japan, 2018年, Journal of Nutritional Science and Vitaminology., 64 (2), 151 - 160, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Our previous report demonstrated that epigallocatechin gallate (EGCg) promotes translocation of glucose transporter 4 (GLUT4) in skeletal muscle. In this study, we investigated the molecular mechanism of GLUT4 translocation by EGCg at the physiological concentration range. In L6 cells, EGCg induced phosphorylation of phosphatidylinositide 3'-kinase (PI3K) and downstream protein kinase C (PKC) λ/ξ without affecting the phosphorylation of insulin receptor and Akt. EGCg-induced GLUT4 translocation was suppressed by RNA interference-mediated knockdown of PI3K and treatment with PKC inhibitor Go6983. Moreover, EGCg increased Rac1 activity and actin remodelling as downstream events of PKCλ/ξ. These results indicate that EGCg induced GLUT4 translocation through a PI3K-dependent pathway, but its mode of action differed from that of insulin. EGCg also induced GLUT4 translocation through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway. 67 kDa laminin receptor, which is a target molecule of EGCg, was not involved in EGCg-induced glucose uptake in L6 cells. The oral administration of EGCg suppressed postprandial hyperglycaemia accompanied by GLUT4 translocation through both PI3K- and AMPK-dependent pathways, and promoted glycogen accumulation in skeletal muscle of ICR mice. EGCg promotes GLUT4 translocation through both PI3K- and AMPK-dependent pathways and glycogen accumulation in skeletal muscle.
2018年, Food and Function, 9 (8), 4223 - 4233, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Certain dioxins, including 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD), are exogenous ligands for an aryl hydrocarbon receptor (AhR) and induces various drug-metabolizing enzymes. In this study, we examined the effect of curcumin on expression of drug-metabolizing enzymes through the AhR and NF-E2 related factor 2 (Nrf2) pathways. Curcumin dose-dependently inhibited TCDD-induced expression of phase I enzyme cytochrome P450 1A1 (CYP1A1) and phase II enzymes NAD(P)H:quinone oxidoreductase-1 (NQO1) and heme oxygenase 1 (HO-1) but not tert-butyl hydroquinone-induced NQO1 and HO-1, suggesting that curcumin inhibited only AhR pathway, but not Nrf2 one directly. Furthermore, we used 14 curcumin derivatives and obtained the correlation between hydrophobicity of the compounds and suppressive effect against AhR transformation. Results from the quantitative structure active correlative analysis indicated that methoxy groups and β-diketone structure possessing keto-enol tautomerism in curcumin were necessary to inhibit AhR transformation, and the addition of methyl and methoxy group(s) to the curcumin increased the inhibition effect.
Japan Society for Bioscience Biotechnology and Agrochemistry, 2018年, Bioscience, Biotechnology and Biochemistry, 82 (4), 616 - 628, 英語[査読有り]
研究論文(学術雑誌)
We investigated the absorption, metabolism, distribution and faecal excretion of 3 B-type procyanidin oligomers, including procyanidin B2, procyanidin C1 and cinnamtannin A2, and their monomeric unit (-)-epicatechin after a single oral administration of black soybean seed coat extract (BE) to male ICR mice at 250 mg per kg body weight. Plasma, tissues and faeces samples were collected within 24 h for the determination of (-)-epicatechin, procyandidin B2, procyanidin C1 and cinnamtannin A2 with or without β-glucuronidase and sulfatase treatment by the high-performance liquid chromatography method. A portion of the B-type procyanidin oligomers and (-)-epicatechin in BE was absorbed from the small intestine after the oral administration of BE. In the plasma, absorbed procyanidins and (-)-epicatechin existed mainly as conjugates. In the tissues, procyanidin B2, procyandin C1 and cinnamtannin A2, in addition to (-)-epicatechin distributed widely, primarily in their free forms. Their conjugation occurred mainly in the small intestine, rather than in the liver. Monomeric unit (-)-epicatechin had the highest bioavailability, followed by procyanidin B2, procyanidin C1 and cinnamtannin A2.
2018年, Food and Function,, 9 (10), 5362 - 5370, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Diabetic nephropathy (DN) is a diabetic vascular complication, and abnormal protein kinase C (PKC) activation from increased diacylglycerol (DG) production in diabetic hyperglycemia is one of the causes of DN. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. In other words, DGK can attenuate PKC activity by reducing the amount of DG. Recently, we reported that intraperitoneally administered d-α-Tocopherol (Vitamin E, αToc) induces an amelioration of DN in vivo through the activation of DGKα and the prevention of podocyte loss. However, the effect of the oral administration of αToc on DN in mice remains unknown. Here, we evaluated the effect of oral administration of αToc on DN and its molecular mechanism using streptozocininduced diabetic mice. Consequently, the oral administration of αToc significantly ameliorated the symptoms of DN by preventing the loss of podocytes, and it was revealed that the inhibition of PKC activity was involved in this amelioration.
Japan Society for Bioscience Biotechnology and Agrochemistry, 2018年, Bioscience Biotechnology and Biochemistry, 82 (1), 65 - 73, 英語[査読有り]
研究論文(学術雑誌)
Periods of skeletal muscle disuse, for example due to a sedentary lifestyle or bed rest, are associated with aging and can lead to muscle atrophy. We previously found that the flavan 3-ol fraction derived from cocoa (FL) enhanced energy expenditure with metabolic changes in skeletal muscle. In the present study, we examined the effect of FL on disuse muscle atrophy induced by hindlimb suspension in mice. Male C57BL/6J mice were assigned to four groups as follows: unsuspended-vehicle, unsuspended-FL, suspended-vehicle, and suspended-FL. Mice in the vehicle treatment groups were administered distilled water and those in the FL treatment groups were dosed with FL (50mg/kg/day) for 2weeks. The weights of the gastrocnemius (GC), tibialis anterior (TA), and soleus (SOL), but not the extensor digitorum longus (EDL), decreased significantly in mice with hindlimb suspension (-11.8%, -16.5%, and -41.0%, respectively). This reduction in GC, TA, and SOL mass was inhibited by FL (-5.3%, +2.0%, and -16.6%, respectively). The FL increased the EDL weight >20% with or without hindlimb suspension. The protein level of the ubiquitin ligase, muscle ring finger-1, in the SOL was significantly increased by hindlimb suspension, but inhibited by treatment with FL. Protein expression of p70S6 kinase in the SOL was significantly decreased by hindlimb suspension, and FL treatment inhibited this change. These results suggested that FL delayed disuse muscle atrophy by metabolic alteration.
2017年11月, Experimental gerontology, 98, 120 - 123, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Background: Glucose transporter 4 (GLUT4) is firmly established to play a pivotal role in glucose metabolism and in particular in modulating the insulin-stimulated glucose transport in several tissues, such as skeletal muscle and adipose tissue. Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane, activation of several kinases, and finally in a large glucose influx into cells. Purpose: In this study we investigated the modulating properties of four biologically active oxyprenylated ferulic acid and umbelliferone derivatives and of their unprenylated parent compounds on GLUT-4 mediated glucose uptake and translocation. Methods: Oxyprenylated phenylpropanoids have been synthesized in high yields and purity by already reported methodologies. All the synthesized chemicals were tested for their capacity to modulate GLUT4 mediated glucose uptake and GLUT4 translocation in L6 rat skeletal myoblasts in the concentration range 0.1 - 10 mu M. Insulin (0.1 mu M) was used as positive control. Western blot analysis was employed to assess if GLUT4 translocation occurred prior to increase of glucose uptake. Statistical analyses were carried out by the Dunnett multiple comparison test. Results: 4'-Geranyloxyferulic acid (GOFA), 7-isopentenyloxycoumarin, and auraptene (7-geranyloxycoumarin) increased glucose uptake in a concentration-dependent manner, and significant increases were observed at 0.1 mu M for GOFA, and 10 mu M for 7-isopentenyloxycoumarin, and auraptene. These products also were able to significantly promote the translocation of GLUT4 to the plasma membrane of L6 myotubes. After treatment with compounds for 15 min, the incorporated amounts of GOFA, 7-isopentenyloxucoumarin, and auraptene were 0.15, 0.32, and 1.77 nmols/60-mm culture dish, respectively. A sample of raw Italian propolis, found to be rich in GOFA and auraptene, was also seen to mimic insulin-effect in the concentration range 0.01 - 1.0 mg/ml. Conclusions: Among the compounds assayed, auraptene showed to possess potentialities to be a potent activator of both translocation of GLUT4 and glucose influx into skeletal muscle cells with the highest bioavailability among effective compounds. Its capacity to modulate sugar metabolism, coupled to its presence in edible Citrus fruits, can be regarded as an additional reason to account for the already known stimulating properties of some vegetable (e.g. bitter orange).
ELSEVIER GMBH, URBAN & FISCHER VERLAG, 2017年08月, PHYTOMEDICINE, 32, 74 - 79, 英語[査読有り]
研究論文(学術雑誌)
Procyanidins belong to a family of flavan-3-ols, which consist of monomers, (+)-catechin and (-)-epicatechin, and their oligomers and polymers, and are distributed in many plant-derived foods. Procyanidins are reported to have many beneficial physiological activities, such as antihypertensive and anticancer effects. However, the bioavailability of procyanidins is not well understood owing to a lack of convenient and high-sensitive analysis methods. The aim of this study was to develop an improved method for determining procyanidin content in both food materials and biological samples. High performance liquid chromatography (HPLC) coupled with a fluorescence detector was used in this study. The limits of detection (LODs) of (+)-catechin, (-)-epicatechin, procyanidin B2, procyanidin C1, and cinnamtannin A2 were 3.0 x 10(-3) ng, 4.0 x 10(-3) ng, 14.0 x 10(-3) ng, 18.5 x 10(-3) ng, and 23.0 x 10(-3) ng, respectively; the limits of quantification (LOQs) were 10.0 x 10(-3) ng, 29.0 x 10(-3) ng, 28.5 x 10(-3) ng, 54.1 x 10(-3) ng, and 115.0 x 10(-3) ng, respectively. The LOD and LOQ values indicated that the sensitivity of the fluorescence detector method was around 1000 times higher than that of conventional HPLC coupled with a UV-detector. We applied the developed method to measure procyanidins in black soybean seed coat extract (BE) prepared from soybeans grown under three different fertilization conditions, namely, conventional farming, basal manure application, and intertillage. The amount of flavan-3-ols in these BEs decreased in the order intertillage > basal manure application > conventional farming. Commercially available BE was orally administered to mice at a dose of 250 mg/kg body weight, and we measured the blood flavan-3-ol content. Data from plasma analysis indicated that up to the tetramer oligomerization, procyanidins were detectable and flavan-3-ols mainly existed in conjugated forms in the plasma. In conclusion, we developed a highly sensitive and convenient analytical method for the analysis of flavan-3-ols, and applied this technique to investigate the bioavailability of flavan-3-ols in biological samples and to measure flavan-3-ol content in food material and plants. Copyright (C) 2017, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC.
FOOD & DRUG ADMINSTRATION, 2017年07月, JOURNAL OF FOOD AND DRUG ANALYSIS, 25 (3), 478 - 487, 英語[査読有り]
研究論文(学術雑誌)
Grifola gargal, an edible mushroom originating in southern Argentina and Chile, is known to have such beneficial health effects as antioxidant and anti-inflammatory activities. A low molecular weight fraction from Grifola gargal (GLF) decreased fasting blood glucose levels in high-fat diet-induced diabetic mice. This implicated Grifola gargal as a functional food to prevent type 2 diabetes mellitus (T2DM). To address the unknown underlying molecular mechanisms, we investigated, using L6 myotubes, whether GLF promoted GLUT4 translocation to the plasma membrane and its related signalling pathways. In addition, adenosine was isolated and identified the active compound in GLF to increase glucose uptake and promote GLUT4 translocation in L6 myotubes. Adenosine activated PI3K/Akt signalling and phosphorylation of AMPK, by binding to the adenosine receptor A1. Thus, Grifola gargal is a promising functional food to prevent post-prandial hyperglycaemia and T2DM by promoting glucose uptake in muscle. (C) 2017 Elsevier Ltd. All rights reserved.
ELSEVIER SCIENCE BV, 2017年06月, JOURNAL OF FUNCTIONAL FOODS, 33, 268 - 277, 英語[査読有り]
研究論文(学術雑誌)
Inflammatory bowel diseases are a group of chronic inflammation conditions of the gastrointestinal tract. Disruption of the mucosal immune response causes accumulation of oxidative stress, resulting in the induction of inflammatory bowel disease. In this study, we investigated the effect of enzymatically synthesized glycogen (ESG), which is produced from starch, on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in C57BL/6 mice. Oral administration of ESG suppressed DSS- and TNBS-induced shortening of large intestine in female mice and significant decreased DSS-induced oxidative stress and TNBS-induced pro-inflammatory cytokine expression in the large intestine. ESG increase in the expression levels of heme oxygenase-1 (HO-1) and NF-E2-related factor-2 (Nrf2), a transcription factor for HO-1 expressed in the large intestine. Furthermore, ESG-induced HO-1 and Nrf2 were expressed mainly in intestinal macrophages. ESG is considered to be metabolized to resistant glycogen (RG) during digestion with alpha-amylase in vivo. In mouse macrophage RAW264.7 cells, RG, but not ESG decreased 2,2'-azobis(2-amidinopropane) dihydrochloride (A APH)-induced reactive oxygen species (ROS). Knockdown of Nrf2 inhibited RG-induced HO-1 expression and negated the decrease in AAPH-induced ROS brought about by RG. RG up-regulated the protein stability of Nrf2 to decrease the formation of Nrf2-Keapl complexes. RG-induced phosphorylation of Nrf2 at Ser40 was suppressed by ERK1/2 and JNK inhibitors. Our data indicate that ESG, digested with alpha-amylase to RG, suppresses DSS- and TNBS-induced colitis by increasing the expression of HO-1 in the large intestine of mice. Furthermore, we demonstrate that RG induces HO-1 expression by promoting phosphorylation of Nrf2 at Ser40 through activation of the ERK1/2 and JNK cascade in macrophages.
ELSEVIER SCIENCE INC, 2017年05月, FREE RADICAL BIOLOGY AND MEDICINE, 106, 355 - 367, 英語[査読有り]
研究論文(学術雑誌)
Black soybean seed coat extract (BE), which contains abundant polyphenols such as procyanidins, cyanidin 3-glucoside, (+)-catechin, and (-)-epicatechin, has been reported on health beneficial functions such as antioxidant activity, anti-inflammatory, anti obesity, and anti-diabetic activities. In this study, we investigated that prevention of BE and its polyphenols on 2,2'-azobis(2-methylpropionamide) dihydrochloride (AAPH)-induced oxidative DNA damage, and found that these polyphenols inhibited AAPH-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a biomarker for oxidative DNA damage in HepG2 cells. Under the same conditions, these polyphenols also inhibited AAPH-induced accumulation of reactive oxygen species (ROS) in the cells. Inhibition of ROS accumulation was observed in both cytosol and nucleus. It was confirmed that these polyphenols inhibited formation of AAPH radical using oxygen radical absorbance capacity assay under the cell-free conditions. These results indicate that polyphenols in BE inhibit free radical-induced oxidative DNA damages by their potent antioxidant activity. Thus, BE is an effective food material for prevention of oxidative stress and oxidative DNA damages.
JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION, 2017年03月, JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, 60 (2), 108 - 114, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Caffeine is a methylxanthine derived from plant foods such as coffee beans and tea leaves, and has multiple biological activities against physiological response and several diseases. Although there are some reports about the direct effect of caffeine against anti-lipid accumulation in vitro, the effect of caffeine on lipid accumulation in adipocytes through stimulating intestinal epithelial cells is unknown. Since direct treatment with caffeine to 3T3-L1 cells did not affect lipid accumulation, we determined whether caffeinestimulated intestinal epithelial Caco-2 cells influence the lipid accumulation in 3T3-L1 adipocytes. Caco-2 cells were cultured on a transwell insert with or without caffeine for 24 h. Subsequently, the basolateral component of the Caco-2 cell culture on the transwell was collected and termed caffeine-conditioning medium (CCM). When 3T3-L1 adipocytes were incubated with CCM, CCM decreased lipid accumulation and suppressed gene expression of proliferator activated receptor (PPAR) γ and CCAAT/enhancer binding protein (C/EBP) α in 3T3-L1 adipocytes. Furthermore, CCM decreased the expression of C/EBPβ and C/EBPδ at the protein level, but not at the mRNA level. We observed that a proteasome inhibitor, MG132, inhibited CCM-caused down-expression of C/EBPβ and C/EBPδ proteins, and that CCM promoted the ubiquitination level of C/EBPβ and C/EBPδ proteins. Protein microarray analysis showed caffeine suppresses the secretion of inflammatory cytokines, interleukin-8 and plasminogen activator inhibitor-1 from Caco-2 cells. These results suggest that caffeine indirectly suppresses lipid accumulation in 3T3-L1 adipocytes through decreasing secretion of inflammatory cytokines from Caco-2 cells.
Center for Academic Publications Japan, 2017年, Journal of Nutritional Science and Vitaminology, 63 (5), 331 - 338, 英語[査読有り]
研究論文(学術雑誌)
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.
ELSEVIER SCIENCE BV, 2016年11月, FOOD RESEARCH INTERNATIONAL, 89, 716 - 723, 英語[査読有り]
研究論文(学術雑誌)
Several p-terphenyl compounds have been isolated from the edible Chinese mushroom Thelephora vialis. Vialinin A, a p-terphenyl compound, strongly inhibits tumor necrosis factor-alpha production and release. Vialinin A inhibits the enzymatic activity of ubiquitin-specific peptidase 5, one of the target molecules in RBL-2H3 cells. Here we examined the inhibitory effect of p-terphenyl compounds, including vialinin A, against sentrin/SUMO-specific protease 1 (SENP1) enzymatic activity. The half maximal inhibitory concentration values of vialinin A and thelephantin G against full-length SENP1 were 1.64 +/- 0.23 mu M and 2.48 +/- 0.021 mu M, respectively. These findings suggest that p-terphenyl compounds are potent SENPI inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.
PERGAMON-ELSEVIER SCIENCE LTD, 2016年09月, Bioorganic & Medicinal Chemistry Letters, 26 (17), 4237 - 4240, 英語[査読有り]
研究論文(学術雑誌)
In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well-defined glycogen immunoreactive signals compared with the conventional periodic acid-Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3-CA1 and striatum had a 'patchy' appearance with glycogen-rich and glycogen-poor astrocytes appearing in alternation. The glycogen patches were more evident with large-molecule glycogen in young adult mice but they were hardly observable in aged mice (1-2 years old). Our results reveal brain region-dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes.
WILEY, 2016年09月, GLIA, 64 (9), 1532 - 1545, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Prostate cancer grows under hypoxic conditions. Hypoxia decreases androgen receptor (AR) protein levels. However, the molecular mechanism remains unclear. Here, we report that p62-mediated autophagy degrades AR protein and suppresses apoptosis in prostate cancer LNCaP cells in hypoxia. In LNCaP cells, hypoxia decreased AR at the protein level, but not at the mRNA level. Hypoxia-induced AR degradation was inhibited not only by knockdown of LC3, a key component of the autophagy machinery, but also by knockdown of p62. Depletion of p62 enhanced hypoxia-induced poly(ADP-ribose) polymerase cleavage and caspase-3 cleavage, markers of apoptosis, whereas-simultaneous knockdown of p62 and AR suppressed hypoxia-induced apoptosis. Hypoxia increased the formation of a cytosolic p62-AR complex and enhanced sequestration of AR from the nucleus. Formation of this complex was promoted by the increased phosphorylation of serine 403 in the ubiquitin-associated domain of p62 during hypoxia. An antioxidant and an AMP-activated protein kinase (AMPK) inhibitor reduced hypoxia-induced p62 phosphorylation at serine 403 and suppressed hypoxia-induced complex formation between AR and p62. These results demonstrate that hypoxia enhances the complex formation between p62 and AR by promoting phosphorylation of p62 at serine 403, probably through activating AMPK, and that p62-mediated autophagy degrades AR protein for cell survival in hypoxia. (C) 2015 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2015年10月, CELLULAR SIGNALLING, 27 (10), 1994 - 2001, 英語[査読有り]
研究論文(学術雑誌)
Soy beta-conglycinin (beta CG) consumption has been shown to improve insulin resistance and suppress diet-induced obesity. These physiological effects seem to be mediated by the normalization of adiponectin and insulin sensitivity. Here, we show that artificial enzyme-hydrolyzed beta CG peptides promote uptake of 2-deoxyglucose, a glucose analogue, accompanied by translocation of glucose transporter 4 in skeletal L6 myotubes. Inhibition of AMP-activated protein kinase (AMPK) attenuated beta CG peptides-induced glucose uptake activity, while inhibition of both insulin and nitrogen monoxide signaling did not affect the glucose uptake activity. Taken together, these results indicate that beta CG peptides directly induced glucose uptake through the AMPK signaling pathway in muscle cells and might function to prevent insulin resistance.
KARGER, 2015年09月, Food Science and Technology Research, 21 (5), 727 - 732, 英語[査読有り]
研究論文(学術雑誌)
Tea catechins promote glucose uptake in skeletal muscle cells. In this study, we investigated whether the addition of an acyl group to the C-3 position of catechins to generate 3-O-acyl-catechins promoted glucose uptake in L6 myotubes. 3-O-Myristoyl-(-)-epicatechin (EC-C14) and 3-O-palmitoyl-(-)-epicatechin (EC-C16) promoted glucose uptake and translocation of glucose transporter (GLUT) 4 in the cells. The effect of 3-O-acyl-(-)-epicatechins was stronger than that of (-)-epicatechin (EC), whereas neither 3-O-myristoyl-(+)-catechin (C-C14) nor 3-O-palmitoyl-(+)catechin (C-C16) promoted glucose uptake or GLUT4 translocation as well as (+)-catechin (C). We further investigated an affinity of catechins and 3-O-acyl-catechins to the lipid bilayer membrane by using surface plasma resonance analysis. Maximum binding amounts of EC-C16 and C-C16 to the lipid bilayer clearly increased compared with that of (-)-EC and (+)-C, respectively. We also examined the mechanism of GLUT4 translocation and found EC-C14 and EC-C16 induced the phosphorylation of PI3K, but did not affect phosphorylation of Akt or IR. In conclusion, the addition of an acyl group to the C-3 position of (-)-EC increases its affinity for the lipid bilayer membrane and promotes GLUT4 translocation through PI3K-dependent pathways in L6 myotubes.
MDPI AG, 2015年07月, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 16 (7), 16288 - 16299, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
We previously reported that the intake of black tea promotes translocation of the insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle. In this study, we investigated whether black tea polyphenols (BTP) promote GLUT4 translocation in L6 myotubes. BTP promoted glucose uptake accompanied by GLUT4 translocation in L6 myotubes. As the molecular mechanism, BTP induced the phosphorylation of insulin receptor substrate-1, atypical protein kinase C, Akt Thr308, Akt substrate 160, and AMP-activated protein kinase (AMPK), but did not affect that of Akt Ser473. BTP increased glycogen accumulation through inactivation of glycogen synthase kinase 3 beta (GSK-3 beta). Theaflavin, one of the major components in black tea, also promoted the glucose uptake accompanied by GLUT4 translocation observed with BTP in L6 myotubes. These results indicate that BTP activates both PI3K- and AMPK-dependent pathways to promote GLUT4 translocation and glycogen accumulation in skeletal muscle cells. Moreover, theaflavin is one of the active components in BTP.
KARGER, 2015年05月, FOOD SCIENCE AND TECHNOLOGY RESEARCH, 21 (3), 489 - 494, 英語[査読有り]
研究論文(学術雑誌)
To develop a functional food for improvement and/or prevention of diabetic nephropathy, we investigated whether catechins can activate DGK alpha, which is involved in the vitamin E-induced improvement of diabetic renal dysfunction. Among the catechins tested, (-)-epicatechin-3-gallate, (-)-epigallocatechin-3-gallate (EGCg), (-)-catechin-3-gallate and (-)-gallocatechin-3-gallate induced DGKa translocation from the cytoplasm to the plasma membrane, which is an index of DGKa activation. In contrast, (-)-epicatechin, (-)epigallocatechin and gallic acid did not induce the translocation. Among the four galloylated catechins, EGCg was most effective, dose-dependent and subtype-specific among type I DGKs. Importantly, EGCg did indeed up-regulate DGK alpha activity. In addition, we found that a 67 kDa laminin receptor (67LR) mediates the EGCg-induced activation of DGKa, and both 67LR and DGK alpha; are expressed in podocyte among glomerular cells. Finally, the EGCg-induced translocation of DGKa was confirmed in cultured podocytes. Thus, EGCg activates DGKa via 67LR, providing the possibility that EGCg may improve and/or prevent diabetic renal dysfunction. (C) 2015 Elsevier Ltd. All rights reserved.
ELSEVIER SCIENCE BV, 2015年05月, JOURNAL OF FUNCTIONAL FOODS, 15, 561 - 569, 英語[査読有り]
研究論文(学術雑誌)
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various toxic effects, including wasting syndrome, through activation of an aryl hydrocarbon receptor (AhR). Our previous report demonstrated that certain flavonoids inhibit the activation of AhR and suppress its DNA binding activity. In this study, we searched for an active compound among 13 flavonoids that suppressed TCDD-induced loss of lipid accumulation using 3T3-L1 adipocytes as a cell culture model for wasting syndrome. Two flavonoids, luteolin and epigallocatechin gallate, suppressed TCDD-induced loss of lipid accumulation in this model. We further investigated luteolin to clarify the underlying molecular mechanism and confirmed that luteolin inhibited nuclear translocation of AhR caused by TCDD. Luteolin also inhibited the TCDD-driven decrease in protein expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) and CCAAT/enhancer-binding protein alpha (C/EBP alpha). Although TCDD alone did not change protein expression of C/EBP beta and C/EBP delta, luteolin and TCDD up-regulated C/EBP delta expression in a dose-dependent manner. On the other hand, TCDD significantly decreased DNA binding of C/EBP beta and C/EBP delta, and luteolin completely canceled TCDD-decreased DNA binding of them. We conclude that luteolin suppresses the TCDD-induced loss of lipid accumulation in 3T3-L1 adipocytes by preventing a decrease in protein expression of PPAR gamma and C/EBP alpha, the master regulators of adipocyte differentiation and in DNA binding of C/EBP beta and C/EBP delta. Moreover, luteolin was rapidly incorporated and accumulated in 3T3-L1 adipocytes. Thus, luteolin is an attractive compound for the prevention of TCDD-induced wasting syndrome. (C) 2014 Elsevier Inc. All rights reserved.
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015年05月, PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY, 120, 14 - 20, 英語[査読有り]
研究論文(学術雑誌)
Polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) develop various adverse effects through activation of an aryl hydrocarbon receptor (AhR). The suppressive effects of brewed green tea and black tea on 3-methylcholanthrene (MC)-induced AhR activation and its downstream events were examined in the liver of rats. Ad-libitum drinking of green tea and black tea suppressed MC-induced AhR activation and elevation of ethoxyresorufin O-deethylase activity in the liver, whereas the teas themselves did not induce them. Tea showed a suppressive fashion on the expression of cytochrome P450 1A1 (CYP1A1). Tea suppressed the AhR activation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ex vivo. A part of catechins and theaflavins was present in plasma and liver as conjugated and intact forms. The results of this study suggested that active component(s) of tea are incorporated in the liver and suppress the activity of CYP1As through the AhR activation pathway.
INFORMA HEALTHCARE, 2015年05月, INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION, 66 (3), 300 - 307, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Two main chalcones, 4-hydroxyderricin and xanthoangelol, from Ashitaba, which is a food ingredient and a folk medicine in Asia, have been demonstrated to modulate lipid metabolism in 3T3-L1 and HepG2 cells. In this study, we investigated the effects of Ashitaba extract on adiposity in mice fed a high-fat (HF) diet and its underlying mechanisms based on adipose tissue and hepatic lipid metabolism. C57BL/6 mice were fed a normal or HF diet supplemented with Ashitaba extract (0.01% and 0.1%, w/w) for 16 weeks. Ashitaba extract suppressed the HF diet-induced body weight gain and fat deposition in white adipose tissue, reduced plasma cholesterol, glucose, and insulin levels, increased the adiponectin level, lowered triglyceride and the liver cholesterol content, increased phosphorylation of AMP-activated protein kinase (AMPK) in adipose tissue and liver, inhibited lipogenesis in adipose tissue by down-expression of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding protein 1 (SREBP1), inhibited lipogenesis in the liver by down-expression of SREBP1 and its target enzyme fatty acid synthase, and promoted fatty acid oxidation by up-expression of carnitine palmitoyltransferase-1A and PPAR alpha. In conclusion, Ashitaba extract can possibly prevent adiposity through modulating lipid metabolism through phosphorylation of AMPK in adipose tissue and liver.
ROYAL SOC CHEMISTRY, 2015年, FOOD & FUNCTION, 6 (1), 135 - 145, 英語[査読有り]
研究論文(学術雑誌)
Two main chalcones, 4-hydroxyderricin and xanthoangelol, from Ashitaba, which is a food ingredient and a folk medicine in Asia, have been demonstrated to modulate lipid metabolism in 3T3-L1 and HepG2 cells. In this study, we investigated the effects of Ashitaba extract on adiposity in mice fed a high-fat (HF) diet and its underlying mechanisms based on adipose tissue and hepatic lipid metabolism. C57BL/6 mice were fed a normal or HF diet supplemented with Ashitaba extract (0.01% and 0.1%, w/w) for 16 weeks. Ashitaba extract suppressed the HF diet-induced body weight gain and fat deposition in white adipose tissue, reduced plasma cholesterol, glucose, and insulin levels, increased the adiponectin level, lowered triglyceride and the liver cholesterol content, increased phosphorylation of AMP-activated protein kinase (AMPK) in adipose tissue and liver, inhibited lipogenesis in adipose tissue by down-expression of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding protein 1 (SREBP1), inhibited lipogenesis in the liver by down-expression of SREBP1 and its target enzyme fatty acid synthase, and promoted fatty acid oxidation by up-expression of carnitine palmitoyltransferase-1A and PPAR alpha. In conclusion, Ashitaba extract can possibly prevent adiposity through modulating lipid metabolism through phosphorylation of AMPK in adipose tissue and liver.
ROYAL SOC CHEMISTRY, 2015年, FOOD & FUNCTION, 6 (1), 135 - 145, 英語[査読有り]
研究論文(学術雑誌)
It is well known that tea has a variety of beneficial impacts on human health, including anti-obesity effects. It is well documented that green tea and its constituent catechins suppress obesity, but the effects of other types of tea on obesity and the potential mechanisms involved are not yet fully understood. In this study, we investigated the suppression of adiposity by oolong, black and pu-erh tea and characterized the underlying molecular mechanism in vivo. We found that the consumption of oolong, black or pu-erh tea for a period of one week significantly decreased visceral fat without affecting body weight in male ICR mice. On a mechanistic level, the consumption of tea enhanced the phosphorylation of AMP-activated protein kinase (AMPK) in white adipose tissue (WAT). This was accompanied by the induction of WAT protein levels of uncoupling protein 1 and insulin-like growth factor binding protein 1. Our results indicate that oolong, black and pu-erh tea, and in particular, black tea, suppresses adiposity via phosphorylation of the key metabolic regulator AMPK and increases browning of WAT.
ROYAL SOC CHEMISTRY, 2014年10月, FOOD & FUNCTION, 5 (10), 2420 - 2429, 英語[査読有り]
研究論文(学術雑誌)
Drugs, xenobiotics including environmental pollutants, and certain food components modulate expression of drug-metabolizing enzymes. An aryl hydrocarbon receptor (AhR) possesses possible expression of phase I and phase II enzymes directly by binding of its ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and indirectly by regulating expression of nuclear factor-erythroid-2-related factor 2 (Nrf2). Previous our result demonstrated that luteolin, a natural flavonoid existing in vegetables and herbs, competed the binding of TCDD to AhR. In the present study, we investigated the effect of luteolin on the expression of drug-metabolizing enzymes through the AhR and Nrf2 pathways. Luteolin inhibited TCDD-induced protein expression of phase I enzyme cytochrome P450 1A1 (CYP1A1), phase II enzymes NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutathione-S-transferase P1 (GSTP1) in HepG2, Hepa1c1c7 and RL-34 cells in a dose-dependent manner. Luteolin suppressed TCDD- and tert-butylhydroquinone-induced Nrf2 protein by decreasing its stability in HepG2 cells. In tert-butylhydroquinone treated cells, luteolin dose-dependently inhibited NQO1, GSTP1 and aldo-keto reductases (AKRs). Of these, protein expression of CYP1A1 and GSTP1 was mainly dominated by the AhR pathway, while that of NQO1 and AKRs was by the Nrf2 pathway. In conclusion, luteolin inhibits expression of phase I and phase II drug-metabolizing enzymes by modulating the AhR and Nrf2 pathways. (C) 2014 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2014年09月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 557, 36 - 46, 英語[査読有り]
研究論文(学術雑誌)
The aim of this study is to elucidate the effect of lipid extracts from Solidago canadensis for phytomonitoring of polychlorinated biphenyl (PCB) 126 in the transgenic Arabidopsis plant XgD2V11-6 carrying the recombinant guinea pig (g) aryl hydrocarbon receptor (AhR)-mediated p-glucuronidase (GUS) reporter gene expression system. A lipid extract was prepared from S. canadensis and separated into simple lipid, glycolipid, and phospholipid fractions by silica gel column chromatography. Sterylglucoside (SG), monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and glucosyl ceramide were found in the glycolipid fraction. When the transgenic Arabidopsis plants were treated with the glycolipid fraction together with PCB126, PCB126-induced GUS activity significantly increased in the whole plant Moreover, S. canadensis-derived SG, MGDG, and DGDG also significantly increased PCB126-induced GUS activity. These results indicated that glycolipids in S. canadensis enhanced the sensitivity of this monitoring assay. (C) 2014 Elsevier B.V. All rights reserved.
ELSEVIER SCIENCE BV, 2014年09月, SCIENCE OF THE TOTAL ENVIRONMENT, 491, 240 - 245, 英語[査読有り]
研究論文(学術雑誌)
The present study demonstrates that glabridin, a prenylated isoflavone in licorice, stimulates glucose uptake through the adenosine monophosphate-activated protein kinase (AMPK) pathway in L6 myotubes. Treatment with glabridin for 4 h induced glucose uptake in a dose-dependent manner accompanied by the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane. Glabridin needed at least 4 h to increase glucose uptake, while it significantly decreased glycogen and increased lactic acid within 15 min. Pharmacological inhibition of AMPK by Compound C suppressed the glabridin-induced glucose uptake, whereas phosphoinositide 3-kinase and Akt inhibition by LY294002 and Akt1/2 inhibitor, respectively, did not. Furthermore, glabridin induced AMPK phosphorylation, and siRNA for AMPK completely abolished glabridin-induced glucose uptake. We confirmed that glabridin-rich licorice extract prevent glucose intolerance accompanied by the AMPK-dependent GLUT4 translocation in the plasma membrane of mice skeletal muscle. These results indicate that glabridin may possess a therapeutic effect on metabolic disorders, such as diabetes and hyperglycemia, by modulating glucose metabolism through AMPK in skeletal muscle cells. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
ELSEVIER IRELAND LTD, 2014年08月, MOLECULAR AND CELLULAR ENDOCRINOLOGY, 393 (1-2), 99 - 108, 英語[査読有り]
研究論文(学術雑誌)
Aim: We searched for polyphenols capable of inhibiting the lipid accumulation in 3T3-L1 cells, and investigated the mechanisms of two effective chalcones cardamonin and flavokawain B on differentiation of preadipocytes. Method and results: We treated 3T3-L1 cells with a panel of 46 polyphenols and measured intracellular lipid accumulation by Sudan II staining. Four of them, including cardamonin and flavokawain B, inhibited lipid accumulation. In the further study, cardamonin and flavokawain B inhibited lipid accumulation by downregulating the expression of CCAAT/enhancer binding protein (C/EBP)-beta. C/EBP alpha, and peroxisome proliferator-activated receptor-gamma (PPAR gamma) at both mRNA and protein levels. Cardamonin and flavokawain B also increased phosphorylation of extracellular signal-regulated kinase (ERK) in the early phase of adipocyte differentiation. PD98059, an ERK inhibitor, restored C/EBP beta, PPAR gamma expression and intracellular lipid accumulation in adipocytes. Moreover, cardamonin and flavokawain B also modulated the secretion of C-reactive protein, dipeptidyl peptidase IV, interleukin-6, tumor necrosis factor-alpha and fibroblast growth factor-21 in mature adipocytes. Conclusions: These results indicate that ERk activation and consequent downregulation of adipocyte-specific transcription factors are involved in the inhibitory effects of the chalcones cardamonin and flavokawain B on adipocyte differentiation. Moreover, cardamonin and flavokawain B are able to modulate secretion of adipokines in mature adipocytes. (C) 2014 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2014年07月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 554, 44 - 54, 英語[査読有り]
研究論文(学術雑誌)
Thioredoxin (TRX) is a redox regulating protein which has protective effects against oxidative stress-induced damage to cells and tissues. In this study, we investigated the effects of orally administered TRX derived from edible yeast, Saccharomyces cerevisiae, on gastric mucosa. First, we examined the digestibility of orally administered yeast TRX in mice, and detected yeast TRX in the stomach for 4 h after administration. Next, we investigated the mitigation of gastric mucosal injury after the oral administration of yeast TRX in water-immersion restraint stress and HCl/ethanol-induced gastric ulcer models. Furthermore, we conducted DNA microarray analysis, using the HCl/ethanol-induced model, which revealed that several groups of genes related to tissue repair were upregulated in ulcer regions in the stomachs of rats administered with yeast TRX. These results demonstrated the viability of the use of oral administrations of yeast TRX to protect the gastric mucosa.
TAYLOR & FRANCIS LTD, 2014年07月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 78 (7), 1221 - 1230, 英語[査読有り]
研究論文(学術雑誌)
Excessive lipid accumulation in the liver has been proposed to cause hyperlipidemia, diabetes and fatty liver disease. 4-Hydroxyderricin (4HD), xanthoangelol (XAG), cardamonin (CAR) and flavokawain B (FKB) are chalcones that have exhibited various biological effects against obesity, inflammation, and diabetes; however, little is known about the inhibitory effects of these chalcones on fatty liver disease. In the present study, we investigated the ability of 4HD, XAG, CAR, and FKB to reduce lipid accumulation in hepatocytes. When HepG2 cells were treated with a mixture of fatty acids (FAs; palmitic acid : oleic acid 1 : 2 ratio), significant lipid accumulation was observed. Under the same experimental conditions, addition of chalcones at 5 mu M significantly suppressed the FA-induced lipid accumulation. We found that the expression of sterol regulatory element-binding protein-1 (SREBP-1), a key molecule involved in lipogenesis, was decreased in these chalcone-treated cells. We also found that these chalcones increased the expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), which is involved in FA oxidation. Moreover, these chalcones increased phosphorylation of AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1), upstream regulators of SREBP-1 and PPAR alpha. We confirmed that an AMPK inhibitor, compound C, reversed chalcone-induced changes in SREBP-1 and PPAR alpha expression in the HepG2 cells. Collectively, we found that 4HD, XAG, CAR, and XAG attenuated lipid accumulation through activation of the LKB1/AMPK signaling pathway in HepG2 cells.
ROYAL SOC CHEMISTRY, 2014年06月, FOOD & FUNCTION, 5 (6), 1134 - 1141, 英語[査読有り]
研究論文(学術雑誌)
Resveratrol (3,4',5-trihydroxy-trans-stilbene) is known to enhance the cytotoxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resveratrol and its derivative 3,5-dihydroxy-4'-methoxy-trans-stilbene, but not 3,5-dimethoxy-4'-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 mu M. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxia-inducible factor (HIF)-1 alpha repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIP-1 alpha protein, but not HIP-1 alpha mRNA, and decreased hypoxia-activated HIP-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4'-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4'-hydroxy-trans-stilbene. Furthermore, resveratrol decreased the expression of HIF-1 alpha protein even in the presence of the proteasome inhibitor MC 132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1 alpha-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4'-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1 alpha protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.
CENTER ACADEMIC PUBL JAPAN, 2014年04月, JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY, 60 (2), 122 - 128, 英語[査読有り]
研究論文(学術雑誌)
Although the underlying mechanism is unclear, beta-conglycinin (beta CG), the major component of soy proteins, regulates blood glucose levels. Here, we hypothesized that consumption of beta CG would normalize blood glucose levels by ameliorating insulin resistance and stimulating glucose uptake in skeletal muscle's. To test our hypothesis, we investigated the antidiabetic action of beta CG in spontaneously diabetic Goto-Kakizaki (GK) rats. Our results revealed that plasma adiponectin levels and adiponectin receptor 1 messenger RNA expression in skeletal muscle were higher in beta CG-fed rats than in casein-fed rats. Phosphorylation of adenosine monophosphate-activated protein kinase (AMP kinase) but not phosphatidylinositol-3 kinase was activated in beta CG-fed GK rats. Subsequently, beta CG increased translocation of glucose transporter 4 to the plasma membrane. Unlike the results in skeletal muscle, the increase in adiponectin receptor 1 did not lead to AMP kinase activation in the liver of beta CG-fed rats. The down-regulation of sterol regulatory element-binding factor 1, which is induced by low insulin levels, promoted the increase in hepatic insulin receptor substrate 2 expression. Based on these findings, we concluded that consumption of soy beta CG improves glucose uptake in skeletal muscle via AMP kinase activation and ameliorates hepatic insulin resistance and that these actions may help normalize blood glucose levels in GK rats. (C) 2014 Elsevier Inc. All rights reserved.
PERGAMON-ELSEVIER SCIENCE LTD, 2014年02月, Nutrition Research, 34 (2), 160 - 167, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
研究論文(国際会議プロシーディングス)
The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In. the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 mu M) and xanthoangelol (5 mu M) compared with their parent compound, chalcone (25 mu M). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-alpha) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-kappa B. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-kappa B. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.
AMER CHEMICAL SOC, 2014年01月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 62 (2), 462 - 467, 英語[査読有り]
研究論文(学術雑誌)
研究論文(国際会議プロシーディングス)
[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
研究論文(国際会議プロシーディングス)
研究論文(国際会議プロシーディングス)
Carcinogenicity induced by phase I and phase II drug-metabolizing enzymes (DMEs) involves the following: certain procarcinogens are metabolized and activated into carcinogens by phase I CYPs or phase II GSTs, and the resultant carcinogens bind with biological macromolecules this is an initiation step of carcinogenicity. Conversely, multidrug resistance is caused by an overexpression of transporters excreting chemotherapeutic agents in cancer cells. Naturally occurring polyphenols have been reported to possess anticancer effects. In this review, strategies for preventing carcinogenicity involving DMEs and transporters by polyphenols are discussed. Regarding DMEs, the balance of phase I and phase II enzymes is important for preventing carcinogenicity, and tea polyphenols, flavonoids, curcumin and resveratrol are candidates for suppressing tumorigenesis. Tea polyphenols, flavonoids, resveratrol, tannic acid, and curcumin all inhibit, or modulate, ABC transporters, and could prevent multidrug resistance in cancer cells. © 2014 Elsevier Inc. All rights reserved.
Elsevier Inc., 2013年11月, Polyphenols in Human Health and Disease, 2, 1127 - 1135, 英語[査読有り]
論文集(書籍)内論文
Scope: Adipocytes differentiation is deeply involved in the onset of obesity. 4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are the chalcones that are derived from Ashitaba (Angelica keiskei). In this study, we demonstrated the inhibitory effects of these chalcones on adipocytes differentiation. Methods and results: 4HD and XAG suppressed intracellular lipid accumulation by Oil red O staining at 5 μM without cytotoxicity. They inhibited adipocytes differentiation accompanied by down-expression of adipocyte-specific transcription factors, CCAAT/enhancer-binding protein-β (C/EBP-β), C/EBP-α, and peroxisome proliferator-activated receptor gamma (PPAR-γ) using RT-PCR and Western blotting analysis. To obtain insights into the underlying mechanism, the activation of AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase pathways was investigated. These two chalcones promoted phosphorylation of AMPK and acetyl CoA carboxylase during differentiation of 3T3-L1 adipocytes accompanied by a decrease in glycerol-3-phosphate acyl transferase-1 and an increase in carnitine palmitoyltransferase-1 mRNA expression. These chalcones also promoted phosphorylation of extracellular signal-regulated kinases and Jun aminoterminal kinases, but not p38. Moreover, the inhibitors for AMPK and extracellular signal-regulated kinases abolished the chalcones-caused down-expression of C/EBP-β, C/EBP-α, and PPAR-γ. Treatment with Jun aminoterminal kinases inhibitor abolished the down-expression of C/EBP-α and PPAR-γ, but not C/EBP-β. Conclusion: 4HD and XAG inhibit adipocytes differentiation through AMPK and mitogen-activated protein kinase pathways, resulting in the down-expression of adipocyte-specific transcription factors. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
2013年10月, Molecular Nutrition and Food Research, 57 (10), 1729 - 1740, 英語[査読有り]
研究論文(学術雑誌)
Scope10-Hydroxy-2-decenoic acid (10H2DA) is one of the unique medium-chain fatty acids (MCFAs) specifically found in royal jelly. We hypothesize that 10H2DA has multiple biological functions and may aid in 5-AMP-activated protein kinase (AMPK) activation and affect the glucose transport system in skeletal muscle. Methods and resultsWe examined whether various MCFAs present in royal jelly activated AMPK. Treatment of L6 myotubes with various MCFAs showed that 10H2DA administration resulted in a significant increase in phosphorylated AMPK. 10H2DA activates AMPK independently of insulin and significantly increased glucose uptake into L6 myotubes following translocation of glucose transporter 4 (Glut4) to the plasma membrane (PM). The activation was induced by the upstream kinase Ca2+/calmodulin-dependent kinase kinase , but was independent of changes in AMP:ATP ratio and the liver kinase B1 pathway. Oral administration of 10H2DA significantly stimulated phosphorylation of AMPK and Glut4 translocation to the PM in mouse skeletal muscle. ConclusionThese findings indicate that (i) 10H2DA activates AMPK, and insulin independently enhances glucose uptake following translocation of Glut4 to PM, (ii) activation of AMPK by 10H2DA is mediated via extracellular Ca2+-dependent Ca2+/calmodulin-dependent kinase kinase , without alteration in the AMP:ATP ratio, and liver kinase B1 was not involved in the activation.
WILEY-BLACKWELL, 2013年10月, MOLECULAR NUTRITION & FOOD RESEARCH, 57 (10), 1794 - 1802, 英語[査読有り]
研究論文(学術雑誌)
Previously, we developed enzymatically synthesized glycogen (ESG) from starch, and showed its immunomodulatory and dietary fiber-like activities. In this study, we investigated the metabolism of ESG and its immunomodulatory activity using differentiated Caco-2 cells as a model of the intestinal barrier. In a co-culture system consisting of differentiated Caco-2 cells and RAW264.7 macrophages, mRNA expression of IL-6, IL-8, IL-1 beta and BAFF cytokines was up-regulated in Caco-2 cells and IL-8 production in basolateral medium was induced after 24 h apical treatment with 5 mg ml(-1) of ESG. The mRNA level of iNOS was also up-regulated in RAW264.7 macrophages. After characterization of the binding of anti-glycogen monoclonal antibodies (IV58B6 and ESG1A9) to ESG and its digested metabolite resistant glycogen (RG), an enzyme-linked immunosorbent assay (ELISA) system was developed to quantify ESG and RG. Using this system, we investigated the metabolism of ESG in differentiated Caco-2 cells. When ESG (7000 kDa, 5 mg ml(-1)) was added to the apical side of Caco-2 monolayers, ESG disappeared and RG (about 3000 kDa, 3.5 mg ml(-1)) appeared in the apical solution during a 24 h incubation. Neither ESG nor RG was detected in the basolateral solution. In addition, both ESG and RG were bound to TLR2 in Caco-2 cells. In conclusion, we suggest that ESG is metabolized to a RG-like structure in the intestine, and this metabolite activates the immune system via stimulation of the intestinal epithelium, although neither ESG nor its metabolite could permeate the intestinal cells under our experimental conditions. These results provide evidence for the beneficial function of ESG as a food ingredient.
ROYAL SOC CHEMISTRY, 2013年09月, FOOD & FUNCTION, 4 (9), 1387 - 1393, 英語[査読有り]
研究論文(学術雑誌)
Based on a recent study indicating that enzymatically synthesized glycogen (ESG) possesses a dietary, fiber-like action, we hypothesized that ESG can reduce the risk of obesity. In this study, the antiobesity effects of ESG were investigated in a model of diet-induced obesity. Male Sprague-Dawley rats were divided into 4 groups and fed a normal or high-fat diet, with or without 20% ESG, for 4 weeks. Body weight, food intake, lipid deposition in the white adipose tissues and liver, fecal lipid excretion, and plasma lipid profiles were measured. At week 3, the body fat mass was measured using an x-ray computed tomography system, which showed that ESG significantly suppressed the high-fat diet induced lipid accumulation. Similar results were observed in the weight of the adipose tissue after the experiment. Moreover, ESG significantly suppressed the lipid accumulation in the liver but increased fecal lipid excretion. The plasma concentrations of triacylglycerol and nonesterified fatty acid were lowered after a high-fat diet, whereas the total bile acid concentration was increased by ESG. However, the hepatic messenger RNA (mRNA) levels of enzymes related to lipid metabolism were not affected by ESG. Conversely, the mRNA levels of long-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase were up-regulated by ESG in the muscle. These results suggest that the combined effects of increased fecal lipid excretion, increased mRNA levels of enzymes that oxidize fatty acids in the muscle, and increased total bile acid concentration in the plasma mediate the inhibitory effect of ESG on lipid accumulation. (C) 2013 Elsevier Inc. All rights reserved.
PERGAMON-ELSEVIER SCIENCE LTD, 2013年09月, NUTRITION RESEARCH, 33 (9), 743 - 752, 英語[査読有り]
研究論文(学術雑誌)
It is well known that propolis has the ability to prevent hyperglycemia. However, the underlying mechanism is not yet fully understood. We therefore investigated whether a Brazilian propolis ethanol extract affects glucose uptake and translocation of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle cells. In L6 myotubes, the extract at 1 g/mL significantly promoted GLUT4 translocation and glucose uptake activity. Regarding the mechanism of GLUT4 translocation, propolis extract induced both PI3K and AMPK phosphorylation in a dose-dependent manner in L6 myotubes. However, we could not define which pathway was preferentially associated with GLUT4 translocation, because both PI3K and AMPK inhibitors revealed off-target effects to each other. The main polyphenols found in the propolis extract, artepillin C, coumaric acid, and kaempferide, promoted GLUT4 translocation in L6 myotubes. Additionally, these compounds activated both PI3K- and AMPK-dependent dual-signaling pathways. However, only kaempferide increased glucose uptake activity under our experimental conditions. Single oral administrations of propolis extract, at 250 mg/kg body weight, lowered postprandial blood glucose levels in ICR mice. The extract promoted GLUT4 translocation in skeletal muscle of rats and mice, but did not inhibit -glucosidase activity in the small intestine under our experimental conditions. It was confirmed that propolis extract promoted phosphorylation of both PI3K and AMPK in rat skeletal muscle. In conclusion, we show that Brazilian propolis has the potential to prevent hyperglycemia through the promotion of GLUT4 translocation in skeletal muscle and that kaempferide is one of the candidates for active compound in propolis. (c) 2013 BioFactors, 39(4):457-466, 2013
WILEY-BLACKWELL, 2013年07月, BIOFACTORS, 39 (4), 457 - 466, 英語[査読有り]
研究論文(学術雑誌)
Black soybean seed coat is a rich source of polyphenols reported to have various physiological functions. The present study investigated the potential protective effects of polyphenolic extracts from black soybean seed coat on mutagen-induced DNA damage in Salmonella typhimurium. Results from the Ames test using Salmonella stains revealed that black soybean seed coat extract (BE) at 5000 mu g/plate showed neither mutagenicity nor cytotoxicity. In contrast, BE, its component cyanidin 3-glucoside (C3G), or procyanidin-rich BE (PC-rich BE) dose-dependently inhibited B(a)P- and 4NQO-induced mutagenesis in the rank order: C3G > BE > PC-rich BE. At 5 mu M/plate, C3G and procyanidins, the major polyphenols in BE, inhibited B(a)P-induced mutagenesis in TA 98 and TA 100 by 28 - 59%. They also inhibited 4NQO-induced mutagenesis by 26 - 56%. Collectively, we found that C3G and procyanidins, which are the main active compounds in BE, effectively protected against DNA mutagenic damage in Salmonella typhimurium.
KARGER, 2013年07月, FOOD SCIENCE AND TECHNOLOGY RESEARCH, 19 (4), 685 - 690, 英語[査読有り]
研究論文(学術雑誌)
Black soybean seed coat has abundant levels of polyphenols such as anthocyanins (cyanidin 3-glucoside C3G) and procyanidins (PCs). This study found that dietary black soybean seed coat extract (BE) ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in type 2 diabetic mice. Dietary BE significantly reduced blood glucose levels and enhanced insulin sensitivity. AMPK was activated in the skeletal muscle and liver of diabetic mice fed BE. This activation was accompanied by the up-regulation of glucose transporter 4 in skeletal muscle and the down-regulation of gluconeogenesis in the liver. These changes resulted in improved hyperglycemia and insulin sensitivity in type 2 diabetic mice. In vitro studies using L6 myotubes showed that C3G and PCs significantly induced AMPK activation and enhanced glucose uptake into the cells. © 2013 American Chemical Society.
2013年06月12日, Journal of Agricultural and Food Chemistry, 61 (23), 5558 - 5564, 英語[査読有り]
研究論文(学術雑誌)
Simple pharmacological studies on inositol stereoisomers are presented in this study. Male ICR mice were orally administered 1 g/kg BW of three inositol stereoisomers, myo-inositol (MI), d-chiro-inositol (DCI), and scyllo-inositol (SI), and blood plasma samples and skeletal muscle fractions were prepared after an hour. The plasma samples were subjected to gas chromatography-coupled time-of-flight mass spectrometry (GC-TOF-MS) analysis. None of the three stereoisomers was seen in untreated samples, but substantial amounts ranging from 2.5 to 6.5 mM were detected only after administration, indicating that orally administered inositol stereoisomers were readily absorbed and their levels elevated in the bloodstream. In addition, plasma of SI-administered animals contained substantial MI, suggesting a possible metabolic conversion of SI to MI. In the skeletal muscle fractions, glucose transporter type 4 (GLUT4) content in the plasma membrane increased, indicating that inositol stereoisomers stimulated GLUT4 translocation. © 2013 American Chemical Society.
2013年05月22日, Journal of Agricultural and Food Chemistry, 61 (20), 4850 - 4854, 英語[査読有り]
研究論文(学術雑誌)
Black soybean seed coat is a rich source of polyphenols that have been reported to have various physiological functions. The present study investigated the potential protective effects of polyphenolic extracts from black soybean seed coat on DNA damage in human hepatoma HepG2 cells and ICR mice. The results from micronucleus (MN) assay revealed that black soybean seed coat extract (BE) at concentrations up to 25 mu g/mL was non-genotoxic. It is noteworthy that BE (at 4.85 mu g/mL) and its main components, procyanidins (PCs) and cyanidin 3-glucoside (C3G), at 10 mu M significantly reduced the genotoxic effect induced by benzo[a]pyrene [B(a)P]. To obtain insights into the underlying mechanism, we investigated BE and its main components on drug-metabolizing enzyme expression. The results of this study demonstrate that BE and its main components, PCs and C3G, down-regulated B(a)P-induced cytochrome P4501A1 (CYP1A1) expression by inhibiting the transformation of aryl hydrocarbon receptor. Moreover, they increased expression of detoxifying defense enzymes, glutathione S-transferases (GSTs) via increasing the binding of nuclear factor-erythroid-2-related factor 2 to antioxidant response elements. Collectively, we found that PCs and C3G, which are the main active compounds of BE, down-regulated CYP1A1 and upregulated GST expression to protect B(a)P-induced DNA damage in HepG2 cells and ICR mice effectively. (c) 2013 Elsevier B.V. All rights reserved.
ELSEVIER SCIENCE BV, 2013年04月, MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 752 (1-2), 34 - 41, 英語[査読有り]
研究論文(学術雑誌)
研究論文(研究会,シンポジウム資料等)
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Procyanidins are oligomers and polymers of flavan-3- ols consisting of (-)-epicatechin subunits. In this study, we isolated and purified dimeric, trimeric and tetrameric procyanidins from cacao liquor and investigated their influence on the "incretin effect" as compared to the monomer, (-)-epicatechin in mice. Cinnamtannin A2 specifically increased the glucagon-like peptide-1 (GLP-1) and insulin secretion levels in the plasma after 60 min administration. As evidence of the action of insulin, activation of insulin receptor and insulin receptor substrate-1 was observed in the soleus muscle. These results indicate that the intake of cinnamtannin A2 may improve hyperglycemia through an incretinlike effect, accompanied by activation of the insulinsignaling pathway.
2013年, Bioscience, Biotechnology and Biochemistry, 77 (4), 888 - 891, 英語[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
研究論文(学術雑誌)
Coffee has an anti-diabetic effect, specifically the amelioration of both hyperglycemia and insulin resistance, in KK-A(y) mice, a type 2 diabetes animal model. To investigate coffee's effect on insulin signaling in liver, skeletal muscle, and adipose tissue (epididymal fat), we assayed the tyrosine phosphorylation of insulin receptor (IR) and serine phosphorylation of Akt. In Expt. 1, we assayed insulin signaling under nonfasting conditions in KK-A(y) mice that ingested water or coffee for 4 wk. Coffee ingestion ameliorated the development of hyperglycemia but did not affect insulin signaling in liver or skeletal muscle under such conditions. In Expt. 2, we assayed insulin signaling under basal and insulin-stimulated conditions in KK-A(y) mice that ingested water or coffee for 3 wk. The levels of tyrosine phosphorylation of insulin receptor in response to insulin injection in insulin-sensitive tissues were not different between mice that drank water and those that drank coffee. Coffee ingestion significantly increased the insulin-induced serine phosphorylation of Akt in liver and skeletal muscle, but not in epididymal fat, of KK-A(y) mice. Our results also indicated that coffee ingestion may contribute to the improvement of insulin resistance and hyperglycemia in KK-A(y) mice via the activation of Akt in insulin signaling in liver and skeletal muscle.
CENTER ACADEMIC PUBL JAPAN, 2012年12月, JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY, 58 (6), 408 - 414, 英語[査読有り]
研究論文(学術雑誌)
The antihyperglycemic effects of tea are well documented. However; the effects of fermented tea on the translocation of glucose transporter 4 (GLUT4), the major glucose transporter for glucose uptake in the postprandial period, in skeletal muscle and the underlying molecular mechanisms are not fully understood. This study investigated the translocation of GLUT4 and its related signaling pathways in skeletal muscle of male ICR mice given fermented tea. Intake of oolong, black, or pu-erh tea for 7 days enhanced GLUT4 translocation to the plasma membrane of skeletal muscle. Each type of fermented tea stimulated the phosphorylation of phosphoinositide 3-kinase (PI3K), Akt/protein kinase B, and AMP-activated protein kinase (AMPK). Fermented tea also increased the protein expression of insulin receptor. These results strongly suggest that fermented tea activates both PI3K/Akt- and AMPK-dependent signaling pathways to induce GLUT4 translocation and increases the expression of insulin receptor to improve glucose intolerance.
AMER CHEMICAL SOC, 2012年11月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 60 (45), 11366 - 11371, 英語[査読有り]
研究論文(学術雑誌)
In this study, we investigated whether cacao liquor procyanidin (CLPr) extract, which consists of 4.3% catechin, 61% epicatechin, 39.4% procyanidins and others, ameliorated hyperglycemia and obesity in C57BL/6 mice fed a control or high-fat diet for 13 weeks. CLPr suppressed high-fat diet-induced hyperglycemia, glucose intolerance and fat accumulation in white adipose tissue. CLPr also promoted translocation of glucose transporter 4 (GLUT4) and phosphorylation of AMP-activated protein kinase alpha (AMPK alpha) in the plasma membrane of skeletal muscle and brown adipose tissue. Phosphorylation of AMPK alpha was also enhanced in the liver and white adipose tissue. CLPr up-regulated the gene and protein expression levels of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 in skeletal muscle. These results indicate that CLPr is a beneficial food material for the prevention of hyperglycemia and obesity. Activation of AMPK alpha, translocation of GLUT4 and up-regulation of UCP expression in skeletal muscle and adipose tissue are involved in the molecular mechanisms by which CLPr prevents hyperglycemia and obesity. (C) 2012 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2012年11月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 527 (2), 95 - 104, 英語[査読有り]
研究論文(学術雑誌)
Background: beta-Glucans obtained from fungi, such as baker's yeast (Saccharomyces cerevisiae)-derived beta-glucan (BBG), potently activate macrophages through nuclear factor kappa B (NF kappa B) translocation and activation of its signaling pathways. The mechanisms by which beta-glucans activate these signaling pathways differ from that of lipopolysaccharide (LPS). However, the effects of beta-glucans on LPS-induced inflammatory responses are poorly understood. Here, we examined the effects of BBG on LPS-induced inflammatory responses in RAW264.7 mouse macrophages. Methods: We explored the actions of BBG in RAW264.7 macrophages. Results: BBG inhibited LPS-stimulated nitric oxide (NO) production in RAW264.7 macrophages by 35-70% at concentrations of 120-200 mu g/ml. BBG also suppressed mRNA and protein expression of LPS-induced inducible NO synthase (iNOS) and mitogen-activated protein kinase phosphorylation, but not NF kappa B activation. By contrast, a neutralizing antibody against dectin-1, a beta-glucan receptor, did not affect BBG-mediated inhibition of NO production. Meanwhile, BBG suppressed Pam3CSK-induced NO production. Moreover, BBG suppressed LPS-induced production of pro-and anti-inflammatory cytokines, including interleukin (IL)-1 alpha, IL-1ra, and IL-27. Conclusions: Our results indicate that BBG is a powerful inhibitor of LPS-induced NO production by down-regulating iNOS expression. The mechanism involves inactivation of mitogen-activated protein kinase and TLR2 pathway, but is independent of dectin-1. General significance: BBG might be useful as a novel agent for the chemoprevention of inflammatory diseases. (c) 2012 Elsevier B.V. All rights reserved.
ELSEVIER SCIENCE BV, 2012年10月, Biochmica Biophysica et Acta, General Subject, 1820 (10), 1656 - 1663, 英語[査読有り]
研究論文(学術雑誌)
Grape pomace is generated in the production process of wine and grape juices and is an industrial waste. This study investigated whether an intake of grape pomace was able to suppress chronic inflammation induced by lipopolysaccharide (LPS) and galactosamine (GalN) in vivo. When Sprague-Dawley rats were orally given methanolic extracts from red and white grape pomace, the extracts inhibited the LPS/GalN-evoked activation of nuclear factor-kappa B (NF-kappa B) dose-dependently, and red grape pomace exerted a stronger effect than white grape one. Next, rats were fed an AIN93 M-based diet containing 5% red grape pomace for 7 days, followed by the intraperitoneal injection of LPS and GalN. The intake of the red grape pomace-supplemented diet was found to suppress the LPS/GalN-induced activation of NF-kappa B and expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. These results suggest that red grape pomace may contain an abundance of effective compound(s) for anti-inflammatory action.
AMER CHEMICAL SOC, 2012年09月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 60 (36), 9315 - 9320, 英語[査読有り]
研究論文(学術雑誌)
To investigate the absorption and metabolism of 4-hydroxyderricin and xanthoangelol, we established an analytical method based on liquid chromatography-tandem mass spectrometry and measured these compounds, in the plasma, urine, feces, liver, kidney, spleen, muscle and white adipose tissues of mice orally administered with Ashitaba extract (50-500 mg/kg body weight). 4-Hydroxyderricin and xanthoangelol were quickly absorbed into the plasma, with time-to-maximum plasma concentrations of 2 and 0.5 h for 4-hydroxyderricin and xanthoangelol, respectively. Although these compounds have similar structures, the total plasma concentration of 4-hydroxyderricin and its metabolites was approximately 4-fold greater than that of xanthoangelol and its metabolites at 24 h. 4-Hydroxyderricin and xanthoangelol were mostly excreted in their aglycone forms and related metabolites (glucuronate and/or sulfate forms) in urine between 2 and 4 h after oral administration of Ashitaba extract. On the other hand, these compounds were only excreted in their aglycone forms in feces. When tissue distribution of 4-hydroxyderricin and xanthoangelol was estimated 2 h after administration of Ashitaba extract, both compounds were detected in all of the tissues assessed, mainly in their aglycone forms, except in the mesenteric adipose tissue. These results suggest that 4-hydroxyderricin and xanthoangelol are rapidly absorbed and distributed to various tissues. (C) 2012 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2012年05月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 521 (1-2), 71 - 76, 英語[査読有り]
研究論文(学術雑誌)
Procyanidins are thought to be effective for prevention of hyperglycemia. To clarify the degree of polymerization (DP) of procyanidins on anti-hyperglycemic effects, we prepared low-DP (DP <= 3) and high-DP (DP >= 4) procyanidin fractions from cacao liquor, and examined whether these procyanidin fractions prevent hyperglycemia in vitro. We found that both fractions promoted glucose uptake in L6 myotubes in a dose-dependent manner accompanied by translocation of GLUT4 to the plasma membrane. Moreover, both fractions stimulate phosphorylation of AMP-activated protein kinase (AMPK). In these beneficial effects, low-DP fraction was more effective than high-DP one. On the other hand, high-DP fraction showed greater inhibitory effect of intestinal alpha-glucosidase activity than low-DP fraction in a cell free-incubation system. In conclusion, cacao liquor procyanidins have anti-hyperglycemic activities and low-DP procyanidins mainly contribute to stimulate glucose uptake by glucose transporter 4 translocation through AMPK-dependent pathway in skeletal muscle while high-DP procyanidins mainly contributes to inhibit the alpha-glucosidase activity in small intestine.
BUREAU FOOD DRUG ANALYSIS, 2012年04月, JOURNAL OF FOOD AND DRUG ANALYSIS, 20, 283 - 287, 英語[査読有り]
研究論文(学術雑誌)
A new descriptor showing the positions of functional groups in compounds with the same main backbone was developed. This descriptor was applied to the Quantitative Structure-Activity Relationship (QSAR) study on the suppression activities of anthraquinones via transformation of the aryl hydrogen receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin. It was shown that the newly developed descriptor played an important role in the QSAR study.
KARGER, 2012年03月, FOOD SCIENCE AND TECHNOLOGY RESEARCH, 18 (2), 173 - 176, 英語[査読有り]
研究論文(学術雑誌)
For immunological experiments on glycogens, anti-glycogen antibodies are indispensable to capture, detect, and visualize sugar molecules. An anti-glycogen monoclonal antibody (IV58B6) and newly constructed antibody (ESG1A9mAb) have a common immunoglobulin type (IgM) and binding ability to glycogens, but overall possess different binding features. Therefore, they may prove useful for the construction of an advanced system of quantitative ELISA based on their molecular structures. For this purpose, detailed information on the carbohydrate-specificities of ESG1A9mAb and IV58B6 is first required, but their fine specificities for various types of glycogens have not been elucidated. To overcome this problem, we performed interaction analysis by ELISA of ESG1A9mAb and IV58B6 toward 15 glucose polymers, that is, 5 enzymatically-synthesized glycogens (ESGs), 6 natural source glycogens (NSGs), 3 enzymatically digested glycogens (EDGs), and soluble starch. To provide a more detailed analysis, we determined the association constants (K-a) of the two antibodies toward these glycogens by surface plasmon resonance. The results indicated that the carbohydrate-binding properties toward NSGs of ESG1A9mAb and IV58B6 were similar, but markedly differed for ESGs and EDGs. ESG1A9mAb showed significant affinity for all the ESGs and NSGs tested, whereas IV58B6 had only slight affinity for ESGs, although the affinities were increased when the ESGs were enzymatically digested. This information should be helpful for the design of both in vitro and in vivo immunological assays. (C) 2012 Elsevier Ltd. All rights reserved.
ELSEVIER SCI LTD, 2012年03月, CARBOHYDRATE RESEARCH, 350, 49 - 54, 英語[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
Four glucans (LNT-H, LNT-S, LNT-E, and LNT-B) were successively isolated from the fruiting bodies of Lentinus edodes by hot-water, sonication, enzyme, and NaOH. The chemical structures were characterized by GC, FTIR, and (13)C NMR, which demonstrated that the four samples are (1 -> 3)-beta-D-glucans with (1 -> 6)-glucopyranoside side groups having different molecular weight. The results of viscometry and atomic force microscopy (AFM) proved that LNT-H, LNT-S, LNT-E, and LNT-B exist as stiff triple helices in water and random coil in dimethyl sulfoxide (DMSO). The morphology of the original triple helix was almost dominated by linear shape, but the renatured LNT-B contains some branched structures in AFM image. Among the four glucans, LNT-H, LNT-E, and LNT-B are clearly contaminated by endotoxin, while LNT-S significantly exhibits nitric oxide (NO) inhibition effect in LPS-stimulated RAW 264.7 macrophages in a dose-dependent manner. Therefore, LNT-S is probably used as a promising molecule which can be helpful to the diseases associated with NO overproduction. This is the first primary report dealing with the suppression of LPS-induced NO from macrophage RAW 264.7 cells by Lentinan. (C) 2011 Published by Elsevier Ltd.
ELSEVIER SCI LTD, 2012年01月, CARBOHYDRATE POLYMERS, 87 (2), 1855 - 1862, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Black soybean (Glycine max) has been used for traditional medicine and food in Asian countries, but safety of its hull has not been studied. We conducted acute and chronic oral toxicity studies. For the acute study, an extract of black soybean hull (BE; 2.5 g/kg body weight) was administered singly by intragastric intubation to Sprague-Dawley rats and C57BL/6 mice. There was no death or significant decrease in body weight in rats and mice, and the oral LD50 of BE was >2.5 g/kg body weight. In the chronic study, BE was administered at dietary levels of 0% (control), 2.0%, and 5.0% to male and female C57BL/6 mice for 26 weeks. No mortality or toxicologically significant clinical changes were observed through the experimental period. Although body weights, as well as abdominal fat, blood levels of triglyceride and total cholesterol in 5.0% males were significantly lower than that in control and 2.0% groups, these changes were considered not to be adverse. Hematology and histopathological observation revealed no toxicologically significant changes. The no-observed adverse-effect-level of BE was estimated to be 5.0% in the diet (5074.1 mg/kg body weight/day for males and 7617.9 mg/kg body weight/day for females). (C) 2011 Elsevier Ltd. All rights reserved.
PERGAMON-ELSEVIER SCIENCE LTD, 2011年12月, FOOD AND CHEMICAL TOXICOLOGY, 49 (12), 3272 - 3278, 英語[査読有り]
研究論文(学術雑誌)
Skeletal muscles express estrogen receptor (ER) alpha and ER beta. However, the roles of estrogens acting through the ERs in skeletal muscles remain unclear. The effects of 17 beta-estradiol (E2) on myogenesis were studied in C2C12 myoblasts. E2 and an ER alpha-selective agonist propylpyrazole-triol depressed myosin heavy chain (MHC), tropomyosin, and rnyogenin levels and repressed the fusion of myoblasts into myotubes. ER antagonist ICI 182,780 cancelled E2-repressed myogenesis. E2 induced ubiquitin-specific peptidase 19 (USP19) expression during myogenesis. E2 replacement increased USP19 expression in the gastrocnemius and soleus muscles of ovariectomized mice. Knockdown of USP19 inhibited E2-repressed myogenesis. Mutant forms of USP19 lacking deubiquitinating activity increased MHC and tropomyosin levels. E2 decreased ubiquitinated proteins during rnyogenesis, and the E2-decreased ubiquitinated proteins were increased by knockdown of USP19. Propylpyrazole-triol increased USP19 expression, and ICI 182,780 inhibited E2-increased USP19 expression. Overexpression of ER alpha or knockdown of ER beta enhanced the effects of E2 on the levels of USP19, MHC, and tropomyosin, whereas knockdown of ER alpha, overexpression of ER beta, or an ER beta-selective agonist diarylpropionitrile abolished their effects. A mutant form of ER alpha that is constitutively localized in the nucleus increased USP19 expression and decreased MHC and tropomyosin expression in the presence of E2. Furthermore, in skeletal muscle satellite cells, E2 inhibited myogenesis and increased USP19 expression, and diarylpropionitrile repressed E2-increased USP19 expression. These results demonstrate that (i) E2 induces USP19 expression through nuclear ER alpha, (ii) increased USP19-mediated deubiquitiunating activity represses myogenesis, and (iii) ER beta inhibits ER alpha-activated USP19 expression.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011年12月, Journal of Biological Chemistry, 286 (48), 41455 - 41465, 英語[査読有り]
研究論文(学術雑誌)
The aryl hydrocarbon receptor (AhR), which is a member of the basic helix-loop-helix/Per-Arnt-Sim homology superfamily, plays an important role in multiple biological functions, and AhR knockout (AhR KO) animals suffer from a variety of organ disorders including a decline in the efficacy of their immune system. In addition, AhR activation is known to aid the maintenance of homeostasis in vivo. In this study, we investigated whether AhR is functionally associated with intestinal immunity. In in vivo experiments, it was found that dextran sodium sulfate (DSS)-evoked colitis was more severe in AhR KO mice than in C57BL/6J wild type mice. It was also revealed that the administration of DSS increased the expression levels of AhR and CYP1A1 mRNA in the colon epithelium. In addition, oral administration of beta-naphthoflavone (beta NF), a non-toxic agonist of AhR, suppressed the pathogenesis of DSS-induced colitis. beta NF also attenuated DSS-induced colitis. In cell culture experiments, downregulation of AhR in human colon carcinoma SW480 cells enhanced the inflammatory responses evoked by lipopolysaccharide (LPS), and furthermore, AhR activation attenuated LPS-induced inflammatory responses, suggesting that AhR expressing intestinal epithelial cells are involved in the prevention of colitis. Our findings about the potential role of AhR activators in epithelial immune regulation aid our understanding of mucosal homeostasis and inflammatory bowl disease (IBD) and suggest that AhR activation has therapeutic value for the treatment of IBD.
SPRINGER, 2011年09月, DIGESTIVE DISEASES AND SCIENCES, 56 (9), 2532 - 2544, 英語[査読有り]
研究論文(学術雑誌)
Lentinan, a cell wall beta-glucan from the fruiting bodies of Lentinus edodes, is well known to be a biological defense modifier, but the signal transduction pathway(s) induced by Lentinan have not been elucidated. In this study, we extracted Lentinan (LNT-S) by ultrasonication from Lentinus edodes and report that, in murine RAW 264.7 macrophages, LNT-S glucan activated NF-kappa B p65 and triggered its nuclear translocation as determined by Western blotting. Moreover, LNT-S enhanced NF-kappa B-luciferase activity in the Dual-Luciferase gene system assay. Its upstream signaling molecules, MAPKs such as ERK1/2 and JNK1/2, were shown to be activated by assessing the level of phosphorylation in a time- and concentration-dependent manner, but its downstream proinflammatory enzyme, inducible NOS, was not observed. The data evaluated using a TNF-alpha ELISA kit and Griess reagent further demonstrated that no proinflammatory mediators such as TNF-alpha and NO were produced by LNT-S stimulation in RAW 264.7 cells. In contrast, LPS significantly induced inducible NOS expression and increased NO and TNF-alpha production, which are associated with activation of the NF-kappa B p65/p50 heterodimer complex. It is possible that LNT-S did not activate NF-kappa B p65/p50, and the activation of NF-kappa B p65 was not sufficient to stimulate cytokine production. These data demonstrate that LNT-S glucan carries out its immunomodulating activity by activating MAPK signaling pathways without secretion of TNF-alpha and NO.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011年09月, Journal of Biological Chemistry, 286 (36), 31194 - 31198, 英語[査読有り]
研究論文(学術雑誌)
beta-Glucuronidase and sulfatase are the major deconjugating enzymes used in the cleavage of the glucuronate and sulfate moieties, respectively, from certain conjugated food factors including polyphenols. In the present study, we found that compounds having the same molecular weights as catechins were present in Helix pomatia- and/or Abalone entrails-derived beta-glucuronidase and sulfatase by liquid chromatography tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring methods. On the other hand, the same molecular weights as catechins were undetectable in Escherichia coli-derived beta-glucuronidase and Aerobacter aerogenes-derived sulfatase. By high performance liquid chromatography, enzyme-derived catechins were not detected because of approximately 1,000-fold lower sensitivity as compared to LC-MS/MS. These results suggest that the catechins in these enzymes might be attributed to the diets of the organisms as the enzyme sources.
TAYLOR & FRANCIS LTD, 2011年08月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 75 (8), 1506 - 1510, 英語[査読有り]
研究論文(学術雑誌)
Glucose transporter-4 (GLUT4) is a transmembrane protein that plays a major role in insulin-mediated glucose transport in muscle and adipocytes. For glucose transport to occur, the GLUT4 protein needs to be translocated from the intracellular pool to the plasma membrane, and certain compounds may enhance this process. The present study investigated the promotion of glucose uptake in differentiated L6 myotubes by cardamonin, isolated from Alpinia katsumadai. Cardamonin increased translocation of GLUT4 to the plasma membrane in L6 cells, but did not activate protein kinase C zeta/lambda, Akt, or AMP-activated protein-kinase, all of which are known to regulate GLUT4 translocation. The glucose-uptake-promoting activity of cardamonin was not lowered by treatment with a phosphatidylinositol 3'-kinase inhibitor. These results suggest that cardamonin is a promising active compound for maintaining glucose homeostasis, and that it acts via an unknown mechanism that does not involve activation of the downstream insulin signal and AMP-activated protein kinase. Copyright (C) 2011 John Wiley & Sons, Ltd.
WILEY-BLACKWELL, 2011年08月, PHYTOTHERAPY RESEARCH, 25 (8), 1218 - 1224, 英語[査読有り]
研究論文(学術雑誌)
We developed a new process for enzymatically synthesized glycogen (ESG), which is equivalent in physicochemical properties to natural-source glycogen (NSG) except its resistant property to degradation by alpha-amylase in vitro. In this study the metabolic fates of orally administered ESG in rats were investigated by a single oral administration test and a 2 week ingestion test. The glycemic index of ESG was 79. After the 2 week ingestion of ESG, the cecal content and production of short chain fatty acids were significantly increased, the pH value of cecal content was lowered, and the counts of Bifidobacterium and Lactobacillus in feces were significantly increased. Additionally, plasma levels of triacylglycerol and total cholesterol were significantly reduced by ESG. In contrast, NSG did not affect these parameters at all. The results collectively suggest that around 20% of orally administered ESG was transferred to the cecum in the form of polymer and assimilated into short chain fatty acids by microbiota and the polymer affected lipid metabolism.
ROYAL SOC CHEMISTRY, 2011年04月, FOOD & FUNCTION, 2 (3-4), 183 - 189, 英語[査読有り]
研究論文(学術雑誌)
Scope: Glucose uptake in skeletal muscle is crucial for glucose homeostasis. Methods and results: Insulin and muscle contraction increase glucose uptake accompanied by the translocation of glucose transporter (GLUT) 4. In a search for promising foods, which can increase glucose uptake in skeletal muscle, we screened for active polyphenols by assaying for uptake of 2-deoxyglucose (2DG) in rat L6 muscle cells. Among 37 compounds, 4-hydroxyderricin and xanthoangelol, prenylated chalcones abundant in Ashitaba (Angelica keiskei Koidzumi, family Apiaceae), significantly increased 2DG uptake in L6 cells by 1.9-fold at 10 mu M, compared with the level in DMSO-treated control cells. Next, we investigated the effect of these chalcones on the translocation of GLUT4 and its underlying mechanisms. The chalcones increased the GLUT4 level in the plasma membrane of L6 cells, but activated neither protein kinase C zeta/lambda, Akt, nor adenosine monophosphate-activated protein kinase, all of which regulate the GLUT4 translocation. Interestingly, the oral administration of a titrated chalcone-enriched Ashitaba extract containing 150.6 mg/g (dry base) of 4-hydroxyderricin and 146.0 mg/g (dry base) of xanthoangelol suppressed acute hyperglycemia in oral glucose tolerance tests of mice. Conclusions: Ashitaba is a promising functional food for the maintenance of the blood glucose level by inducing skeletal muscle-associated glucose uptake.
WILEY-BLACKWELL, 2011年03月, MOLECULAR NUTRITION & FOOD RESEARCH, 55 (3), 467 - 475, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
Artemisia princeps is commonly used as a food ingredient and in traditional Asian medicine. In this study, we examined the effects of long-term administration of an ethanol extract of A. princeps (APE) on body weight, white adipose tissue, blood glucose, insulin, plasma and hepatic lipids, and adipocytokines in C57BL/6 mice fed a high-fat diet. Daily feeding of a 1% APE diet for 14 weeks normalized elevated body weight, white adipose tissue, and plasma glucose and insulin levels, and delayed impaired glucose tolerance in mice a fed high-fat diet. These events were not observed in mice fed a control diet containing 1% APE. Liver triglyceride and cholesterol levels were similar in mice fed a 1% APE-diet and those fed a control diet. In the high-fat diet groups, APE inhibited hepatic fatty acid synthase (FAS) and suppressed the elevation of plasma leptin, but had no effect on adiponectin levels. These findings suggest that the regulation of leptin secretion by APE may inhibit FAS activity with subsequent suppression of triglyceride accumulation in the liver and adipose tissues. Inhibition of lipid accumulation can, in turn, lead to improvements in impaired glucose tolerance.
ROYAL SOC CHEMISTRY, 2011年01月, FOOD & FUNCTION, 2 (1), 45 - 52, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/Per-ARNT-Sim domain transcription factor, which is activated by various xenobiotic ligands. AHR is known to be abundant in liver tissue and to be associated with hepatic steatosis. However, it has not yet been elucidated how the activation of AHR promotes hepatic steatosis. The aim of this study is to clarify the role of AHR in hepatic steatosis. The intraperitoneal injection of 3-methylcholanthrene (3MC), a potent AHR ligand, into C57BL/6J mice significantly increased the levels of triglycerides and six long-chain monounsaturated fatty acids in the livers of mice, resulting in hepatic microvesicular steatosis. 3MC significantly enhanced the expression level of fatty acid translocase (FAT), a factor regulating the uptake of long-chain fatty acids into hepatocytes, in the liver. In an in vitro experiment using human hepatoma HepG2 cells, 3MC increased the expression level of FAT, and the downregulation of AHR by AHR siRNA led to the suppression of 3MC-induced FAT expression. In addition, the mRNA level of peroxisome proliferator-activated receptor (PPAR) alpha, an upstream factor of FAT, was increased in the livers of 3MC-treated mice. Taking together, AHR activation induces hepatic microvesicular steatosis by increasing the expression level of FAT. (C) 2010 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2010年12月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 504 (2), 221 - 227, 英語[査読有り]
研究論文(学術雑誌)
To investigate the preventive effects of tea on hyperglycemia and insulin resistance, male C57BL/6J mice were given a high-fat diet containing 29% lard and also green or black tea ad libitum for 14 weeks. Both teas suppressed body weight gain and deposition of white adipose tissue caused by the diet. In addition, they improved hyperglycemia and glucose intolerance by stimulating glucose uptake activity accompanied by the translocation of glucose transporter (GLUT) 4 to the plasma membrane in muscle. Long-term consumption of the high-fat diet reduced levels of insulin receptor beta-subunit, GLUT4 and AMP-activated protein kinase a in muscle, and green and black tea suppressed these decreases. The results strongly suggest that green and black tea suppress high-fat diet-evoked hyperglycemia and insulin resistance by retaining the level of GLUT4 and increasing the level of GLUT4 on the plasma membrane in muscle.
AMER CHEMICAL SOC, 2010年12月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 58 (24), 12916 - 12923, 英語[査読有り]
研究論文(学術雑誌)
In this study, we investigated the effects of tea catechins on the translocation of glucose transporter (GLUT) 4 in 3T3-L1 adipocytes. We found that the ethyl acetate fraction of green tea extract, containing abundant catechins, most decreased insulin-induced glucose uptake activity in 3T3-L1 cells. When the cells were treated with 50 mu M catechins in the absence or presence of insulin for 30 min, nongallate-type catechins increased glucose uptake activity without insulin, whereas gallate-type catechins decreased insulin-induced glucose uptake activity. (-)-Epicatechin (EC) and (-)-epigallocatechin (EGC), nongallate-type catechins, increased glucose uptake activity in the dose- and time-dependent manner, whereas (-)-catechin 3-gallate (Cg) and (-)-epigallocatechin 3-gallate (EGCg), gallate-type catechins, decreased insulin-induced glucose uptake activity in the dose- and time-dependent manner. When the cells were treated with 50 mu M catechins for 30 min, EC and EGC promoted GLUT4 translocation, whereas Cg and EGCg decreased the insulin-induced translocation in the cells. EC and EGC increased phosphorylation of PKC lambda/zeta without phosphorylation of insulin receptor (IR) and Akt. Wortmannin and LY294002, inhibitors for phosphatidylinositol 3'-kinase (PI3K), decreased EC- and EGC-induced glucose uptake activity in the cells. Cg and EGCg decreased phosphorylation of PKC lambda/zeta in the presence of insulin without affecting insulin-induced phosphorylation of IR, and Akt. Therefore, EC and EGC promote the translocation of GLUT4 through activation of PI3K, and Cg and EGCg inhibit insulin-induced translocation of GLUT4 by the insulin signaling pathway in 3T3-L1 cells.
ROYAL SOC CHEMISTRY, 2010年11月, FOOD & FUNCTION, 1 (2), 167 - 173, 英語[査読有り]
研究論文(学術雑誌)
Artemisia princeps is a familiar plant as a food substance and medicinal herb. In this study, we evaluated the effects of an ethanol extract of A. princeps (APE) on glucose uptake in differentiated L6 muscle cells. Treatment with APE elevated deoxyglucose uptake, and translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane in L6 myotubes occurred. The PI3K inhibitor LY294002 attenuated glucose uptake induced by APE. Phosphorylation of the Ser(473) residue of Akt was not observed, but phosphorylation of PI3K, Akt (Thr(308)), and atypical PKC was. In addition, APE stimulated phosphorylation of AMP-activated protein kinase (AMPK) at a level similar to 5'-amino-5-imidazolecarboxamide-riboside (AICAR). These results indicate that APE stimulates glucose uptake by inducing GLUT4 translocation, which is in part mediated by combination of the PI3K-dependent atypical PKC pathway and AMPK pathways.
TAYLOR & FRANCIS LTD, 2010年10月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 74 (10), 2036 - 2042, 英語[査読有り]
研究論文(学術雑誌)
Previously, we developed a microplate assay to quantitate 2-deoxyglucose (2DG) and 2-deoxyglucose-6-phosphate in samples for in vitro and in vivo use. In this assay system, four different reaction mixtures were used, and the difference in the reactivity of the two types of glucose-6-phosphate dehydrogenase (G6PDH) variants was used. Because G6PDH from tolura yeast was no longer available, we modified our assay system for the use of G6PDH from Leuconostoc. Using this improved assay system, concentrations of glucose, 2DG, glucose-6-phosphate, and 2-deoxyglucose-6-phosphate were easily measured. This assay may be useful for measuring uptake of 2DG without the use of radioisotopes. (C) 2010 Elsevier Inc. All rights reserved.
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2010年09月, ANALYTICAL BIOCHEMISTRY, 404 (2), 238 - 240, 英語[査読有り]
研究論文(学術雑誌)
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates biological and toxicological effects by binding to its agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Previously we demonstrated that flavonoids suppressed the TCDD-induced DNA-binding activity of the AhR in a structure-dependent manner. In this study, we investigated the mechanisms by which flavonoids suppressed the AhR-mediated signal transduction in mouse hepatoma Hepa-1c1c7 cells. Flavones and flavonols suppressed the TCDD-induced nuclear translocation of the AhR and dissociation of its partner proteins, heat shock protein 90 and X-associated protein 2, whereas flavanones and catechins did not. Flavonoids of all these four subclasses suppressed the phosphorylation of both AhR and Arnt and the formation of a heterodimer consisting of these proteins. Since certain flavonoids are known to inhibit mitogen-activated protein kinases (MAPKs), we confirmed the contribution of MAPK/ERK kinase (MEK) to the AhR-mediated signal transduction by using U0126, an inhibitor of MEK1/2. U0126 suppressed TCDD-induced phosphorylation of the AhR and Arnt followed by the DNA-binding activity of the AhR. Flavanones and catechins suppressed the TCDD-induced phosphorylation of ERK1/2. The inhibition of MEK/ERK phosphorylation is one of the mechanisms by which flavanones and catechins suppress the AhR-mediated signal transduction in Hepa-1c1c7 cells. (C) 2010 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2010年09月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 501 (1), 134 - 141, 英語[査読有り]
研究論文(学術雑誌)
Galangin, a dietary flavonoid, inhibited cytochrome P450 1A1 (CYP1A1) expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This inhibitory activity remained after permeating human intestinal epithelial Caco-2 cell monolayers, but was reduced when galangin permeated TCDD-pretreated Caco-2 cells. The present study tested whether TCDD affected the intestinal metabolism of flavonoids. LC-MS/MS analyses showed that galangin and two galangin glucuronoconjugates were reduced 0.7-fold, whereas kaempferol (a galangin oxidate) and kaempferol glucuronoconjugate were increased 1.5-fold by permeating TCDD-pretreated Caco-2 cells, as compared to untreated Caco-2 cells. An assay using recombinant human CYP1A1 and the CYP1A1 inhibitor a-naphthoflavone revealed that CYP1A1 oxidized galangin to kaempferol. These results indicated that galangin was metabolized to kaempferol by TODD-inducible CYP1A1 in Caco-2 cells. A previous study revealed that kaempferol had much weaker inhibitory activity than galangin toward TODD-induced CYP1A1 expression. Therefore, the oxidative metabolism of galangin to kaempferol in TCDD-pretreated Caco-2 cells implicated reduction in the inhibitory activity of galangin.
AMER CHEMICAL SOC, 2010年07月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 58 (13), 8111 - 8118, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(国際会議プロシーディングス)
Bacillus subtilis IolT is the major myo-inositol transporter for growth, while IolF is a minor one unable to support growth. We found that either loIT or IolF was sufficient for moderate growth using D-chiro-inositol. Conversely to IolT, IolF transported n-chiro-inositol more preferentially than myo-inositol. These results indicate that IolT and IolF are different in substrate specificity.
TAYLOR & FRANCIS LTD, 2010年06月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 74 (6), 1312 - 1314, 英語[査読有り]
研究論文(学術雑誌)
Diabetes mellitus is a complex disease that is characterized by the defection of insulin sensitivity in such peripheral tissues as skeletal muscle, adipose tissue and liver. We have previously demonstrated that certain inositol derivatives stimulated glucose uptake accompanied by the translocation of glucose transporter 4 (GLUT4) to the plasma membrane in L6 myotubes. We investigated in this present study whether an oral intake of D-pinitol (PI) and myo-inositol (MI) would affect GLUT4 translocation in the skeletal muscle of mice. PI or MI at 1 g/kg BW administered orally to mice 30 min before a post-oral injection of glucose at 2 g/kg BW resulted in both PI and MI increasing GLUT4 translocation in the skeletal muscle and lowering the plasma glucose and insulin levels. PI and MI, therefore, have the potential to prevent diabetes mellitus by reducing the postprandial blood glucose level and stimulating GLUT4 translocation in the skeletal muscle.
TAYLOR & FRANCIS LTD, 2010年05月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 74 (5), 1062 - 1067, 英語[査読有り]
研究論文(学術雑誌)
The present study performed proteomic analysis of the midbrain and striatum of 6-hydroxydopamine (6-OHDA)-treated neonatal rats-a model of attention-deficit hyperactivity disorder (ADHD). Proteomic analysis revealed that a 58-kDa glucose-regulated protein (Grp58) was temporarily phosphorylated and its level was elevated by 6-OHDA. Furthermore, 6-OHDA increased the expression level of C/EBP homologous protein (CHOP), a mediator of endoplasmic reticulum (ER) stress response, in the midbrain and striatum. In vitro experiments using PC12 cells revealed that 6-OHDA or hydrogen peroxide could induce the elevation of Grp58 and CHOP. 6-OHDA could induce the elevation of Grp58 and CHOP in the presence of catalase, a hydrogen peroxide-removing enzyme, suggesting that the elevation of Grp58 and CHOP are induced by both hydrogen peroxide and p-quinone generated by 6-OHDA. Collectively, these findings suggest that ER stress involving the alteration of Grp58 and CHOP play a significant role in the induction of insults by 6-OHDA in vivo.
TAYLOR & FRANCIS LTD, 2010年04月, FREE RADICAL RESEARCH, 44 (4), 410 - 421, 英語[査読有り]
研究論文(学術雑誌)
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研究論文(国際会議プロシーディングス)
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研究論文(学術雑誌)
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研究論文(学術雑誌)
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研究論文(学術雑誌)
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研究論文(学術雑誌)
Upon binding to ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) is activated to form a heterodimer with an aryl hydrocarbon receptor nuclear translocator (Arnt). This complex binds to DNA. It has been shown that the AhR bonds to a DNA sequence called the dioxin response element (DRE), which controls the expression of battery genes. It is reported that TCDD releases arachidonic acid from membrane phospholipids via activation of phospholipase A(2)s (PLA(2)s) in various cell types. Recently, we demonstrated that the TCDD-activated AhR binds to the second intron of the Pla2g4a gene, which encodes cytosolic phospholipase A(2)alpha (cPLA(2)alpha), in mouse hepatoma Hepa-1c1c7 cells. This result suggests that Pla2g4a appears to be a target gene of the AhR. In the present study, we investigated whether the transcriptional regulation of Pla2g4a is dependent on the AhR in Hepa-1c1c7 cells. Treatment of the cells with TCDD increased mRNA expression of Pla2g4a and enzymatic activity of PLA(2). while this increased expression was not observed in AhR-defective c12 cells. After transient transfection of an Ahr gene-expressing plasmid into the 02 cells, expression of Pla2g4a was increased by TCDD. These results indicate that Pla2g4a may be a novel target gene of the AhR, and its transcriptional induction is mediated through binding of the AhR to the second intron of Pla2g4a, although this target site does not have a typical DRE sequence. (C) 2009, The Society for Biotechnology, Japan. All rights reserved.
SOC BIOSCIENCE BIOENGINEERING JAPAN, 2009年10月, Journal of Bioscience and Bioengineering, 108 (4), 277 - 281, 英語[査読有り]
研究論文(学術雑誌)
Dioxins enter the body mainly through the diet, bind to the aryl hydrocarbon receptor (AhR), and cause various toxicological effects. In this study, we found that oral administration of kaempferol or ginkgo biloba extract (EGb) containing 24% flavonol at 100 mg/kg body weight suppressed AhR transformation induced by 3-methylcholanthrene at 10 mg/kg body weight in the liver of mice. The suppressive effect of kaempferol was enhanced by verapamil, an inhibitor of P-glycoprotein (P-gp), in ex vivo experiments using a hepatic cytosolic fraction and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Enhancement of the suppressive effect by verapamil was also observed in mouse hepatoma Hepa-1c1c7 cells, accompanied,by an increase in the uptake of kaempferol into the cells. In conclusion, inhibition of P-gp enhanced the suppressive effect of kaempferol on AhR transformation through an increase in the intracellular kaempferol concentration.
TAYLOR & FRANCIS LTD, 2009年07月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 73 (7), 1635 - 1639, 英語[査読有り]
研究論文(学術雑誌)
The suppression of cytochrome P450 1A1 (CYP1A1) expression was examined in mouse hepatoma Hepa-1c1c7 cells treated with serum prepared from (-)-epigallocatechin-3-gallate- and green tea extract-administered rats. Catechins were found in the rat plasma after the administration. In Hepa-1c1c7 cells, 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 expression was suppressed by treatment with the rat serum. It is concluded that catechins can possibly modulate CYP1A1 expression.
TAYLOR & FRANCIS LTD, 2009年05月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 73 (5), 1206 - 1208, 英語[査読有り]
研究論文(学術雑誌)
Flavonoids are widely distributed in the plant kingdom and show various biological activities. The bioavailability of flavonoids in biological samples has conventionally been quantified by high-performance liquid chromatography and mass spectrometry, but with these analytical techniques it is difficult to estimate the subcellular localization of flavonoids in intact cells. In this study, we attempted to examine the localization of flavonoids in cultured cells using a confocal laser scanning fluorescence microscope and mouse hepatoma Hepa-1c1c7 cells. Five flavonol aglycones showed autofluorescence in the cells under the conditions (Ex. 488 nm to Em. 515-535 nm), whereas three flavonol glycosides and eight compounds belonging to other flavonoid subclasses, i.e., flavones, flavanones, and catechins, did not. The autofluorescence of galangin and kaempferol appeared stronger in the nucleus than cytoplasm, suggesting that they are incorporated into the cells and accumulated in the nucleus. The proposed method provided evidence that flavonol aglycones are incorporated into, and accumulated in the nucleus of, hepatocytes.
SPRINGER, 2009年04月, CYTOTECHNOLOGY, 59 (3), 177 - 182, 英語[査読有り]
研究論文(学術雑誌)
Anthraquinones are widely present in plant kingdom, and clinically used as laxatives. Environmental contaminants, dioxins, develop various adverse effects through transformation of a cytosolic aryl hydrocarbon receptor (AhR). We investigated the effects of 18 anthraquinones and 7 of their structurally related compounds on transformation of the AhR estimated by its DNA-binding activity in the cell-free system. 1,4-Dihydroxyanthraquinone (quinizarin), 1,5-dihydroxyanthraquinone (anthrarufin), 1,8-dihydroxyanthraquinone (danthron), and 5-hydroxy-1,4-naphthoquinone (juglone) strongly suppressed DNA-binding activity of the AhR induced by 0.1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with their IC(50) values around 1 mu M. On the other hand, anthraquinone, 2,6-dihydroxyanthraquinone (anthraflavic acid), and 2-hydroxy-1,4-naphthalendione (lawsone) showed moderate effects. Quantitative structure-activity relationships analysis demonstrated that hydroxyl groups at C1 or C4 but not C3 position of anthraquinone structure are critical for the suppressive effects. In addition, all compounds except lawsone had no agonistic effect. The suppressive effects of anthraquinones in a cultured cell system were also confirmed. In human hepatoma HepG2 cells, chrysophanol, danthron, and rhein also suppressed the DNA-binding activity in a dose-dependent manner, although aloe-emodin showed a moderate effect. The findings of this study may be useful for the design of the novel antagonists of the AhR. (C) 2008, The Society for Biotechnology. Japan. All rights reserved.
SOC BIOSCIENCE BIOENGINEERING JAPAN, 2009年03月, JOURNAL OF BIOSCIENCE AND BIOENGINEERING, 107 (3), 296 - 300, 英語[査読有り]
研究論文(学術雑誌)
Inositol derivatives are natural ingredients found in plants and animals. Some of them have been reported to help the action of insulin, which induces glucose uptake involving the translocation of glucose transporter 4 (GLUT4) to the plasma membrane particularly in muscle tissues. Here, we investigated the effect of eight inositol derivatives on glucose uptake in L6 muscle myotubes, and on GLUT 4 translocation to plasma membrane in ex vivo assay Using murine skeletal muscle. At 1 mM, seven inositol derivatives other than myo-inositol stimulated glucose uptake in the absence Of insulin. However, at 100 mu M, only L-chiro-inositol, muco-inositol and epi-inositol increased the glucose uptake compared to control. The ex vivo assay confirmed that D-pinitol, D-chiro-inositol, L-chiro-inositol, muco-inositol and epi-inositol stimulated GLUT4 translocation. These results suggest that inositol derivatives can exert insulin-like effect in muscle cells.
SPRINGER, 2009年, ANIMAL CELL TECHNOLOGY: BASIC AND APPLIED ASPECTS, VOL 15, 15, 217 - 222, 英語[査読有り]
研究論文(国際会議プロシーディングス)
食物繊維不足は消化管疾患をもたらすことが知られている.本研究では,精製したパン酵母由来β-グルカン(BBG)によるラット盲腸内容物および糞排泄に及ぼす影響をセルロース(CE)を対照繊維として用いて比較検討した.BBGまたはCEを1%,3%,5%となるようAIN-93M粉末食に混合し,これらと無繊維食をラットに4週間自由摂取させた.盲腸組織重量は5%BBG食摂取群で5%CE食摂取群と比較して有意に増加し,一方で,盲腸内容物のpHは有意に低下した.ラット盲腸内容物中の酢酸,プロピオン酸,n-酪酸は5%BBG食摂取群で5%CE食摂取群と比較して有意に増加したことから,これらの短鎖脂肪酸の増加が盲腸内容物のpH低下に寄与していることが示唆された.さらに,糞の水分含量も5%BBG食摂取群で5%CE食摂取群と比較して有意に増加したことから,BBGは盲腸内発酵を促進して大腸管腔の水分保持に寄与することが示唆された.以上のことから,BBGは腸機能を調節することで便秘の抑制効果を発揮すること,およびその効果はCEよりすぐれていることが明らかとなった.
日本生物工学会, 2009年, 生物工学会誌, 87 (4), 170 - 174, 日本語[査読有り]
研究論文(学術雑誌)
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研究論文(学術雑誌)
オオト麦や大麦由来の水溶性β-グルカンは血漿や肝臓中コレステロール値を低下させることが知られているが,パン酵母由来β-グルカン(BBG)の効果については未だ明らかとなっていない.本研究ではBBGがコレステロール吸収と排泄に及ぼす影響について,セルロース(CE)を対照食物繊維として用いて検討した.AIN-93M粉末食に2%コレステロール(CHL)または0.5%コレステロール/0.2%コール酸(CA)を添加し,さらに食物繊維量として5%となるようBBGまたはCEを添加し,これらをラットに4週間自由摂取させた.血漿中総コレステロール値はCE群でCHL添加によって上昇傾向を示し,CA添加によって有意に上昇した.これに対してBBG群では,これらを低下させる傾向にあった.一方,血漿中HDL-コレステロール値はCE群でCHLおよびCA添加によって有意に低下したが,BBG群では低下傾向にあったもののCHLおよびCAを添加しない対照群と有意差はなかった.さらに,BBGは肝肥大化を抑制し,糞中コレステロール量を増加させる傾向を示した.これらのことは,BBGが食事性コレステロールの排泄を促進することで血中コレステロールの上昇を抑制することを示唆している.以上のことから,BBGは脂質異常症とその関連疾病の発症を予防するCEより高機能の食物繊維であることが示唆された.
日本生物工学会, 2009年, 生物工学会誌, 87 (3), 129 - 134, 日本語[査読有り]
研究論文(学術雑誌)
A number of 2',3',4'-trihydroxy-2-phenylacetophenone derivatives were synthesized and examined for growth inhibition of several kinds of bacteria. 2',3',4'-Trihydroxy-2-phenylacetophenone itself exhibited no antibacterial activity, but some of its derivatives showed various antibacterial activities depending on functional groups introduced on the 2-phenyl ring. Eighteen out of 24 compounds synthesized in this study appeared to possess antibacterial activities against at least two Gram-positive strains of Bacillus subtilis and Staphylococcus aureus, 2-(biphenyl-4-yl)-2',3',4'-trihydroxy-acetophenone being the most active with LC50 of 5.8 mu M and 5.6 mu M respectively. However, none of the synthesized compounds exhibited inhibitory effects on Gram-negative strains, such as Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Salmonella enterica, suggesting that anti-Gram-positive specificity of the antibacterial compounds.
TAYLOR & FRANCIS LTD, 2009年01月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 73 (1), 124 - 128, 英語[査読有り]
研究論文(学術雑誌)
In this study, We investigated whether epigallocatechin gallate (EGCg) affects glucose uptake activity and the translocation Of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle. A single oral administration of EGCg at 75 mg/kg body weight promoted GLUT4 translocation in skeletal muscle of rats. EGCg significantly increased glucose uptake accompanying GLUT4 translocation in L6 myotubes at 1 nM. The translocation of GLUT4 was also observed both in skeletal muscle of mice and rats ex vivo and in insulin-resistant L6 myotubes. Wortmannin, an inhibitor of phosphatidylinositol 3'-kinase, inhibited both EGCg- and insulin-increased glucose uptakes, while genistein, an inhibitor of tyrosine kinase, failed to inhibit the EGC-increasecl uptake. Therefore, ECCg may improve hyperglycemia by promoting GLUT4 translocation in skeletal muscle with partially different mechanism from insulin. (C) 2008 Elsevier Inc. All rights reserved.
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2008年12月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 377 (1), 286 - 290, 英語[査読有り]
研究論文(学術雑誌)
Dioxins enter the body through the diet and cause various toxicological effects through transformation of an aryl hydrocarbon receptor (AhR). Plant extracts and phytochemicals including flavonoids are reported to suppress this transformation. This paper investigates the suppression by a cacao polyphenol extract (CPE) of AhR transformation in vivo. The CPE was administered orally to C57BL/6 mice at 100 mg/kg of body weight, followed 1 h later by 3-methylcholanthrene (MC), an AhR agonist, injected intraperitoneally at 10 mg/kg of body weight. CPE suppressed the MC-induced transformation to the control level by inhibiting the formation of a heterodimer between AhR and an aryl hydrocarbon receptor nuclear translocator in the liver at 3 h postadministration. It also suppressed MC-induced cytochrome P4501A1 expression and NAD(P)H:quinone-oxidoreductase activity, whereas it increased glutathione S-transferase activity at 25 h. CPE constituents and their metabolites might contribute, at least in part, to the suppression of AhR transformation. The results indicate that the intake of CPE suppressed the toxicological effects of dioxins in the body.
AMER CHEMICAL SOC, 2008年11月, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 56 (21), 10399 - 10405, 英語[査読有り]
研究論文(学術雑誌)
Dioxins develop various adverse effects through transformation of the aryl hydrocarbon receptor (AhR). Since dioxins invade the body mainly with diet, it is important to search for AhR antagonists from a dietary source. Our findings have demonstrated that the suppressive effects of flavonoids on AhR transformation was classified into their subclasses with the following order flavones = flavonols = theaflavins > flavanones > catechins > isoflavones and anthocyans. Regarding flavonols, the competitive ligand binding analysis revealed that kaempferol, quercetin, and galangin inhibited the specific binding between the AhR and its agonist, 3-methylcholanthrene (MC) in a dose-dependent manner, indicating that at least flavonols acts as competitive antagonists of the AhR. These results suggest that the mechanisms by which flavonoids suppress AhR transformation differs in their subclasses. © 2008 American Chemical Society.
American Chemical Society, 2008年09月19日, ACS Symposium Series, 993, 369 - 374, 英語[査読有り]
研究論文(国際会議プロシーディングス)
Halogenated and polycyclic aromatic hydrocarbons, exogenous ligands of the aryl hydrocarbon receptor (AhR), cause various toxicological effects through the transformation of the AhR. In this study, we investigated the antagonistic effects of indigoids on the transformation in addition to their agonistic ones. In a cell-free system, indigoids induced the transformation dose-dependently, but suppressed the transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the binding of 3-methyleholanthrene to the AhR. In mouse hepatoma Hepa-1clc7 cells, indigoids, especially indirubin, suppressed the transformation and expression of CYPIAI by inhibiting the translocation of AhR into the nucleus. When orally administered to mice at 10 mg/kg BW/day for three successive days, indigoids did not induce AhR transformation and expression of the CYPIA subfamily in the liver, while indirubin and indigo upregulated quinone reductase activity. These results indicate that indigoids are able to bind to the AhR as ligands and exhibit antagonistic effects at lower concentrations in mammalian cells. (c) 2007 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2008年02月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 470 (2), 187 - 199, 英語[査読有り]
研究論文(学術雑誌)
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Some of inositol derivatives have been reported to help the action of insulin stimulating glucose uptake in skeletal muscle cells. Rat L6 myotubes were employed in an attempt to develop an in vitro model system for investigation of the possible insulin-like effect of eight inositol derivatives, namely allo-inositol, D-chiro-inositol L-chiro-inositol, epi-inositol, muco-inositol, myo-inositol, scyllo-inositol and D-pinitol. At a higher concentration of 1 mM seven inositol derivatives other than myo-inositol were able to stimulate glucose uptake, while at 0.1 mM seven inositol derivatives other than myo-inositol were able to stimulate glucose uptake, while at 0.1mM only D-chiro-inositol, L-chiro-inositol, epi-inositol and muco-inositol could induce glucose uptake, indicating their significant insulin-mimetic activity. Immunoblot analyses revealed that at least D-chiro-inositol, L-chiro-inositol, epi-inositol, muco-inositol and D-pinitol were able to induce translocation of glucose transporter 4 (GLUT4) to plasma membrane not only in L6 myotubes but also in skeletal muscles of rats ex vivo. These results demonstrated that L6 myotubes appeared efficient as an in vitro system to identify inositol derivatives exerting an insulin-like effect on muscle cells depending on the induced translocation of GLUT4.
SPRINGER, 2007年12月, CYTOTECHNOLOGY, 55 (2-3), 103 - 108, 英語研究論文(学術雑誌)
Halogenated and polycyclic aromatic hydrocarbons induce diverse biochemical responses through the transformation of a cytosolic aryl hydrocarbon receptor (AhR). In mouse hepatoma Hepa-1c1c7 cells, curcumin, a yellow pigment of Curcuma longa, did not inhibit the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced translocation of the AhR into the nucleus, but rather accelerated it. In the nucleus, curcumin inhibited the TCDD-induced heterodimerization of the AhR with an AhR nuclear translocator (Arnt), an essential partner for the transformation, and also dose-dependently inhibited the TCDD-evoked phosphorylation of both the AhR and Arnt. Moreover, curcumin significantly inhibited the TCDD-induced activation of protein kinase C (PKC), which is involved in the transformation, decreased the TCDD-induced DNA-binding activity of the AhR/Arnt heterodimer, and downregulated CYP1A1 expression. In a cell-free system, curcumin inhibited the binding of 3-methylcholanthrene, an AhR agonist, to the receptor. These results indicate that curcumin is able to bind to the AhR as a ligand, but suppresses its transformation by inhibiting the phosphorylation of AhR and Arm, probably by PKC. (c) 2007 Elsevier Inc. All rights reserved.
ELSEVIER SCIENCE INC, 2007年10月, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 466 (2), 267 - 273, 英語[査読有り]
研究論文(学術雑誌)
The aim of this study was to establish a rapid preparation of plasma membrane from adipocytes and muscle cells to detect translocated glucose transporter (GLUT) 4. A plasma membrane fraction was prepared by sequential centrifugation with buffer containing detergents, and its purity was estimated by detecting insulin receptor beta-subunit (IR beta). After insulin stimulus, GLUT4 translocation was observed in 3T3-L1 adipocytes and L6 myotubes. It was found that IR beta and GLUT4 levels on the plasma membrane decreased in adipose and muscle with intake of a 29% lard diet for 14 weeks. Hence, this method should be useful for rapid preparation of the plasma membrane fraction.
TAYLOR & FRANCIS LTD, 2007年09月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 71 (9), 2343 - 2346, 英語[査読有り]
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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with which halogenated and polycyclic aromatic hydrocarbons such as dioxins and benzo[a]pyrene interact as ligands. Since such compounds cause various toxicological effects, including cancer, through the transformation of AhR, it is important to determine influence of modulating factors. It has been reported that certain plant components such as flavonoids and indoles can affect AhR transformation. In this study, to obtain clues to novel ligands of AhR, 191 species of indigenous plants were collected in Japan, and their 50% methanolic extracts (total 368 plant parts) were tested for modulating effects on AhR transformation in a cell-free system using a rat hepatic cytosolic fraction. Among tested extracts at a concentration of 1 mg dry weight of plant/mL, 174 of 368 extracts suppressed 1 nM 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD)-induced AhR transformation to 50% or less, while 9 extracts per se induced AhR transformation equivalent to more than 20% of that induced by 1 nM TCDD. Mallotus japonicus (Thunb.) Muell. (leaf) and Trichosanthes rostrata Kitamura (fruit and fruit skin) strongly suppressed 1 nM TCDD-induced AhR transformation, while Phellodendron amurense Ruprecht (seed) per se strongly induced AhR transformation. These results suggest that a large variety of plants in Japan contain various compounds modulating, mainly suppressing, AhR transformation.
Asian Pacific Organization for Cancer Prevention, 2006年, Asian Pacific Journal of Cancer Prevention, 7 (2), 208 - 220, 英語[査読有り]
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3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in diet, induces apoptosis in immunocytes such as splenocytes and thymocytes. In rat mononuclear cells (MNCs), Trp-P-1 also induces apoptosis, in which caspase-8 dominated the caspase cascade. Since Trp-P-1-induced apoptosis in immunocytes may be led to immunodeficiency, it is important for a living body to prevent the apoptosis. Although Trp-P-1 increased the generation of reactive oxygen species, both ascorbic acid and alpha-tocophrol did not inhibite the apoptosis. This indicates that the induction of apoptosis was not mediated through reactive oxygen species. On the other hand, certain food components such as dopamine, myricetin, robinetin, delphinidin, pyrogallol, and gallic acid inhibited Trp-P-1-induced apoptosis. Thus, these food components in our dairy diet may prevent chemical-induced cytotoxicity in immunocytes.
AMER CHEMICAL SOC, 2003年, FOOD FACTORS IN HEALTH PROMOTION AND DISEASE PREVENTION, 851, 128 - 140, 英語[査読有り]
研究論文(学術雑誌)
Mushrooms have been consumed as flavorful and medicinal foods for millenniums. Mushroom polysaccharides possess antitumor activity through the stimulation of cytokine productions from immunocytes. On the other hand, lipopolysaccharide suppresses the expression of various hepatic cytochrome P450s (CYPs) through the production of cytokines such as tumor necrosis factor (TNF)-alpha. In this study, lentinan prepared from Lentinus edodes and polysaccharides from Agaricus blazei (ABPS) were intraperitoneally injected to female BALB/c mice, and the effects of these polysaccharides on the expression of CYPs were investigated in the liver. Both polysaccharides down-regulated the activity and level of constitutive and 3-methylcholanthrene-inducible CYP1A accompanied by the TNF-alpha production. When lentinan was orally administered to mice, down-regulation of the level and activity of CYP1A through the suppression of DNA binding activity of aryl hydrocarbon receptor also occurred. These results suggest that the mushroom polysaccharides such as lentinan and ABPS have an anti-carcinogenic activity, since the down-regulation of CYP1A is considered to prevent the metabolic activation of procarcinogens.
AMER CHEMICAL SOC, 2003年, FOOD FACTORS IN HEALTH PROMOTION AND DISEASE PREVENTION, 851, 235 - 248, 英語[査読有り]
研究論文(学術雑誌)
研究論文(学術雑誌)
研究論文(学術雑誌)
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which is a tryptophan pyrolysate formed during cooking, induces apoptosis in rat splenocytes, thymocytes, and hepatocytes. In this study, we investigated whether Trp-P-1 is transported into these cells and causes apoptosis. Trp-P-1 was immediately incorporated into rat splenocytes, thymocytes, and hepatocytes in a dose- and time-dependent manner. Dopamine and serotonin significantly competed with the uptake of Trp-P-1 into these cells, and nomifensine and indatraline, which are inhibitors of dopamine- and serotonin-transporters, respectively, markedly suppressed the uptake of Trp-P-1. On the other hand, amino acids including tryptophan did not compete with Trp-P-1. Inhibition of monoamine transporters using nomifensine and indatraline partially suppressed Trp-P-1-induced cell death in these cells. In hepatocytes, the inhibition of transporters prevented Trp-P-1-induced morphological changes and activation of caspase-3. These results demonstrated that Trp-P-1 is incorporated into the cells through monoamine transporters and induces apoptosis.
社団法人日本農芸化学会, 2002年06月23日, Bioscience, biotechnology, and biochemistry, 66 (6), 1205 - 1212, 英語3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in our daily diet, induces apoptosis in cultured immunocytes. In this study, Trp-P-1 (1 mg/kg) was injected introperitoneally into male Wistar rats to investigate whether Trp-P-1 induces apoptosis in immune tissues in vivo. In the thymus, Trp-P-1 induced DNA fragmentation and morphological changes. Trp-P-1 also activated the initiator and executioner caspases, caspase-8 and -3, respectively, and activated caspase-3 in turn cleaved its intracellular substrate poly(ADP-ribose) polymerose 1 hr after injection. On the other hand, Trp-P-1 upregulated anti-apoptotic factors Bcl-2 and Bcl-XL and downregulated pro-apoptotic factor Bax in mitochondria 1 hr after injection, indicating that Trp-P-1 also stimulated anti-apoptotic signals. Trp-P-1 activated the serine-threonine protein kinase Akt, which is known to be an anti-apoptotic protein, and increased the DNA binding activities of apoptosis-associated transcription factors NF-κB and AP-1. In addition to the thymus, increases in the activities of these transcription factors were also observed in the spleen and in mononuclear cells from the blood. Therefore, Trp-P-1 activates both pro- and antiapoptotic signals in vivo in the immune system, particularly in the thymus, and the former signal overcomes the latter. © 2002 Wiley-Liss, Inc.
2002年, Environmental and Molecular Mutagenesis, 40 (3), 175 - 183, 英語[査読有り]
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3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), one of the tryptophan pyrolysates, is a dietary carcinogen and is formed in cooked meat and fish in our daily diet. Trp-P-1 will affect the cells in the blood circulation system before it causes carcinogenicity in target organs such as the liver. In this study, the cytotoxicity of Trp-P-1 was investigated in mononuclear cells (MNCs) from blood. Trp-P-1 (10-15 CIM) decreased cell viability and induced apoptosis characterized both by morphological changes and by DNA fragmentation 4 h after treatment. DNA fragmentation was also observed following treatment at 1 nM after 24 h in culture. This result suggested that apoptosis would occur in the body following unexpected intake of foods containing Trp-P-1. To determine the mechanism of apoptosis, we investigated the activation of the caspase cascade in MNCs. Trp-P-1 (10-15 muM) activated the caspase cascade, i.e. the activity of caspase-3,-6,-7,-8 and -9 increased dose-dependently using peptide substrates, the active forms of caspase-3, -8 and -9 were detected by immunoblotting, and cleavage of poly(ADP-ribose) polymerase and protein kinase C-delta as the intracellular substrates for caspases was observed. A peptide inhibitor of caspase-8 completely suppressed activation of all other caspases, while an inhibitor of caspase-9 did not. These results indicated that caspase-8 may act as an apical caspase in the Trp-P-1-activated cascade. (C) 2001 Elsevier Science B.V. All rights reserved.
ELSEVIER SCIENCE BV, 2001年05月, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1539 (1-2), 44 - 57, 英語[査読有り]
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The synergistic effect of food additives or food colors on the toxicity of 3-amino-l, 4-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P-1) was investigated using primary cul-tured rat hepatocytes. When hepatocytes from rats fed a standard diet were treated with a mixture of four major food additives (sorbitol, sodium L(+)-glutamate, benzoic acid, and propylene glycol) or a mixture of six typical artificial food colors (erythrosine, allura red, new coccine, brilliant blue, tertrazine, and fast green), the in vitro treated food-color mix-ture itself showed cytotoxicity; the reduction of cell viability and decreases in the activities of gluconeogenesis and ureogenesis. The food-color mixture enhanced cytotoxicity of Trp-P-1 obviously. We then investigated the effects of in vivo-dosed food additives or food colors on Trp-P-l-caused toxicity. Hepatocytes were isolated and cultured from rats fed a diet contain-ing a mixture of food additives or a mixture of food colors with half the amount of their re-spective acceptable daily intake for 4 wk. Trp-P-1 was administered to the hepatocytes at various concentrations for 12 h. Synergistic effects of in vivo-dosed food additives and food colors were not observed on Trp-P-l-caused cytotoxicity as estimated by a loss of cell viabil-ity and the reductions of DNA and protein syntheses. On the contrary, we have observed that in vivo administered food colors synergistically facilitated to reduce the activities of glu-coneogenesis and ureogenesis in Trp-P-l-treated hepatocytes. These results suggest that the daily intake of artificial food colors may impair hepatic functions such as gluconeogenesis and ureogenesis, when dietary carcinogens are exposed to the liver cells.
財団法人 学会誌刊行センター, 2000年06月01日, Journal of nutritional science and vitaminology, 46 (3), 130 - 136, 英語Eight species of mushrooms were evaluated for mitogenic activity by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method using spleen cells of C3H/HeN female mice. The hot water-soluble (HWS) fraction extracted from Sarcodon aspratus showed the highest activity. The mitogen in Sa. aspratus was isolated by Sepharose 6B and DEAE-Sepharose CL-6B column chromatography. Preliminary structural analyses indicated that the mitogen was a fucogalactan. Fucogalactan elicited the release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in macrophages of mice in vitro. TNF-alpha production induced with 50 mu g/ml of fucogalactan was significantly higher than that induced by lentinan (500 mu g/ml) by approximately 4.3-fold. Also, fucogalactan showed dose dependence at concentrations from 5 to 500 mu g/ml in NO production. Thus, fucogalactan does elicit the release of cytokines such as TNF-alpha and NO. (C) 2000 Elsevier Science B.V. All rights reserved.
ELSEVIER SCIENCE BV, 2000年02月, IMMUNOPHARMACOLOGY, 46 (2), 113 - 121, 英語[査読有り]
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The diet and nutritional status dominate a tolerance to en-vironmental xenobiotics. In this study, the cytotoxic action of carbon tetrachloride (CCl4) and 3-amino-1, 4-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P-1), one of the dietary carcinogens, was investigated using primary cultured hepatocytes from rats fed a high-fat (23% corn oil) or high-pro-tein (50% casein) diet for three weeks. Both chemicals showed strong cytotoxicity to hepatocytes, which was judged by measurement with the MTT-test and lactate dehydrogenase leakage test. A dietary effect on cytotoxicity was observed; hepatocytes from rats fed the high-protein diet were more susceptible to cytotoxicity than the cells from rats fed a standard diet. On the other hand, ureogenesis, as a cellular function of hepato-cytes, was markedly decreased in the cells from rats fed the high-fat diet. These activities were affected in the CCl4-treated cells but not in the Trp-P-l-treated cells. The same trend of both diet and chemical effects was observed in gluconeogenesis from fructose. We conclude that the hepatocytes from rats fed a high-protein diet have high susceptibility to the cytotoxicity of CCl4 and Trp-P-1, but cytotoxicity was not related to the reduction of cellular functions.
財団法人 学会誌刊行センター, 1998年, Journal of Nutritional Science and Vitaminology, 44 (1), 89 - 102, 英語[査読有り]
研究論文(学術雑誌)
In order to find the markers of the toxicity of the autoxi-dized lipids in the liver, rats were given a lethal amount of secondary autoxidation products of linoleic acid (400mg/rat/day for 3 days) and then changes in the hepatic metabolic functions were analyzed. A decrease in acetyl-CoA level to half caused by the depletion of CoASH was reported in an associated paper (J. Nutr. Sci. Vitaminol, 35, 11-23, 1989). Citrate, isocitrate, and 2-oxoglutarate also decreased to half the level of those of the control group. Reduction in isocitrate dehydrogenase activity was only 25%, while NADH2 and ATP levels remained unchanged. Thus, the reduction in the citrate cycle activity was due to the decrease in acetyl-CoA. The activity of mitochondrial succinate dehydrogenase was de-creased to 1/5. Other appreciable changes were depletion of glucose 6-phosphate and fructose 6-phosphate, accumulation of glucose 1-phos-phate, reductions in hexokinase, phosphofructokinase, glucose-6-phos-phatase, phosphoglucomutase, and phosphogluconate dehydrogenase activities, and decrease in the NADPH2 level. It was considered that these changes were caused by the depletion of glucose 6-phosphate whose synthetic pathways were abnormal. Therefore, the markers of the hepatotoxicity of secondary products were the changes in the CoASH level and the activities of succinate dehydrogenase and synthetic pathways for glucose 6-phosphate.
財団法人 学会誌刊行センター, 1989年, Journal of Nutritional Science and Vitaminology, 35 (1), 25 - 37, 英語Linoleic acid, and its hydroperoxides and secondary autoxidation products were orally administered to rats (400 mg/rat). Their effects on hepatic lipid metabolism were examined. Linoleic acid reduced the activities of de novo synthesis of fatty acids and acetyl-CoA carboxylase. It decreased the CoASH level and caused the accumulation of long-chain acyl-CoA. Hydroperoxides changed the compositions of unsaturated fatty acids in the hepatic lipids and lowered the content of neutral lipids. Secondary products stimulated carnitine palmitoyltransferase and decreased the content of neutral lipids. They reduced the activities of de novo synthesis of fatty acids and acetyl-CoA carboxylase, and the levels of CoASH and acetyl-CoA. Thus, the effect of secondary products was apparently different from those of Linoleic acid and its hydroperoxides.
社団法人日本農芸化学会, 1988年08月23日, Agricultural and Biological Chemistry, 52 (8), 2007 - 2014, 英語The hepatotoxicity of orally administered secondary autoxidation products of linoleic acid was investigated, as compared with the administration of a saline solution and linoleic acid as controls. The de novo synthesis of fatty acids was strongly reduced in the secondary products group. The level of NADPH in the liver significantly decreased while that of NADH did not. The activities of glucose-6-phoshate dehydrogenase and phosphogluconate dehydrogenase apparently decreased. The activities of NAD^+ kinase and NAD^+ synthetase decreased and that of NAD^+ nucleosidase increased in the secondary products group. Therefore, the depletion of NADPH can be attributed to the inhibition of two metabolic systems (an NADPH-supplemental system, and a synthetic system of NADP and NAD), and resulted in the reduction of lipogenesis in the liver.
社団法人日本農芸化学会, 1987年11月23日, Agricultural and Biological Chemistry, 51 (11), 2951 - 2957, 英語The expression of drug-metabolizing enzymes is deeply involved in chemical-induced cancer progression and prevention. The aryl hydrocarbon receptor (AhR) induces phase I, and certain phase II drug-metabolizing enzymes after the binding of ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We have previously demonstrated that luteolin inhibited TCDD-induced AhR transformation, and modulated the expression of drug-metabolizing enzymes through not only the AhR, but also the nuclear factor-erythroid-2-related factor 2 (Nrf2). We have examined the effect of kaempferol on the expression of drug-metabolizing enzymes through modulation of the AhR- and Nrf2-pathways, and the effect of co-treatment with kaempferol and luteolin. Kaempferol dose-dependently inhibited not only the TCDD-induced expression of phase I and phase II drug-metabolizing enzymes, but also the tertiary butylhydroquinone (t-BHQ)-induced expression of phase II drug-metabolizing enzymes, by modulating the AhR- and Nrf2-pathways. Co-treatment with kaempferol and luteolin enhanced the inhibitory effect on the expression of drug-metabolizing enzymes, compared with either kaempferol or luteolin alone. Moreover, co-treatment with kaempferol and luteolin increased the cellular levels of kaempferol without affecting the levels of luteolin. An in vivo study was also performed and the results demonstrated that co-treatment with kaempferol and luteolin enhanced the inhibition of benzo[a]pyrene-induced drug-metabolizing enzymes compared with either kaempferol or luteolin alone, in the liver of ICR mice. These results suggest that luteolin promoted the incorporation of kaempferol into hepatocytes and enhanced the inhibitory effect of kaempferol on chemical-induced drug-metabolizing enzymes. Thus, luteolin enhances the kaempferol-inhibited expression of drug-metabolizing enzymes.
2020年04月17日, Food & function, 11 (4), 3668 - 3680, 英語, 国際誌A flavone luteolin has various health-promoting activities. Several studies reported that high dose of luteolin activates the Nrf2/ARE pathway in the liver. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear. It is expected that the flavonoid metabolism possesses a circadian rhythm, since nutritional metabolism processes daily cycle. In this study we investigated whether an administration affects the Nrf2 activation. ICR mice were orally administered 0.01-10 mg/kg body weight of luteolin once a day for 7 days at two time-points: at the start of active phase (ZT12) or at that of inactive phase (ZT0). Luteolin increased the nuclear translocation of Nrf2, resulting in the increases in its target gene products HO-1 and NQO1 at ZT12 but not at ZT0. The expression level of Nrf2 was lower at ZT12 than at ZT0 in the liver. We also found that the level of luteolin aglycon in the plasma is higher at ZT12 than at ZT0. These results suggest that the low dose of luteolin can activate Nrf2 pathway and the aglycon form of luteolin may mainly contribute to activate the Nrf2 pathway at ZT12 in the liver.
2020年, PloS one, 15 (4), e0231403, 英語, 国際誌記事・総説・解説・論説等(その他)
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Sinorhizobium fredii USDA191 is a Gram-negative bacterium capable of forming nitrogen-fixing nodules on soybean roots. The USDA191 idhA gene encoding myo-inositol dehydrogenase, an enzyme necessary for myo-inositol utilization, is known to be involved in competitive nodulation and nitrogen fixation. In Bacillus subtilis, myo-inositol dehydrogenase catalyzes the first step of the myo-inositol catabolic pathway. Recently WE was identified as the gene encoding 2-keto-myo-inositol dehydratase, which catalyzes the second step in the pathway. Here we report the presence of 2-keto-myo-inositol dehydratase activity in free-living USDA191 cells cultured in a medium containing myo-inositol. An WE ortholog was cloned from USDA191. USDA191 WE was expressed in Escherichia coli as a His(6)-tag fusion and purified to exhibit 2-keto-myo-inositol dehydratase activity. Inactivation of USDA191 WE led to defective myo-inositol utilization. USDA191 iolE partially complemented a B. subtilis WE deficient mutant. These results suggest that S. fredii USDA191 utilizes a myoinositol catabolic pathway, analogous to that of B. subtilis, involving at least idhA and WE.
TAYLOR & FRANCIS LTD, 2006年12月, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 70 (12), 2957 - 2964, 英語研究発表ペーパー・要旨(国際会議)
D-chiro-Inositol (DCI) is a drug candidate for the treatment of type 2 diabetes and polycystic ovary syndrome, since it improves the efficiency with which the body uses insulin and also promotes ovulation. Here, we report genetic modification of Bacillus subtilis for production of DCI from myo-inositol (MI). The B. subtilis iolABC-DEFGHIJ operon encodes enzymes for the multiple steps of the MI catabolic pathway. In the first and second steps, MI is converted to 2-keto-MI (2KMI) by IolG and then to 3D-(3,5/4)-trihydroxycyclohexane-1,2-dione by IolE. In this study, we identified iolI encoding inosose isomerase, which converts 2KMI to 1-keto-D-chiro-inositol (1KDCI), and found that IolG reduces 1KDCI to DCI. Inactivation of iolE in a mutant constitutively expressing the iol operon blocked the MI catabolic pathway to accumulate 2KMI, which was converted to DCI via the activity of IolI and IolG. The mutant was able to convert at least 6% of input MI in the culture medium to DCI. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
2006年02月, Applied and Environmental Microbiology, 72 (2), 1310 - 1315, 英語その他
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癌は遺伝子の酸化的損傷で始まる.一方,抗酸化剤は活性酸素を捕獲できる.そこで,日常食品に含まれるフラボノイドなど31種類の抗酸化成分が遺伝子損傷を抑えるか否かを調べた.生体に現れうるラジカルとしてヘテロサイクリックアミンのN-OH体とフェントン系でのOHラジカルを用い,サルモネラ変異原性試験と8-OH-2'-デオキシグアノシン生成で測定した.前者のラジカルを抑える抗酸化成分の有効濃度はmMレベルであり,後者に対して有効なのはα-トコフェロールだけであった.つまり食事抗酸化成分の殆どは,DNAや2'-デオキシグアノシンが損傷を受けるよりも速くラジカルを消去することはできなかった
(公社)日本農芸化学会, 2000年11月, Bioscience, Biotechnology, and Biochemistry, 64 (11), 2395 - 2401, 英語前報でフラボノイド類の抗変異原性はシトクロームP450(CYP)1A1酵素の特異的阻害によることを明らかにした.本報告では別の阻害因子を中国薬草で検索し,アンスラキノン類を同定した.例えばダイオウは乾物10g中にエモジンを3.4mg,クリソファノール2.1mg,レインを1.8mg含んでいた.アンスラキノン類の抗変異原性IC50値は,CYP1A1のN-OH化活性に対するIC50値とほぼ一致した.これより抗変異原性はCYP阻害によると考えた.そこで商標のアンスラキノン14種で,阻害活性の構造相関を解析した.阻害には三環と側環に酸素が必要であった.この化学構造の特徴はフラボノイド類と似ていた
(公社)日本農芸化学会, 2000年07月, Bioscience, Biotechnology, and Biochemistry, 64 (7), 1373 - 1378, 英語学術書
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[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
シンポジウム・ワークショップパネル(公募)
ポスター発表
口頭発表(基調)
ポスター発表
ポスター発表
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
[招待有り]
シンポジウム・ワークショップパネル(指名)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
公開講演,セミナー,チュートリアル,講習,講義等
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
口頭発表(一般)
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
シンポジウム・ワークショップパネル(指名)
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
[招待有り]
シンポジウム・ワークショップパネル(指名)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
[招待有り]
シンポジウム・ワークショップパネル(指名)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
[招待有り]
口頭発表(招待・特別)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
ポスター発表
ポスター発表
ポスター発表
ポスター発表
口頭発表(一般)
ポスター発表
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
ポスター発表
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
口頭発表(一般)
王立化学会
日本食品分析学会
日本カテキン学会
日本ビタミン学会
日本ポリフェノール学会
日本動物細胞工学会
日本香辛料研究会
日本食品科学工学会
日本分子生物学会
日本農芸化学会
日本癌学会
日本フリーラジカル学会
日本フードファクター学会
日本栄養・食糧学会
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
競争的資金
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法(米)
13/127047, 2009年10月30日, 大学長, 8962287, 2015年02月24日特許権
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法
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筋肉の糖取り込み促進剤
特願2010-001594, 2010年01月06日, 大学長, 特許5594719, 2014年08月15日特許権
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法(仏)
09823344.8, 2009年10月30日, 大学長, 2357222, 2014年08月13日特許権
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法(独)
09823344.8, 2009年10月30日, 大学長, 602009026044.8, 2014年08月13日特許権
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法(英)
09823344.8, 2009年10月30日, 大学長, 2357222, 2014年08月13日特許権
シロ-イノシトール産生細胞および当該細胞を用いたシロ-イノシトール製造方法(中)
200980143271.X, 2009年10月30日, 大学長, ZL200980143271.X, 2014年07月30日特許権
ナリンゲニン誘導体、それを含有するグルコース取込み促進剤及び血糖値上昇抑制剤
特願2006-188931, 2006年07月10日, 大学長, 特許5061282, 2012年08月17日特許権