Rie Mukai : 第4章ポリフェノール, CMC Publishing Co.,Ltd., May 2020.
5.
Rie Mukai : Protective effect on vascular endothelium by prenyl flavonoids known as strong bioactive compound in legumes, The Tojuro Iijima Foundation for Food Science and Technology, 2020.
Rie Mukai and Junji Terao : 今日の話題，プレニルフラボノイドの生体利用性「プレニル化は体内滞留時間を延長させて，組織への蓄積を高める」, 日本農芸化学会会誌, Jan. 2015.
13.
Y Bandaruk, Rie Mukai and Junji Terao : Role of flavonoids as possible monoamine oxidase-A regulators in the model of serotoninergic neuroblastoma SH-SY5Y cell., Ed by K. Yoshida, Yujinsha, 2014.
14.
Rie Mukai, N Matsui, N Matsumoto, DX Hou, T Nikawa, H Nemoto and J Terao : Anti-Oxidative Flavonoid suppresses disuse muscle atrophy in denervation mice, Ed by K. Yoshida, Yujinsha, 2014.
Rie Mukai, Hitomi Okuyama, Miku Uchimura, Kozue Sakao, Miyu Matsuhiro, Mayumi Ikeda-Imafuku, Yu Ishima, Miyu Nishikawa, Shinichi Ikushiro and Akihiro Tai : The binding selectivity of quercetin and its structure-related polyphenols to human serum albumin using a fluorescent dye cocktail for multiplex drug-site mapping., Bioorganic Chemistry, Vol.145, 107184, 2024.
(Summary)
Human serum albumin (HSA) is a serum protein that carries flavonoids in blood circulation. In this report, the binding selectivity and strength of interactions to HSA-binding sites (sites I or II) by flavonoids were evaluated using competition experiments and the specific fluorescent dyes, dansylamide and BD140. Most tested flavonoids bound site I preferentially, with the binding strength dependent on the mother structure in the order flavonol > flavone > flavanone > flavan 3-ols. Glycosylation or glucuronidation reduced the binding of quercetin to site I of HSA, whereas sulfation increased binding. Quercetin 7-sulfate showed the strongest binding and molecular docking simulations supported this observation. Prenylation at any position or glucuronidation and sulfation at the C-4' or C-7 position of quercetin facilitated stronger binding to site II. The binding affinity of flavonoids toward site I correlated with the partition coefficient value (logP), whereas no corresponding correlation was observed for site II.
Rie Mukai and Natsumi Hata : Tissue distribution and pharmacokinetics of isoxanthohumol from hops in rodents, Food Science & Nutrition, Vol.12, No.3, 2210-2219, 2023.
Nao Fujiwara, Rie Mukai, Miyu Nishikawa, Shinichi Ikushiro, Akira Murakami and Akari Ishisaka : Transfer of quercetin ingested by maternal mice to neonatal mice via breast milk., Bioscience, Biotechnology, and Biochemistry, Vol.87, No.4, 442-447, 2023.
(Summary)
This is the first study that quantified quercetin (QUE) and its 16 metabolites in the breast milk of QUE-fed maternal mice, the plasma and urine of that, and neonatal mice. Interestingly, the QUE aglycone concentration in the milk was much higher than in the plasma of maternal mice, suggesting that QUE may exert biological activity in neonates.
Nuka Erika, Takahashi Masako, Okitsu Masami, Nayama Chisako, Nishijima Honomi, Sogawa Ryutaro, Kawabata Kyuichi, Terao Junji and Rie Mukai : Lowering effect of combined sweet potato and onion intake on plasma quercetin concentration and underlying mechanism involving intestinal β-glucosidase activity., Bioscience, Biotechnology, and Biochemistry, Vol.86, No.12, 1695-1698, 2022.
(Summary)
A combined intake of cooked sweet potato and fried onion in humans was found to suppress the increase of plasma quercetin metabolite concentration. Experiments using rat β-glucosidase indicated that excess carbohydrate digestion products, especially glucose-containing saccharides, interfere with the deglycosylation of quercetin glucosides during intestinal epithelial uptake. Combined meals of sweet potato and onion may lower the bioavailability of onion quercetin glucosides.
Yoshiaki Tanaka, Hitomi Okuyama, Miyu Nishikawa, Shin-ichi Ikushiro, Mayumi Ikeda, Yu Ishima, Yuichi Ukawa, Kenichi Oe, Junji Terao and Rie Mukai : 8-Prenylnaringenin tissue distribution and pharmacokinetics in mice and its binding to human serum albumin and cellular uptake in human embryonic kidney cells., Food Science & Nutrition, Vol.10, No.4, 1070-1080, 2022.
(Summary)
8-Prenylnaringenin (8-PN), a hop flavonoid, is a promising food substance with health benefits. Compared with nonprenylated naringenin, 8-PN exhibits stronger estrogenic activity and prevents muscle atrophy. Moreover, 8-PN prevents hot flushes and bone loss. Considering that prenylation reportedly improves the bioavailability of flavonoids, we compared the parameters related to the bioavailability [pharmacokinetics and tissue distribution in C57/BL6 mice, binding affinity to human serum albumin (HSA), and cellular uptake in HEK293 cells] of 8-PN and its mother (non-prenylated) compound naringenin. C57/BL6 mice were fed an 8-PN or naringenin mixed diet for 22 days. The amount of 8-PN (nmol/g tissue) in the kidneys (16.8 ± 9.20), liver (14.8 ± 2.58), muscles (3.33 ± 0.60), lungs (2.07 ± 0.68), pancreas (1.80 ± 0.38), heart (1.71 ± 0.27), spleen (1.36 ± 0.29), and brain (0.31 ± 0.09) was higher than that of naringenin. A pharmacokinetic study in mice demonstrated that the of 8-PN (50 mg/kg body weight) was lower than that of naringenin; however, the plasma concentration of 8-PN 8 h after ingestion was higher than that of naringenin. The binding affinity of 8-PN to HSA and cellular uptake in HEK293 cells were higher than those of naringenin. 8-PN bioavailability features assessed in mouse or human model experiments were obviously different from those of naringenin.
Takahiro Takase, Satoshi Ikeuchi, Takashi Inoue and Rie Mukai : Eriocitrin Contained in Lemon Peel Ameliorates Disuse Muscle Atrophy by Suppressing the Expression of Atrogin-1 and MuRF-1 in Denervated Mice., Journal of Natural Products, Vol.84, No.7, 2048-2052, 2021.
(Summary)
Unloading stress enhances oxidative stress, which in turn induces disuse muscle atrophy. This study evaluated the suppressive effect of lemon peel extract containing eriocitrin on muscle atrophy. Both lemon peel extract and eriocitrin suppressed weight loss in the gastrocnemius muscle under denervation in C57BL/6 mice. The mRNA level of ubiquitin ligases and their transcription factor were downregulated by eriocitrin. Eriocitrin inhibited the increase in lipid peroxidation and the ratio of glutathione disulfide/glutathione. These data suggest that eriocitrin ameliorated disuse muscle atrophy by suppressing the expression of ubiquitin ligase genes by its antioxidative effect.
Akari Kondo-Kawai, Tohru Sakai, Junji Terao and Rie Mukai : Suppressive effects of quercetin on hydrogen peroxide-induced caveolin-1 phosphorylation in endothelial cells, Journal of Clinical Biochemistry and Nutrition, Vol.69, No.1, 1-9, 2021.
(Summary)
Caveolin-1 is a major protein of the caveolae structure in vascular endothelial cell membrane. Phosphorylation of caveolin-1 is one of the initial events leading to exacerbation of vascular permeability caused by oxidative stress. Although quercetin is known to be an anti-atherosclerosis factor that acts as a dietary antioxidant, little is known about its role in the regulation of caveolin-1 phosphorylation. In this study, we investigated the inhibitory effect of quercetin on hydrogen peroxide-induced caveolin-1 phosphorylation in human umbilical vein endothelial cells. Quercetin inhibited caveolin-1 phosphorylation in cells pretreated with quercetin for 24 h and then exposed to hydrogen peroxide. However, quercetin 3--β-glucuronide, a conjugated metabolite of quercetin, did not exert this inhibitory effect. Exposure to hydrogen peroxide increased vascular permeability and reduced mRNA expression of the intercellular adhesion protein, vascular endothelial cadherin (VE-cadherin). By contrast, pretreatment with quercetin suppressed the increase in vascular permeability and decreased VE-cadherin expression. These results indicate that deconjugated quercetin can play a role in the prevention of altered vascular permeability under oxidative stress by suppressing caveolin-1 phosphorylation. Thus, dietary quercetin may be beneficial for the maintenance of endothelial cell function.
Rie Mukai, Takashi Fukuda, Asami Ohnishi, Takeshi Nikawa, Mutsuki Furusawa and Junji Terao : Chocolate as a food matrix reduces the bioavailability of galloylated catechins from green tea in healthy women., Food & Function, Vol.12, No.1, 408-416, 2021.
(Summary)
In this study, we evaluated the food matrix effects of chocolate on the absorption of green tea catechins (GTCs), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), and (-)-epigallocatechin gallate (EGCg), in five healthy 22-year-old women. In the single-intake experiment, the plasma concentrations of ECg (P < 0.05, at 1.5 h) and EGCg (P < 0.05, at 6 h) but not those of EC and EGC were reduced by the chocolate matrix. Regardless of the chocolate matrix, ECg and EGCg were mainly present as their aglycones in the plasma, whereas EGC and EC were found mostly as conjugated metabolites. After daily intake of GTCs mixed with chocolate for 14 days followed by overnight fasting, ECg but not EGCg was detected in the plasma. To compare the plasma profiles of ECg and EGCg, a mixture containing approximately equal amounts of ECg and EGCg was administered to nine rats for 14 days. Following treatment and overnight food deprivation, the plasma content of ECg was higher than that of EGCg. After a single injection of the same mixture in seven rats, ECg levels were higher than those of EGCg, and a greater amount of conjugated metabolites of ECg than those of EGCg was detected in the plasma 10 h after administration. In conclusion, the chocolate matrix affects the plasma profiles of GTCs, particularly ECg. ECg appears to persist in the plasma for a longer period, regardless of the chocolate matrix.
Agustin Martin Morales, Rie Mukai, Kaeko Murota and Junji Terao : Inhibitory effect of catecholic colonic metabolites of rutin on fatty acid hydroperoxide and hemoglobin dependent lipid peroxidation in Caco-2 cells., Journal of Clinical Biochemistry and Nutrition, Vol.63, No.3, 175-180, 2018.
(Summary)
To determine the preventive effect of dietary rutin on oxidative damages occurring in the digestive tract, 13-hydroperoxyoctadecadienoic acid and hemoglobin were exposed to Caco-2 intestinal cells after the pretreatment with colonic rutin metabolites. Among four catechol-type metabolites, quercetin and 3,4-dihydroxytoluene exerted significant protection on 13-hydroperoxyoctadecadienoic and hemoglobin-dependent lipid peroxidation of this epithelial cell. Compared with quercetin, a much lower concentration allowed 3,4-dihydroxytoluene to maximize the protective effect, though it needed a longer pre-incubation period. Neither quercetin nor 3,4-dihydroxytoluene affected the expression of peroxiredoxin-6 protein, which comprises the cellular antioxidant defense system. It is concluded that 3,4-dihydroxytoluene is a plausible rutin colonic metabolite that can suppress oxidative damages of intestinal epithelial cells by directly inhibiting lipid peroxidation. This result may illuminate the preventive role of dietary rutin against colorectal cancer incidence in relation to the consumption of red and processed meat.
Rie Mukai, Hitomi Horikawa, Pei-Yi Lin, Nao Tsukumo, Takeshi Nikawa, Tomoyuki Kawamura, Hisao Nemoto and Junji Terao : 8-Prenylnaringenin promotes recovery from immobilization-induced disuse muscle atrophy through activation of the Akt phosphorylation pathway in mice., American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, Vol.311, No.6, R1022-R1031, 2016.
(Summary)
8-Prenylnaringenin (8-PN) is a prenylflavonoid that originates from hop extracts and is thought to help prevent disuse muscle atrophy. We hypothesized that 8-PN affects muscle plasticity by promoting muscle recovery under disuse muscle atrophy. To test the promoting effect of 8-PN on muscle recovery, we administered an 8-PN mixed diet to mice that had been immobilized with a cast to one leg for 14 days. Intake of the 8-PN mixed diet accelerated recovery from muscle atrophy, and prevented reductions in Akt phosphorylation. Studies on cell cultures of mouse myotubes in vitro demonstrated that 8-PN activated the PI3K/Akt/P70S6K1 pathway at physiological concentrations. A cell-culture study using an inhibitor of estrogen receptors and an in vivo experiment with ovariectomized mice suggested that the estrogenic activity of 8-PN contributed to recovery from disuse muscle atrophy through activation of an Akt phosphorylation pathway. These data strongly suggest that 8-PN is a naturally occurring compound that could be used as a nutritional supplement to aid recovery from disuse muscle atrophy.
(Keyword)
Animals / Cell Line / Enzyme Activation / Flavanones / Hindlimb Suspension / Male / Mice / Mice, Inbred C57BL / Muscle Proteins / Muscle, Skeletal / Muscular Atrophy / Oncogene Protein v-akt / phosphorylation / Phytoestrogens / Protein Biosynthesis / Recovery of Function / signal transduction / Treatment Outcome
Chiemi Kamada, Rie Mukai, Akari Kondo, Shinya Sato and Junji Terao : Effect of quercetin and its metabolite on caveolin-1 expression induced by oxidized LDL and lysophosphatidylcholine in endothelial cells., Journal of Clinical Biochemistry and Nutrition, Vol.58, No.3, 193-201, 2016.
(Summary)
Oxidized low-density lipoprotein contributes to atherosclerotic plaque formation, and quercetin is expected to exert anti-atherosclerotic effects. We previously reported accumulation of conjugated quercetin metabolites in the aorta of rabbits fed high-cholesterol diets with quercetin glucosides, resulting in attenuation of lipid peroxidation and inhibition of lipid accumulation. Caveolin-1, a major structural protein of caveolae in vascular endothelial cells, plays a role in atherosclerosis development. Here we investigated effects of oxidized low-density lipoprotein, quercetin and its metabolite, quercetin 3-O--glucuronide, on caveolin-1 expression. Oxidized low-density lipoprotein significantly upregulated caveolin-1 mRNA expression. An oxidized low-density lipoprotein component, lysophosphatidylcholine, also induced expression of both caveolin-1 mRNA and protein. However, lysophosphatidylcholine did not affect the location of caveolin-1 proteins within caveolae structures. Co-treatment with quercetin or quercetin 3-O--glucuronide inhibited lysophosphatidylcholine-induced caveolin-1 expression. Quercetin and quercetin 3-O--glucuronide also suppressed expression of adhesion molecules induced by oxidized low-density lipoprotein and lysophosphatidylcholine. These results strongly suggest lysophosphatidylcholine derived from oxidized low-density lipoprotein contributes to atherosclerotic events by upregulating caveolin-1 expression, resulting in induction of adhesion molecules. Quercetin metabolites are likely to exert an anti-atherosclerotic effect by attenuating caveolin-1 expression in endothelial cells.
Rie Mukai, Naoko Matsui, Yutaka Fujikura, Norifumi Matsumoto, De-Xing Hou, Noriyuki Kanzaki, Hiroshi Shibata, Manabu Horikawa, Keiko Iwasa, Katsuya Hirasaka, Takeshi Nikawa and Junji Terao : Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice., The Journal of Nutritional Biochemistry, Vol.31, 67-76, 2016.
(Summary)
Quercetin is a major dietary flavonoid in fruits and vegetables. We aimed to clarify the preventive effect of dietary quercetin on disuse muscle atrophy and the underlying mechanisms. We established a mouse denervation model by cutting the sciatic nerve in the right leg (SNX surgery) to lack of mobilization in hind-limb. Preintake of a quercetin-mixed diet for 14days before SNX surgery prevented loss of muscle mass and atrophy of muscle fibers in the gastrocnemius muscle (GM). Phosphorylation of Akt, a key phosphorylation pathway of suppression of protein degradation, was activated in the quercetin-mixed diet group with and without SNX surgery. Intake of a quercetin-mixed diet suppressed the generation of hydrogen peroxide originating from mitochondria and elevated mitochondrial peroxisome proliferator-activated receptor- coactivator 1 mRNA expression as well as NADH dehydrogenase 4 expression in the GM with SNX surgery. Quercetin and its conjugated metabolites reduced hydrogen peroxide production in the mitochondrial fraction obtained from atrophied muscle. In C2C12 myotubes, quercetin reached the mitochondrial fraction. These findings suggest that dietary quercetin can prevent disuse muscle atrophy by targeting mitochondria in skeletal muscle tissue through protecting mitochondria from decreased biogenesis and reducing mitochondrial hydrogen peroxide release, which can be related to decreased hydrogen peroxide production and/or improvements on antioxidant capacity of mitochondria.
Yasuaki Kashino, Kaeko Murota, Namiko Matsuda, Muneaki Tomotake, Takuya Hamano, Rie Mukai and Junji Terao : Effect of Processed Onions on the Plasma Concentration of Quercetin in Rats and Humans., Journal of Food Science, Vol.80, No.11, H2597-H2602, 2015.
(Summary)
Onion is a popular source of antioxidative flavonoid quercetin and its vascular function attracts considerable attention in relation to anti-atherosclerotic effect. The present study estimated the effect of food processing on the bioavailability of onion quercetin aglycone and its glucosides provided through the consumption of onion products. The intake of a peel powder-containing meal showed a significantly higher bioavailability than the peel extract, bulb powder, bulb extract, and bulb sauté containing meals. Hence, food processing of onion peel may enhance the health impact of onion quercetin by elevating its bioavailability.
Manabu Ueda-Wakagi, Rie Mukai, Naoya Fuse, Yoshiyuki Mizushina and Hitoshi Ashida : 3-O-Acyl-epicatechins Increase Glucose Uptake Activity and GLUT4 Translocation through Activation of PI3K Signaling in Skeletal Muscle Cells., International Journal of Molecular Sciences, Vol.16, No.7, 16288-16299, 2015.
(Summary)
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.
(Keyword)
Animals / Catechin / Glucose / Glucose Transporter Type 4 / Insulin / Lipid Bilayers / Muscle Cells / Muscle Fibers, Skeletal / Muscle, Skeletal / Phosphatidylinositol 3-Kinases / Protein Transport / Rats / Signal Transduction
Rita Cristina Orihuela Campos, Naofumi Tamaki, Rie Mukai, Makoto Fukui, Kaname Miki, Junji Terao and Hiro-O Ito : Biological impacts of resveratrol, quercetin, and N-acetylcysteine on oxidative stress in human gingival fibroblasts., Journal of Clinical Biochemistry and Nutrition, Vol.56, No.3, 220-227, 2015.
(Summary)
In periodontitis, production of reactive oxygen species (ROS) by neutrophils induces oxidative stress and deteriorates surrounding tissues. Antioxidants reduce damage caused by ROS and are used to treat diseases involving oxidative stress. This study summarizes the different effects of resveratrol, quercetin, and N-acetylcysteine (NAC) on human gingival fibroblasts (HGFs) under oxidative stress induced by hydrogen peroxide. Real-time cytotoxicity analyses reveals that resveratrol and quercetin enhanced cell proliferation even under oxidative stress. Of the antioxidants tested, resveratrol is the most effective at inhibiting ROS production. HGFs incubated with resveratrol and quercetin up-regulate the transcription of type I collagen gene after 3 h, but only resveratrol sustained this up-regulation for 24 h. A measurement of the oxygen consumption rate (OCR, mitochondrial respiration) shows that resveratrol generates the highest maximal respiratory capacity, followed by quercetin and NAC. Simultaneous measurement of OCR and the extracellular acidification rate (non-mitochondrial respiration) reveals that resveratrol and quercetin induce an increase in mitochondrial respiration when compared with untreated cells. NAC treatment consumes less oxygen and enhances more non-mitochondrial respiration. In conclusion, resveratrol is the most effective antioxidant in terms of real-time cytotoxicity analysis, reduction of ROS production, and enhancement of type I collagen synthesis and mitochondrial respiration in HGFs.
A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120M, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin.
Itsuko Fukuda, Shin Nishiumi, Rie Mukai, Ken-ichi Yoshida and Hitoshi Ashida : Catechins in tea suppress the activity of cytochrome P450 1A1 through the aryl hydrocarbon receptor activation pathway in rat livers., International Journal of Food Sciences and Nutrition, Vol.66, No.3, 300-307, 2015.
(Summary)
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.
Rie Hashimoto, Atsuko Sakai, Masumi Murayama, Arisa Ochi, Tomoki Abe, Katsuya Hirasaka, Ayako Ohno, Shigetada Teshima-Kondo, Hiroaki Yanagawa, Natsuo Yasui, Mikiko Inatsugi, Daisuke Doi, Masanori Takeda, Rie Mukai, Junji Terao and Takeshi Nikawa : Effects of dietary soy protein on skeletal muscle volume and strength in humans with various physical activities, The Journal of Medical Investigation : JMI, Vol.62, No.3, 177-183, 2015.
(Summary)
Background: In recent years, the number of bedridden people is rapidly increasing due to aging or lack of exercise in Japan. This problem is becoming more serious, since there is no countermeasure against it. In the present study, we designed to investigate whether dietary proteins, especially soy, had beneficial effects on skeletal muscle in 59 volunteers with various physical activities. Methods: We subjected 59 volunteers with various physical activities to meal intervention examination. Persons with low and high physical activities were divided into two dietary groups, the casein diet group and the soy diet group. They ate daily meals supplemented with 7.8 g of powdered casein or soy protein isolate every day for 30 days. Bedridden patients in hospitals were further divided into three dietary groups: the no supplementation diet group, the casein diet group and the soy diet group. They were also subjected to a blood test, a urinalysis, magnetic resonance imaging analysis and muscle strength test of the knee before and after the meal intervention study. Results: Thirty-day soy protein supplementation significantly increased skeletal muscle volume in participants with low physical activity, compared with 30-day casein protein supplementation. Both casein and soy protein supplementation increased the volume of quadriceps femoris muscle in bedridden patients. Consistently, soy protein significantly increased their extension power of the knee, compared with casein protein. Although casein protein increased skeletal muscle volume more than soy protein in bedridden patients, their muscle strength changes by soy protein supplementation were bigger than those by casein protein supplementation. Conclusions: The supplementation of soy protein would be one of the effective foods which prevent the skeletal muscle atrophy caused by immobilization or unloading. J. Med. Invest. 62: 177-183, August, 2015
Noriko Bando, 片岡 美樹, Toshiyuki Nakamura, Rie Mukai, 山岸 喬 and Junji Terao : Comparison of Isoflavone Absorption by Soybean Products in Humans, Journal of Japanese Society of Nutrition and Food Science, Vol.68, No.1, 25-29, 2015.
(Summary)
We investigated the bioavailability of soy isoflavones from processed soybean products. Five healthy male volunteers ingested soy milk, soy curd (tofu) , boiled soybeans (nimame) , or fermented soybeans (natto) in a single dose, and blood was collected 90 min later for measurement of the plasma isoflavone concentration. Each subject ingested test meals containing an isoflavone equivalent of 50 mg aglycone. The total amount of each isoflavone was determined by HPLC analysis after deconjugation of conjugated metabolites using sulfatase H-1. The concentration of glycitein was below the detection limit before and after intake of the soybean products. The concentrations of daidzein and genistein were elevated in all subjects after ingestion of all the test meals, and the concentration of genistein was higher than that of daidzein except after ingestion of fermented soybeans. Ingestion of boiled soybeans appeared to result in a higher concentration of total isoflavones (daizein and genistein) than ingestion of soy curd. These results suggest that the bioavailability of isoflavones from soybeans varies according to the type of processing.
(Keyword)
isoflavone / soybean products / bioavailability / human
Bandaruk Yauhen, Rie Mukai and Junji Terao : Cellular uptake of quercetin and luteolin and their effects on monoamine oxidase-A in human neuroblastoma SH-SY5Y cells, Toxicology Reports, Vol.1, No.1, 639-649, 2014.
Akari Ishisaka, Rie Mukai, Junji Terao, Noriyuki Shibata and Yoshichika Kawai : Specific localization of quercetin-3-O-glucuronide in human brain., Archives of Biochemistry and Biophysics, Vol.557, 11-17, 2014.
(Summary)
In recent years, many papers have suggested that dietary flavonoids may exert beneficial effects in the brain tissue for the protection of neurons against oxidative stress and inflammation. However, the bioavailability of flavonoids across the blood-brain barrier and the localization in the brain remain controversial. Thus, we examined the localization of quercetin-3-O-glucuronide (Q3GA), a major phase-II metabolite of quercetin, in the human brain tissues with or without cerebral infarction by immunohistochemical staining using anti-Q3GA antibody. A significant immunoreactivity was observed in the epithelial cells of the choroid plexus, which constitute the structural basis of the blood-cerebrospinal fluid (CSF) barrier, and in the foamy macrophages of recent infarcts. The cellular accumulation of Q3GA was also reproduced in vitro in macrophage-like RAW264, microglial MG6, and brain capillary endothelial RBEC1. It is of interest that a common feature of these cell lines is the deconjugation of Q3GA, resulting in the cellular accumulation of non-conjugated quercetin and the methylated forms. We then examined the anti-inflammatory activity of Q3GA and the deconjugated forms in the lipopolysaccharide-stimulated macrophage cells and revealed that the deconjugated forms (quercetin and a methylated form isorhamnetin), but not Q3GA itself, exhibited inhibitory effects on the inflammatory responses through attenuation of the c-Jun N-terminal kinase pathway. These results suggested that a quercetin glucuronide can pass through the blood-brain barrier, perhaps the CSF barrier, accumulate in specific types of cells, such as macrophages, and act as anti-inflammatory agents in the brain through deconjugation into the bioactive non-conjugated forms.
Itai-itai disease is thought to be the result of chronic cadmium (Cd) intoxication. Renal proximal tubules are a major target of Cd toxicity. The whole mechanism of the adverse effects of Cd remains unresolved, especially how renal damage is related to the development of bone lesions. Fibroblast growth factor 23 (FGF23) is a bone-derived phosphaturic factor that regulates vitamin D and inorganic phosphate metabolism in the kidney. To clarify the role of FGF23 on Cd toxicity, we investigated the mechanisms of Cd-induced FGF23 production in the bone. Cd injection into mice significantly increased plasma FGF23 concentrations, but did not change FGF23 mRNA expression in bone. GalNAc-T3 is involved in secreting intact FGF23. To determine potential roles of GalNAc-T3 in Cd-induced FGF23 production, we examined the effect of Cd on GalNAc-T3 mRNA expression in vivo and in vitro. GalNAc-T3 gene expression was significantly increased in the bones of Cd-injected mice. Cd also enhanced the expression of GalNAc-T3 in cultured osteosarcoma UMR106 cells and primary osteocytes. Cd activated aryl hydrocarbon receptors (AhR) and AhR were required for GalNAc-T3 gene expression induced by Cd. In addition, Cd-dependent FGF23 production was completely inhibited by an AhR antagonist. AhR siRNA markedly suppressed the stimulation of transcriptional activity by Cd. Furthermore, Cd induced AhR activation via phosphorylation of Ser-68 by p38 kinase in the nuclear export signal of AhR. Thus, Cd stimulated GalNAc-T3 gene transcription via enhanced AhR binding to the GalNAc-T3 promoter. These findings suggest that the Cd-induced increase in GalNAc-T3 suppresses proteolytic processing of FGF23 and increases serum FGF23 concentrations.
Akari Ishisaka, Kyuichi Kawabata, Satomi Miki, Yuko Shiba, Shoko Minekawa, Tomomi Nishikawa, Rie Mukai, Junji Terao and Yoshichika Kawai : Mitochondrial dysfunction leads to deconjugation of quercetin glucuronides in inflammatory macrophages., PLoS ONE, Vol.8, No.11, e80843, 2013.
(Summary)
Dietary flavonoids, such as quercetin, have long been recognized to protect blood vessels from atherogenic inflammation by yet unknown mechanisms. We have previously discovered the specific localization of quercetin-3-O-glucuronide (Q3GA), a phase II metabolite of quercetin, in macrophage cells in the human atherosclerotic lesions, but the biological significance is poorly understood. We have now demonstrated the molecular basis of the interaction between quercetin glucuronides and macrophages, leading to deconjugation of the glucuronides into the active aglycone. In vitro experiments showed that Q3GA was bound to the cell surface proteins of macrophages through anion binding and was readily deconjugated into the aglycone. It is of interest that the macrophage-mediated deconjugation of Q3GA was significantly enhanced upon inflammatory activation by lipopolysaccharide (LPS). Zymography and immunoblotting analysis revealed that -glucuronidase is the major enzyme responsible for the deglucuronidation, whereas the secretion rate was not affected after LPS treatment. We found that extracellular acidification, which is required for the activity of -glucuronidase, was significantly induced upon LPS treatment and was due to the increased lactate secretion associated with mitochondrial dysfunction. In addition, the -glucuronidase secretion, which is triggered by intracellular calcium ions, was also induced by mitochondria dysfunction characterized using antimycin-A (a mitochondrial inhibitor) and siRNA-knockdown of Atg7 (an essential gene for autophagy). The deconjugated aglycone, quercetin, acts as an anti-inflammatory agent in the stimulated macrophages by inhibiting the c-Jun N-terminal kinase activation, whereas Q3GA acts only in the presence of extracellular -glucuronidase activity. Finally, we demonstrated the deconjugation of quercetin glucuronides including the sulfoglucuronides in vivo in the spleen of mice challenged with LPS. These results showed that mitochondrial dysfunction plays a crucial role in the deconjugation of quercetin glucuronides in macrophages. Collectively, this study contributes to clarifying the mechanism responsible for the anti-inflammatory activity of dietary flavonoids within the inflammation sites.
Rie Mukai, Yutaka Fujikura, Kaeko Murota, Shoko Minekawa, Naoko Matsui, Hisao Nemoto and Junji Terao : Prenylation enhances quercetin uptake and reduces efflux in Caco-2 cells and enhances tissue accumulation in mice fed long-term., The Journal of Nutrition, Vol.143, No.10, 1558-1564, 2013.
(Summary)
Prenyl flavonoids are widely distributed in plant foods and have attracted appreciable attention in relation to their potential benefits for human health. Prenylation may enhance the biological functions of flavonoids by introducing hydrophobic properties in their basic structures. Previously, we found that 8-prenyl naringenin exerted a greater preventive effect on muscle atrophy than nonprenylated naringenin in a mouse model. Here, we aimed to estimate the effect of prenylation on the bioavailability of dietary quercetin (Q). The cellular uptake of 8-prenyl quercetin (PQ) and Q in Caco-2 cells and C2C12 myotube cells was examined. Prenylation significantly enhanced the cellular uptake by increasing the lipophilicity in both cell types. In Caco-2 cells, efflux of PQ to the basolateral side was <15% of that of Q, suggesting that prenylation attenuates transport from the intestine to the circulation. After intragastric administration of PQ or Q to mice or rats, the area under the concentration-time curve for PQ in plasma and lymph was 52.5% and 37.5% lower than that of Q, respectively. PQ and its O-methylated form (MePQ) accumulated at much higher amounts than Q and O-methylated Q in the liver (Q: 3400%; MePQ: 7570%) and kidney (Q: 385%; MePQ: 736%) of mice after 18 d of feeding. These data suggest that prenylation enhances the accumulation of Q in tissues during long-term feeding, even though prenylation per se lowers its intestinal absorption from the diet.
Tomoki Abe, Shohei Kohno, Tomonari Yama, Arisa Ochi, Takuro Suto, Katsuya Hirasaka, Ayako Ohno, Shigetada Teshima-Kondo, Yuushi Okumura, Motoko Oarada, Inho Choi, Rie Mukai, Junji Terao and Takeshi Nikawa : Soy Glycinin Contains a Functional Inhibitory Sequence against Muscle-Atrophy-Associated Ubiquitin Ligase Cbl-b., International Journal of Endocrinology, Vol.2013, 907565, 2013.
(Summary)
Background. Unloading stress induces skeletal muscle atrophy. We have reported that Cbl-b ubiquitin ligase is a master regulator of unloading-associated muscle atrophy. The present study was designed to elucidate whether dietary soy glycinin protein prevents denervation-mediated muscle atrophy, based on the presence of inhibitory peptides against Cbl-b ubiquitin ligase in soy glycinin protein. Methods. Mice were fed either 20% casein diet, 20% soy protein isolate diet, 10% glycinin diet containing 10% casein, or 20% glycinin diet. One week later, the right sciatic nerve was cut. The wet weight, cross sectional area (CSA), IGF-1 signaling, and atrogene expression in hindlimb muscles were examined at 1, 3, 3.5, or 4 days after denervation. Results. 20% soy glycinin diet significantly prevented denervation-induced decreases in muscle wet weight and myofiber CSA. Furthermore, dietary soy protein inhibited denervation-induced ubiquitination and degradation of IRS-1 in tibialis anterior muscle. Dietary soy glycinin partially suppressed the denervation-mediated expression of atrogenes, such as MAFbx/atrogin-1 and MuRF-1, through the protection of IGF-1 signaling estimated by phosphorylation of Akt-1. Conclusions. Soy glycinin contains a functional inhibitory sequence against muscle-atrophy-associated ubiquitin ligase Cbl-b. Dietary soy glycinin protein significantly prevented muscle atrophy after denervation in mice.
Katsuya Hirasaka, Tasuku Maeda, Chika Ikeda, Marie Haruna, Arisa Ochi, Rie Mukai, Motoko Oarada, Shigetada Kondo, Ayako Ohno, Yuushi Okumura, Junji Terao and Takeshi Nikawa : Isoflavones derived from soy beans prevent MuRF1-mediated muscle atrophy in C2C12 myotubes through SIRT1 activation., Journal of Nutritional Science and Vitaminology, Vol.59, No.4, 317-324, 2013.
(Summary)
Proinflammatory cytokines are factors that induce ubiquitin-proteasome-dependent proteolysis in skeletal muscle, causing muscle atrophy. Although isoflavones, as potent antioxidative nutrients, have been known to reduce muscle damage during the catabolic state, the non-antioxidant effects of isoflavones against muscle atrophy are not well known. Here we report on the inhibitory effects of isoflavones such as genistein and daidzein on muscle atrophy caused by tumor necrosis factor (TNF)- treatment. In C2C12 myotubes, TNF- treatment markedly elevated the expression of the muscle-specific ubiquitin ligase MuRF1, but not of atrogin-1, leading to myotube atrophy. We found that MuRF1 promoter activity was mediated by acetylation of p65, a subunit of NFB, a downstream target of the TNF- signaling pathway; increased MuRF1 promoter activity was abolished by SIRT1, which is associated with deacetylation of p65. Of interest, isoflavones induced expression of SIRT1 mRNA and phosphorylation of AMP kinase, which is well known to stimulate SIRT1 expression, although there was no direct effect on SIRT1 activation. Moreover, isoflavones significantly suppressed MuRF1 promoter activity and myotube atrophy induced by TNF- in C2C12 myotubes. These results suggest that isoflavones suppress myotube atrophy in skeletal muscle cells through activation of SIRT1 signaling. Thus, the efficacy of isoflavones could provide a novel therapeutic approach against inflammation-related muscle atrophy.
Yauhen Bandaruk, Rie Mukai, Tomoyuki Kawamura, Hisao Nemoto and Junji Terao : Evaluation of the inhibitory effects of quercetin-related flavonoids and tea catechins on the monoamine oxidase-A reaction in mouse brain mitochondria., Journal of Agricultural and Food Chemistry, Vol.60, No.41, 10270-10277, 2012.
(Summary)
Quercetin, a typical dietary flavonoid, is thought to exert antidepressant effects by inhibiting the monoamine oxidase-A (MAO-A) reaction, which is responsible for regulation of the metabolism of the neurotransmitter 5-hydroxytryptamine (5-HT) in the brain. This study compared the MAO-A inhibitory activity of quercetin with those of O-methylated quercetin (isorhamnetin, tamarixetin), luteolin, and green tea catechins ((-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin, and (-)-epigallocatechin gallate) by measuring the formation of the oxidative deamination product of 5-HT, 5-hydroxyindole aldehyde (5-HIAL), in mouse brain mitochondria. Quercetin was inferior to luteolin in the inhibition of MAO-A activity, whereas isorhamnetin, tamarixetin, and tea catechins scarcely exerted inhibitory activity. Quercetin did not affect MAO-A activity in mouse intestinal mitochondria, indicating that it does not evoke side effects on the metabolism of dietary monoamines in the gut. These data suggest that quercetin is a weak (but safe) MAO-A inhibitor in the modulation of 5-HT levels in the brain.
Rie Mukai, Hitomi Horikawa, Yutaka Fujikura, Tomoyuki Kawamura, Hisao Nemoto, Takeshi Nikawa and Junji Terao : Prevention of disuse muscle atrophy by dietary ingestion of 8-prenylnaringenin in denervated mice, PLoS ONE, Vol.7, No.9, e45048, 2012.
(Summary)
Flavonoids have attracted considerable attention in relation to their effects upon health. 8-Prenylnaringenin (8-PN) is found in the common hop (Humulus lupulus) and assumed to be responsible for the health impact of beer consumption. We wanted to clarify the effects of prenylation on the physiological functions of dietary flavonoids by comparing the effects of 8-PN with that of intact naringenin in the prevention of disuse muscle atrophy using a model of denervation in mice. Consumption of 8-PN (but not naringenin) prevented loss of weight in the gastrocnemius muscle further supported by the lack of induction of the protein content of a key ubiquitin ligase involved in muscle atrophy, atrogin-1, and by the activation of Akt phosphorylation. 8-PN content in the gastrocnemius muscle was tenfold higher than that of naringenin. These results suggested that, compared with naringenin, 8-PN was effectively concentrated into skeletal muscle to exert its preventive effects upon disuse muscle atrophy. It is likely that prenylation generates novel functions for 8-PN by enhancing its accumulation into muscle tissue through dietary intake.
Shin Nishiumi, Rie Mukai, Takashi Ichiyanagi and Hitoshi Ashida : Suppression of lipopolysaccharide and galactosamine-induced hepatic inflammation by red grape pomace., Journal of Agricultural and Food Chemistry, Vol.60, No.36, 9315-9320, 2012.
(Summary)
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-κB (NF-κB) 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-κB 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.
Rie Mukai, Kyuichi Kawabata, Seiko Otsuka, Akari Ishisaka, Yoshichika Kawai, Zai-Si Ji, Hiroshi Tsuboi and Junji Terao : Effect of quercetin and its glucuronide metabolite upon 6-hydorxydopamine-induced oxidative damage in Neuro-2a cells., Free Radical Research, Vol.46, No.8, 1019-1028, 2012.
(Summary)
Quercetin is ubiquitously distributed in plant foods. This antioxidative polyphenol is mostly converted to conjugated metabolites in the body. Parkinson disease (PD) has been suggested to be related to oxidative stress derived from abnormal dopaminergic activity. We evaluated if dietary quercetin contributes to the antioxidant network in the central nervous system from the viewpoint of PD prevention. A neurotoxin, 6-hydroxydopamine (6-OHDA), was used as a model of PD. 6-OHDA-induced H(2)O(2) production and cell death in mouse neuroblastoma, Neuro-2a. Quercetin aglycone suppressed 6-OHDA-induced H(2)O(2) production and cell death, although aglycone itself reduced cell viability at higher concentration. Quercetin 3-O-β-d-glucuronide (Q3GA), which is an antioxidative metabolite of dietary quercetin, was little incorporated into the cell resulting in neither suppression of 6-OHDA-induced cell death nor reduction of cell viability. Q3GA was found to be deconjugated to quercetin by microglial MG-6 cells. These results indicate that quercetin metabolites should be converted to their aglycone to exert preventive effect on damage to neuronal cells.
Shin Nishiumi, Keizo Hosokawa, Masaki Anetai, Toshiro Shibata, Rie Mukai, Ken-ichi Yoshida and Hitoshi Ashida : Antagonistic effect of the Ainu-selected traditional beneficial plants on the transformation of an aryl hydrocarbon receptor., Journal of Food Science, Vol.77, No.4, C420-429, 2012.
(Summary)
Transformation of an aryl hydrocarbon receptor (AhR) is the initial step to express the multiple toxicity of halogenated and polycyclic aromatic hydrocarbons (HAHs and PAHs) including dioxins. Therefore, it has been suggested that suppression of the transformation induced by HAHs and PAHs leads to reduce their toxicological effects. In this study, the antagonistic effect of 110 indigenous plants (192 plant parts) used as medicine and/or food by the Ainu on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AhR transformation was investigated. Of these, a stalk of Aralia elata (Miq.) Seemann and a bark of Fraxinus mandshurica Rupr. var. japonica Maxim. exhibited the strong antagonistic effect in a dose-dependent manner. An antioxidative activity and polyphenol content were also measured, and the strong correlation (r= 0.96) between these two parameters could be confirmed. However, correlation coefficients of the antagonistic effect of 192 extracts compared to their antioxidative activity and polyphenol content were 0.17 and 0.20, respectively. These results suggest that the Ainu-selected traditional beneficial plants are useful source for findings of novel AhR antagonists, and the antagonistic activity of these plants may be independent on their antioxidative activity and polyphenol content. PRACTICAL APPLICATION: Our findings lead to discovery of the valuable plants used by the Ainu and the novel active compounds useful for human's life, and furthermore, may contribute to the development of new medicines and functional foods.
Hiroko Takumi, Hiroyasu Nakamura, Terumi Simizu, Ryoko Harada, Takashi Kometani, Tomonori Nadamoto, Rie Mukai, Kaeko Murota, Yoshichika Kawai and Junji Terao : Bioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: implication of endothelial functions of plasma conjugated metabolites., Food & Function, Vol.3, No.4, 389-398, 2012.
(Summary)
Hesperetin is an aglycone of citrus flavonoids and is expected to exert a vasodilatation effect in vivo. We developed water-dispersible hesperetin by the process of micronization to enhance the bioavailability of hesperetin. This study aimed to assess the effect of this process on the bioavailability of hesperetin and to estimate its efficiency on vasodilatation-related functions using endothelial cells in vitro and a human volunteer study at a single dose in vivo. We found that water-dispersible hesperetin was absorbed rapidly, with its maximum plasma concentration (C(max)) being 10.2 ± 1.2 μM, and that the time to reach C(max), which is within 1 h if 150 mg of this preparation was orally administered in humans. LC-MS analyses of the plasma at C(max) demonstrated that hesperetin accumulated in the plasma as hesperetin 7-O-β-D-glucuronide (Hp7GA), hesperetin 3'-O-β-D-glucuronide (Hp3'GA) and hesperetin sulfate exclusively. Similar to hesperetin, Hp7GA enhanced nitric oxide (NO) release by inhibiting nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity in a human umbilical vein endothelial cell culture system, indicating that plasma hesperetin metabolites can improve vasodilatation in the vascular system. A volunteer study using women with cold sensitivity showed that a single dose of water-dispersible hesperetin was effective on peripheral vasodilatation.These results strongly suggest that rapid accumulation with higher plasma concentration enables hesperetin to exert a potential vasodilatation effect by the endothelial action of its plasma metabolites. Water-dispersible hesperetin may be useful to improve the health effect of dietary hesperetin.
Hiroko Takumi, Rie Mukai, Sawako Ishiduka, Takashi Kometani and Junji Terao : Tissue distribution of hesperetin in rats after a dietary intake., Bioscience, Biotechnology, and Biochemistry, Vol.75, No.8, 1608-1610, 2011.
(Summary)
Hesperetin, the aglycone of hesperidin present in citrus fruits, possesses various biological activities. We assessed the tissue distribution of hesperetin in rats fed with a 0.2% hesperetin diet for 4 weeks. Its highest concentration was found in the liver, and the second highest was in the aorta. The aorta is assumed to be one of the main target tissues of hesperetin for exerting its functions.
Deficiency of the Cbl-b ubiquitin ligase gene activates macrophages in mice. This study aimed to elucidate the pathophysiological roles of macrophages in muscle degeneration/regeneration in Cbl-b-deficient mice. We examined immune cell infiltration and cytokine expression in cardiotoxin-injected tibialis anterior muscle of Cbl-b-deficient mice. Ablation of the Cbl-b gene expression delayed regeneration of cardiotoxin-induced skeletal muscle damage compared with wild-type mice. CD8-positive T cells were still present in the damaged muscle on day 14 after cardiotoxin injection in Cbl-b-deficient mice, but there was dispersal of the same cells over that time-frame in wild-type mice. Infiltrating macrophages in Cbl-b-deficient mice showed strong expression of RANTES (regulated-on-activation, normal T cell expressed and secreted), a chemokine for CD8-positive T cells. In turn, a neutralizing antibody against RANTES significantly suppressed the infiltration of CD8-positive T cells into the muscle, resulting in restoration of the disturbed muscle regeneration. Cbl-b is an important regulatory factor for cytotoxic T-cell infiltration via RANTES production in macrophages.
Rie Mukai, Reiko Nakao, Hironori Yamamoto, Takeshi Nikawa, Eiji Takeda and Junji Terao : Quercetin Prevents Unloading-Derived Disused Muscle Atrophy by Attenuating the Induction of Ubiquitin Ligases in Tail-Suspension Mice., Journal of Natural Products, Vol.73, No.10, 1708-1710, 2010.
(Summary)
The effects of quercetin (1) were investigated on disused muscle atrophy using mice that underwent tail suspension. Periodic injection of 1 into the gastrocnemius muscle suppressed muscle weight loss and ubiquitin ligase expression. Compound 1 reduced the enhancement of lipid peroxidation in the muscle. Injection of N-acetyl-l-cysteine, but not flavone (2), also prevented muscle weight loss and enhancement of lipid peroxidation. These findings demonstrate that 1 can prevent disused muscle atrophy by attenuating the expression of ubiquitin ligases and that such prevention originates from its antioxidant activity.
Nhung Thuy Dang, Rie Mukai, Ken-Ichi Yoshida and Hitoshi Ashida : D-pinitol and myo-inositol stimulate translocation of glucose transporter 4 in skeletal muscle of C57BL/6 mice., Bioscience, Biotechnology, and Biochemistry, Vol.74, No.5, 1062-1067, 2010.
(Summary)
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.
(Keyword)
Administration, Oral / Animals / Blood Glucose / Glucose Transporter Type 4 / Inositol / insulin / Male / Mice / Mice, Inbred C57BL / Muscle, Skeletal / Protein Transport / Time Factors
Rie Mukai, Yasuhito Shirai, Naoaki Saito, Itsuko Fukuda, Shin Nishiumi, Ken-Ichi Yoshida and Hitoshi Ashida : Suppression mechanisms of flavonoids on aryl hydrocarbon receptor-mediated signal transduction., Archives of Biochemistry and Biophysics, Vol.501, No.1, 134-141, 2010.
(Summary)
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.
Rie Mukai, Hideo Satsu, Makoto Shimizu and Hitoshi Ashida : Inhibition of P-glycoprotein enhances the suppressive effect of kaempferol on transformation of the aryl hydrocarbon receptor., Bioscience, Biotechnology, and Biochemistry, Vol.73, No.7, 1635-1639, 2009.
(Summary)
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.
Rie Mukai, Yasuhito Shirai, Naoaki Saito, Ken-Ichi Yoshida and Hitoshi Ashida : Subcellular localization of flavonol aglycone in hepatocytes visualized by confocal laser scanning fluorescence microscope., Cytotechnology, Vol.59, No.3, 177-182, 2009.
(Summary)
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.
Rie Mukai, Itsuko Fukuda, Shin Nishiumi, Midori Natsume, Naomi Osakabe, Ken-ichi Yoshida and Hitoshi Ashida : Cacao polyphenol extract suppresses transformation of an aryl hydrocarbon receptor in C57BL/6 mice., Journal of Agricultural and Food Chemistry, Vol.56, No.21, 10399-10405, 2008.
(Summary)
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.
Itsuko Fukuda, Rie Mukai, Masaya Kawase, Ken-ichi Yoshida and Hitoshi Ashida : Interaction between the aryl hydrocarbon receptor and its antagonists, flavonoids., Biochemical and Biophysical Research Communications, Vol.359, No.3, 822-827, 2007.
(Summary)
Flavonoids have been reported to be dietary antagonists of an aryl hydrocarbon receptor (AhR). However, little is known about the molecular mechanism on their antagonistic effects. In this study, the inhibitory effect of flavonoids on ligand binding to the AhR and interaction between flavonoids and the AhR complex (AhRc) were investigated in each flavonoid subclass. Flavone, flavonol, and flavanone but not catechin inhibited the specific binding between the AhR and 3-methylcholanthrene dose-dependently, indicating that the former three subclasses possibly act as competitive antagonists of the AhR. However, catechin in addition to the former three subclasses directly interacted with the AhRc by surface plasmon resonance analysis. The dissociation constant values showed an inverse correlation with the suppressive effect on the DNA binding activity. These results suggest that flavone, flavonol, and flavanone act as competitive antagonists of the AhR, while catechin associates with the AhRc and indirectly exhibits its antagonistic effects.
Ken-Ichi Yoshida, Won-Seok Kim, Masaki Kinehara, Rie Mukai, Hitoshi Ashida, Hideki Ikeda, Yasutaro Fujita and Hari B. Krishnan : Identification of a functional 2-keto-myo-inositol dehydratase gene of Sinorhizobium fredii USDA191 required for myo-inositol utilization., Bioscience, Biotechnology, and Biochemistry, Vol.70, No.12, 2957-2964, 2006.
(Summary)
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 iolE 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 iolE ortholog was cloned from USDA191. USDA191 iolE was expressed in Escherichia coli as a His(6)-tag fusion and purified to exhibit 2-keto-myo-inositol dehydratase activity. Inactivation of USDA191 iolE led to defective myo-inositol utilization. USDA191 iolE partially complemented a B. subtilis iolE deficient mutant. These results suggest that S. fredii USDA191 utilizes a myo-inositol catabolic pathway, analogous to that of B. subtilis, involving at least idhA and iolE.
Shin Nishiumi, Keizo Hosokawa, Rie Mukai, Itsuko Fukuda, Atsuyuki Hishida, Osamu Iida, Ken-ichi Yoshida and Hitoshi Ashida : Screening of indigenous plants from Japan for modulating effects on transformation of the aryl hydrocarbon receptor., Asian Pacific Journal of Cancer Prevention : APJCP, Vol.7, No.2, 208-220, 2006.
(Summary)
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-p-dioxin (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.
(Keyword)
Animals / Cell-Free System / Cytosol / Enzyme-Linked Immunosorbent Assay / Japan / Liver / Male / Plant Extracts / Rats / Rats, Sprague-Dawley / Receptors, Aryl Hydrocarbon
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Shin Nishiumi, Yoshiyuki Yabushita, Itsuko Fukuda, Rie Mukai, Ken-Ichi Yoshida and Hitoshi Ashida : Molokhia (Corchorus olitorius L.) extract suppresses transformation of the aryl hydrocarbon receptor induced by dioxins., Food and Chemical Toxicology, Vol.44, No.2, 250-260, 2005.
(Summary)
Dioxins enter the body mainly through diet and cause the various toxicological effects by binding to the cytosolic aryl hydrocarbon receptor (AhR) followed by its transformation. In recent reports, it has been shown that certain natural compounds suppress AhR transformation in vitro. In this study, we demonstrated that ethanolic extract from molokhia, known as Egyptian spinach, showed the strongest suppressive effect on AhR transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in cell-free system using rat hepatic cytosol among 41 kinds of extracts from vegetables and fruits. The molokhia extract also suppressed TCDD-induced AhR transformation in mouse hepatoma Hepa-1c1c7 cells and in intestinal permeability system constructed with human colon adenocarcinoma Caco-2 cells and human hepatoma HepG2 cells. Moreover, oral administration of the molokhia extract (100mg/kg body weight) decreased 3-methylcholanthrene-induced AhR transformation to the control level by inhibiting translocation of the AhR from cytosol into the nucleus in the liver of rats. The molokhia extract-administered rat liver showed a tolerance to TCDD-induced AhR transformation by ex vivo experiment. These results indicate that molokhia is an attractive food for isolation and identification of a natural antagonist for the AhR.
Rie Mukai, Itsuko Fukuda, Keizo Hosokawa, Shin Nishiumi, Atsushi Kaneko and Hitoshi Ashida : Anthocyans fail to suppress transformation of aryl hydrocarbon receptor induced by dioxin., Bioscience, Biotechnology, and Biochemistry, Vol.69, No.5, 896-903, 2005.
(Summary)
Dioxins induce adverse effects through transformation of the cytosolic aryl hydrocarbon receptor (AhR). Our previous study found that flavones and flavonols at dietary levels suppress AhR transformation. In the present study, we investigated whether 20 anthocyans dissolved in trifluoroacetic acid (TFA)-MeOH suppressed AhR transformation in a cell-free system and in Hepa-1c1c7 cells. Although four compounds at 50 muM suppressed 0.1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AhR transformation and their effects were dose-dependent in the cell-free system, they were ineffective at 0.5 muM, which is close to physiological concentration. Moreover, no anthocyan at 50 muM tested here suppressed 0.1 nM TCDD-induced AhR transformation in Hepa-1c1c7 cells. We also confirmed that protocatechuic acid and related compounds, which are possible metabolites of anthocyans, did not affect the transformation in the cell-free system. It is concluded that anthocyans are not suitable candidates for protection from dioxin toxicity.
(Keyword)
Animals / Anthocyanins / Cell Line / Cell-Free System / Mice / molecular structure / Receptors, Aryl Hydrocarbon / Tetrachlorodibenzodioxin
Itsuko Fukuda, Shin Nishiumi, Yoshiyuki Yabushita, Rie Mukai, Rie Kodoi, Kaoru Hashizume, Masashi Mizuno, Yutaka Hatanaka and Hitoshi Ashida : A new southwestern chemistry-based ELISA for detection of aryl hydrocarbon receptor transformation: application to the screening of its receptor agonists and antagonists., Journal of Immunological Methods, Vol.287, No.1-2, 187-201, 2004.
(Summary)
Halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produce a wide variety of biological and toxic effects mainly through the aryl hydrocarbon receptor (AhR)-dependent mechanism. After the binding of HAHs, the AhR subsequently transforms its form in order to interact with a specific DNA sequence, the dioxin responsive element (DRE). Thus, detection of the transformed AhR is a target for estimation of the biological and toxic potency of ligands. In this study, we have developed a simple method for quantitative assessment of the transformation state of AhR based on an enzyme-linked immunosorbent assay (ELISA) combined with southwestern chemistry technique (SW-ELISA) that detects the complex of transformed AhR:fluorescein isothiocyanate (FITC)-labeled DRE probe. SW-ELISA has shown the response to HAHs including TCDD and other known agonists in a dose-dependent manner. In the case of TCDD, SW-ELISA has revealed a minimum detection limit (MDL) of 2 pM (0.026 pg/assay), a median effective concentration (EC(50)) value of 0.125 nM (1.6 pg/assay), and a maximum response at 10 nM (129 pg/assay). Furthermore, SW-ELISA provides the confirmation that flavonoids, the potent antagonists for AhR as reported previously, show the inhibitory effects on TCDD-induced AhR transformation. These results indicate that SW-ELISA is a new and straightforward method for the detection of AhR transformation and will be useful in screening of agonists or antagonists for AhR.
Rie Mukai, Itsuko Fukuda, Shin Nishiumi, Keizo Hosokawa, Kazuki Kanazawa and Hitoshi Ashida : Anthocyan does not suppress transformation of aryl hydrocarbon receptor induced by dioxin., BioFactors, Vol.21, No.1-4, 371-373, 2004.
(Summary)
Dioxins cause a variety of toxic effects through transformation of a cytosolic aryl hydrocarbon receptor (AhR). We have previously demonstrated that certain natural flavones and flavonols at the dietary levels suppress AhR transformation. In this study, we investigated whether 5 anthocyanidins, 15 anthocyanins, and protocatechuic acid suppress AhR transformation in mouse hepatoma Hepa-1c1c7 cells. All the compounds tested here at 5 microM unexpectedly failed to suppress the transformation induced by 0.1 nM TCDD, indicating that anthocyan does not have a potential to prevent dioxin toxicity.
A Ishisaka, N Fujiwara, Rie Mukai, M Nishikawa, S Ikushiro and A Murakami : Flavonoids in breast milk and their absorption, metabolism, and bioactivity in infants., Bioscience, Biotechnology, and Biochemistry, Oct. 2024.
2.
Rie Mukai : Prenylation enhances the biological activity of dietary flavonoids by altering their bioavailability., Bioscience, Biotechnology, and Biochemistry, Vol.82, No.2, 207-215, Jan. 2018.
(Summary)
Flavonoids are distributed across the plant kingdom and have attracted substantial attention owing to their potential benefits for human health. Several studies have demonstrated that flavonoids prenylation enhances various biological activities, suggesting an attractive tool for developing functional foods. This review provides an overview of the current knowledge on how prenylation influences the biological activity and bioavailability of flavonoids. The enhancement effect of prenylation on the biological activities of dietary flavonoids in mammals was demonstrated by comparing the effect of 8-prenyl naringenin (8PN) with that of parent naringenin in the prevention of disuse muscle atrophy in mice. This enhancement results from higher muscular accumulation of 8PN than naringenin. As to bioavailability, despite the lower absorption of 8-prenyl quercetin (8PQ) compared with quercetin, higher 8PQ accumulation was found in the liver and kidney. These data imply that prenylation interferes with the elimination of flavonoids from tissues.
Kyuichi Kawabata, Rie Mukai and Akari Ishisaka : Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability., Food & Function, Vol.6, No.5, 1399-1417, May 2015.
(Summary)
The physiological functions and bioavailability of flavonoids have been widely investigated since their bioactivities were identified about 80 years ago. Quercetin is a typical flavonoid ubiquitously contained in vegetables and fruits with several biological effects demonstrated in vitro and in vivo including antioxidative, anti-inflammatory, anticancer, and antidiabetic activities. After the ingestion of vegetables and fruits, quercetin glycosides are metabolized, absorbed, and circulated as types of conjugates in the blood. Thereafter, quercetin-3-O--D-glucuronide (Q3GA), a major metabolite of quercetin, is distributed throughout the body where it may exert beneficial functions in target tissues. Hydrophilic Q3GA has been found to be deconjugated into hydrophobic quercetin aglycone at injured sites which, in turn, may improve the pathological conditions. This review presents updated information on the biological aspects and mechanisms of action of quercetin and its related polyphenols. In particular, new insights into their beneficial health effects on the brain, blood vessels, muscle, and intestine will be discussed.
Junji Terao and Rie Mukai : Prenylation modulates the bioavailability and bioaccumulation of dietary flavonoids., Archives of Biochemistry and Biophysics, Vol.559, 12-16, Apr. 2014.
(Summary)
Prenylflavonoids are distributed widely in the plant kingdom and have attracted appreciable attention because of their potential benefits for human health. Prenylation may be a promising tool for applying the biological functions of flavonoids to clinical uses. The bioavailability and bioaccumulation of prenylflavonoids have not been clarified, but extensive studies have been accomplished on their biological functions. This review provides current knowledge on the bioavailability of prenylflavonoids, including their absorption and metabolism in the intestine, as well as their bioaccumulation in specific tissues. Despite higher uptake into epithelial cells of the digestive tract, the bioavailability of single-dose prenylflavonoids seems to be lower than that of the parent flavonoids. Efflux from epithelial cells to the blood circulation is likely to be restricted by prenyl groups, resulting in insufficient increase in the plasma concentration. Rodent studies have revealed that prenylation enhances accumulation of naringenin in muscle tissue after long-term feeding; and that prenylation accelerates accumulation of quercetin in liver tissue. Efflux from hepatocytes to blood and enterohepatic circulations may be restricted by prenyl groups, thereby promoting slow excretion of prenylflavonoids from the blood circulation and efficient uptake to tissues. The hepatotoxicity and other deleterious effects, taken together with beneficial effects, should be considered because unexpectedly high accumulation may occur in some tissues after long-term supplementation.
Rie Mukai and Junji Terao : Role of dietary flavonoids in oxidative stress and prevention of muscle atrophy, The Journal of Physical Fitness and Sports Medicine, Vol.2, No.4, 385-392, Nov. 2013.
(Summary)
Functional foods for the prevention of disuse muscle atrophy (DMA) are expected to improve the quality of life (QoL) of bedridden people. Ubiquitin ligases targeting muscle protein degradation, atrogin-1 and muscle-specific ring finger protein (MuRF-1), are critical in the degradation of muscle protein, and oxidative stress induced by mitochondrial dysfunction seems to be involved in muscle atrophy. Dietary antioxidants that attenuate the oxidative stress in skeletal muscle are strong candidates as food ingredients for preventing DMA. The antioxidative flavonoid quercetin was found to prevent DMA by attenuating the induction of atrogin-1/MuRF-1 in mice undertaking the tail suspension test. Several studies revealed that dietary quercetin accumulates in skeletal muscle after metabolic conjugation during absorption. There are many arguments that antioxidant activity is essential for dietary flavonoids to exert their preventive effects, but modulation of the IGF-1 signaling pathway is definitively involved in the mechanism of prevention. Nevertheless, dietary flavonoids (including quercetin) may be potential food factors in the prevention of muscle atrophy. Dietary flavonoids are expected to prevent DMA by attenuating oxidative stress derived from mitochondrial dysfunction.
Shin Nishiumi, Shingo Miyamoto, Kyuichi Kawabata, Kohta Ohnishi, Rie Mukai, Akira Murakami, Hitoshi Ashida and Junji Terao : Dietary flavonoids as cancer-preventive and therapeutic biofactors., Frontiers in Bioscience (Scholar edition), Vol.3, 1332-1362, Jun. 2011.
(Summary)
Flavonoids are present in many plants, and hence, in foods and ingredients derived from them. These polyphenolic compounds have attracted renewed attention as potential anticarcinogens, and the molecular mechanisms of their anticarcinogenic effects and their bioavailability have been extensively explored. In this review, we focus on the major dietary flavonoids; flavones, flavonols, and flavan-3-ols (catechins), and evaluate their roles in cancer prevention. After absorption with or without metabolic conjugation, flavonoids are transported to target organs where they exert their anticarcinogenic activity. The molecular mechanisms of the anticarcinogenic effects of flavonoids include their antagonistic effect on the aryl hydrocarbon receptor (AhR), and regulation of phase I and II drug metabolizing enzymes and phase III transporters. Experimental evidence suggests that flavonoids modulate signal transduction pathways at each stage of carcinogenesis. The interactions between flavonoids and biomolecules in vivo must be investigated in detail to identify specific targets. In addition, the potential side effects should be considered when flavonoid supplements are used for cancer prevention. Therefore, the use of flavonoids as chemopreventive agents should be further investigated to establish safe levels of flavonoid intake.
Rie Mukai, Goto-Inoue Naoko, Ukawa Yuichi, Kohara Akiko, Oe Kenichi and Junji Terao : Tissue distribution of 8-prenylnaringnein in mice, Boston, MA, USA, Oct. 2024.
2.
Ishisaka Akari, Fujiwara Nao, Rie Mukai, nishikawa Miyu, Ikushiro Shinichi and Murakami Akira : Effects of quercetin transfer to breast milk on physiological functionality in infant mice., Boston, MA, USA, Oct. 2024.
3.
Koichi Ohashi, Ryutaro Sogawa, Nene Hashimura, Rie Mukai and Retsuo Kawakami : Increased Polyphenol Content of Harvested Onions Irradiated with Low-Temperature Air Plasma Jet at Quasi-Atmospheric Pressure, Proceedings of International Symposium of Dry Process 2023, 171-172, Nagoya, Nov. 2023.
4.
Fujiwara Nao, Rie Mukai, Murakami Akira and Ishisaka Akari : Infants may be exposed to quercetin and its metabolites via breast and formula milk., Intrernational conference on Nutrition, Tokyo, Dec. 2022.
5.
Matsumura Takumi, Sogawa Ryutaro, Hashimura Nene, Ohashi Koichi, Rie Mukai and Retsuo Kawakami : Effects of Quasi-Atmospheric-Pressure Low-Temperature Air Plasma Jet Irradiation on Increasing Minerals in Fresh Food, Proceedings of International Symposium of Dry Process 2022, 123-124, Osaka, Nov. 2022.
6.
Ishisakai Akari, Fujiwara Nao, Rie Mukai and Murakam Akira : Quercetin ingested by maternal mice may be transferred to newborn mice via breast milk, The 10th International Conference on Polyphenols and Health, London, UK, Apr. 2022.
7.
Hitomi Okuyama, Mayumi Ikeda, Yu Ishima, Miyu Nishikawa, Shinichi Ikushiro and Rie Mukai : Binding profile of quercetin and its derivatives to human serum albumin measured by multiplex drug-site mapping, ICoFF2019/ISNFF2019/ICPH2019, Kobe, Nov. 2019.
8.
Manamu Kitami, Rie Mukai, Miyu Nishikawa, Keisuke Fukaya, Daisuke Urabe, Toshiyuki Sakaki and Shinichi Ilushiro : Whole cell-dependent preparation of 8-prenylnaringenin glucuronides using UDP-glucuronosyltransferase expressing yeast., ICoFF2019/ISNFF2019/ICPH2019, Kobe, Nov. 2019.
9.
Takahito Takase, Naoyuki Kobayashi, Takashi Inoue, Yoichi Tsuchiya and Rie Mukai : Preventive effect of dietary lemon peel extract containing eriocitrin on disuse muscle atrophy in denervated mice, ICoFF2019/ISNFF2019/ICPH2019, Kobe, Nov. 2019.
10.
Rie Mukai, Hisao Nemoto and Junji Terao : Estrogenic activity of 8-renylnaringenin improve skeletal muscle regeneration from disuse muscle atrophy by activating IGF-I/PI3K/Akt pathway, ICoFF2019/ISNFF2019/ICPH2019, Kobe, Nov. 2019.
11.
Hiroaki Kanouchi, Rie Mukai and De-Xing Hou : Comparison of dietary meat types on muscle atrophy and recovery caused by immobilization-induced disuse muscle atrophy., Vancouver, Jul. 2018.
12.
Akari Kondo, Chiemi Kamada, Rie Mukai and Junji Terao : Effect of Quercetin and Its Metabolite on Hydrogen Peroxide-Induced Phosphorylation of Caveolin-1 in Endothelial Cells, The 6th International Conference on Food Factors: Bioconvergence for Food Function, Soul, Republic of Korea, Nov. 2015.
13.
Asami Iwanaka, Mamiko Soga, Eiichi Kotake-Nara, Akihito Nagao, Rie Mukai, Akira Takahashi and Junji Terao : Effect of Fucoxanthin and Neoxanthin on Blue Light-Emitting Diode-Irradiated Photosensitized Oxidation in Liposomal Membranes andMouse Fibroblast Cells, The 6th International Conference on Food Factors: Bioconvergence for Food Function, Soul, Republic of Korea, Nov. 2015.
14.
Hiromi Shono, Hideyuki Saito, Shinya Sato, Tomoyuki Kawamura, Hisao Nemoto, Junji Terao and Rie Mukai : A signal transduction pathway in prenylquercetin-induced heme oxygenase-1 expression in vascular endothelium cells, The 6th International Conference on Food Factors: Bioconvergence for Food Function, Soul, Republic of Korea, Nov. 2015.
15.
Rie Mukai, Onishi Asami, Fukuda Takashi, Furusawa Mutsuki, Ashitani Hiroaki, Koyama Toshiyuki, Usami-Krank Yoko and Junji Terao : Epi-catechin Gallate Selectively Accumulates in Blood Plasma after Continuous Intake of Tea Catechins in Rats and Humans, The 6th International Conference on Food Factors: Bioconvergence for Food Function, Soul, Republic of Korea, Nov. 2015.
16.
Rie Mukai, Hiromi Shono, Shinya Sato, Jeremy Spencer, Tomoyuki Kawamura, Hisao Nemoto and Junji Terao : Positional isomers of prenylquercetin differently induce hemeoxygenase-1 expression in vascular endothelial cells, 7th International Conference on Polyphenols and Health, Tours, France, Oct. 2015.
17.
Lin Yi Pei, Rie Mukai, Horikawa Hitomi and Junji Terao : 8-Prenylnaringenin enhances the recovery from disuse muscle atrophy of mice with cast immobilization, 12th Asian congress of Nutrition, Yokohama, May 2015.
18.
Rie Mukai, Naoko Matsui, Takeshi Nikawa and Junji Terao : Dietary quercetin prevents disuse muscle atrophy of denervated mice through regulation of mitochondrial biogenesis, 12th Asian congress of Nutrition, Yokohama, May 2015.
19.
Yauhen Bandaruk, Rie Mukai and Junji Terao : Role of flavonoids as possible monoamine oxidase-A regulators in the model of serotoninergic neuroblastoma SH-SY5Y cell, XXVIIth International Conference on Polyphenols &8th Tannin Conference, Nagoya, Sep. 2014.
20.
Rie Mukai, Naoko Matsui, Takeshi Nikawa and Junji Terao : Pre-intake of quercetin slow the progression of disuse muscle atrophy by mitochondrial dysfunction., XXVIIth International Conference on Polyphenols &8th Tannin Conference, Nagoya, Sep. 2014.
21.
Rie Mukai, Naoko Matsui, N Matsumoto, N.T. Dang, Takeshi Nikawa, Hisao Nemoto and Junji Terao : Anti-Oxidative Flavonoid suppresses disuse muscle atrophy in denervation mice., XXVIIth International Conference on Polyphenols &8th Tannin Conference., 2014.
22.
Arisa Ochi, Katsuya Hirasaka, Ayako Maita, Shigetada Kondo, Tomoyuki Kawamura, Hisao Nemoto, Rie Mukai, Junji Terao, Taesik Gwang, Inho Choi and Takeshi Nikawa : Development of anti-ubiquitination oligopeptide, Cblin:Cbl-b inhibitor that prevents unloading-induced muscle atorophy., The 29th International Symposium on Space Technology and Science, Nagoya, Jun. 2013.
23.
Yauhen Bandaruk, Rie Mukai and Junji Terao : Attenuation of monoamine oxidase-A activity and its expression level in the brain as possible mechanism of antidepressant-line action of flavonoids., The 17th Biennial Meeting of Society for free radical international, Mar. 2013.
24.
Rie Mukai, Horikawa Hitomi, Fujikura Yutaka, Kaeko Murota, Kawamura Tomoyuki, Hisao Nemoto and Junji Terao : Effect of prenylation on the bioavailability of dietary flavonoids, The International Society for Nutraceuticals and Functional Foods, Dec. 2012.
Kohno Shohei, Shigetada Kondo, Katsuya Hirasaka, Ayako Maita, Yuushi Okumura, Rie Mukai, Junji Terao, Akira Higashibata and Takeshi Nikawa : Regulation of the Gene Expression of Cbl-b Ubiquitin Ligase in Skeletal Muscle During Unloading Conditions., 7th General Meeting of the International Proteolisis Society, 米国, Oct. 2011.
30.
Hironori Yamamoto, Tsuji Mitsuyoshi, Rie Mukai, T Inakuma, Junji Terao and Eiji Takeda : Dietary quercetin and onion powder could prevent immobilization induced bone loss in rats, 5th International Conference on Polyphenols and Health (ICPH), Barcelona, Oct. 2011.
31.
Rie Mukai, Tomoyuki Kawamura, Yutaka Fujikura, Hitomi Horikawa, Hisao Nemoto and Junji Terao : Bioavailability and muscle atrophy-preventive effect of prenylated flavonoids, International Conference on Polyphenols and Health, Sitges, Barcelona, Spain, Oct. 2011.
32.
Rie Mukai, Takeshi Nikawa, Hisao Nemoto, Hironori Yamamoto, Eiji Takeda, Yoshichika Kawai and Junji Terao : Disuse muscle atrophy is suppressed by antioxidative flavonoid quercetin, International Symposium on Free Radical Research: Contribution to Medicine, Kyoto, Jan. 2011.
33.
Ashida. Hitoshi, Rie Mukai, Satsu Hideo and Shimizu Makoto : Suppression of the aryl hydrocarbon receptor-mediated signaling, International Chemical Congress of Pacific Basin Societies., Honolulu, Hawaii, Dec. 2010.
34.
Rie Mukai, Tomoyuki Kawamura, Yutaka Fujikura, Moemi Hayashi, Hisao Nemoto, Takeshi Nikawa, Hironori Yamamoto, Eiji Takeda and Junji Terao : Disuse muscle atrophy is prevented by flavonoids, 2010 International Chemical Congress of Pacific Basin Societies, Honolulu, Dec. 2010.
35.
Tomoyuki Kawamura, Moemi Hayashi, Rie Mukai, Junji Terao and Hisao Nemoto : Chemical Synthesis of O-Methylated and/or C-Prenylated Flabonoid Analogues, Pachifichem 2010, Honolulu, Dec. 2010.
36.
Rie Mukai, Hitoshi Ashida, Takeshi Nikawa and Junji Terao : Nuclear accumulation of flavonol aglycone in cultured cells detected with a fluorescence microscope, 4th International Conference on Polyphenol and Health, Harrogate, United Kingdom, Dec. 2009.
37.
I Fukuda, Rie Mukai, m Kawase, K Yoshida and H Ashida : (-)-Epigallocatechin gallate interacts with an aryl hydrocarbon receptor complex., Proceedings of The 3rd International Conference on O-CHA (Tea) culture and Science (2007)., 2007.
Yauhen Bandaruk, Rie Mukai and Junji Terao : Accumulation of flavonoids quercetin and luteolin in SH-SY5Y cells and their effects on Monoamine oxidase-A, 日本農芸化学会2014年度大会, Mar. 2013.
61.
Rie Mukai : プレニルフラボノイドによる廃用性筋萎縮予防の可能性, 第5回レドックス・ライフイノベーションシンポジウム, Mar. 2013.
Rie Mukai, 堀川 瞳, 河村 知志, Hisao Nemoto, Takeshi Nikawa and Junji Terao : プレニル化フラボノイドによる廃用性筋萎縮の予防, 第66回 日本栄養・食糧学会大会, May 2012.
68.
河村 知志, Rie Mukai, 林 萠未, Junji Terao and Hisao Nemoto : 廃用性筋萎縮抑制作用を有するフラボノイドのC-プレニル化と活性評価, 第132回日本薬学会, Mar. 2012.
69.
Bandaruk Yauhen, Nakamura Toshiyuki, Rie Mukai and Terao Junji : Evaluation of the inhibitory effect of flavonols and catechins on monoamine, 日本農芸化学会2012年度大会, Mar. 2012.
河村 知志, 林 萠未, Rie Mukai, Junji Terao and Hisao Nemoto : An efficient method for C-prenylation of flavonoid and its application to the synthesis of related compounds, 第37回反応と合成の進歩シンポジウム, Nov. 2011.
72.
Rie Mukai and Junji Terao : 抗酸化フラボノイドの廃用性筋萎縮予防効果―モデル動物による評価―, 第11回AOB研究会, Jul. 2011.
73.
Rie Mukai, 水口 八重子, 藤倉 温, 河野 尚平, Takeshi Nikawa, Yoshichika Kawai and Junji Terao : ケルセチンの経口摂取による廃用性筋萎縮予防の可能性, 第65回日本栄養・食糧学会大会, May 2011.
74.
河村 知志, 林 萠未, Rie Mukai, Junji Terao and Hisao Nemoto : A highly efficient prenylation at C-8 position of flavanone analogues, 日本薬学会年会, Mar. 2011.
75.
林 萠未, 河村 知志, Rie Mukai, Junji Terao and Hisao Nemoto : Development of a method for C-prenylation of flavonoids and its application to the synthesis of related compounds, 日本薬学会第131年会, Mar. 2011.
76.
河村 知志, Rie Mukai, 林 萠未, Junji Terao and Hisao Nemoto : 廃用性筋萎縮抑制作用を有するフラボノイドのC-プレニル化と活性評価, 日本薬学会年会, Mar. 2011.