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Ono E.,Suntory Holdings Ltd. | Homma Y.,Tohoku University | Horikawa M.,Suntory Institute for Bioorganic Research | Kunikane-Doi S.,Tohoku University | And 6 more authors.
Plant Cell | Year: 2010

We identified two glycosyltransferases that contribute to the structural diversification of flavonol glycosides in grapevine (Vitis vinifera): glycosyltransferase 5 (Vv GT5) and Vv GT6. Biochemical analyses showed that Vv GT5 is a UDP-glucuronic acid:flavonol-3-O-glucuronosyltransferase (GAT), and Vv GT6 is a bifunctional UDP-glucose/UDP-galactose:flavonol-3-Oglucosyltransferase/galactosyltransferase. The Vv GT5 and Vv GT6 genes have very high sequence similarity (91%) and are located in tandem on chromosome 11, suggesting that one of these genes arose from the other by gene duplication. Both of these enzymes were expressed in accordance with flavonol synthase gene expression and flavonoid distribution patterns in this plant, corroborating their significance in flavonol glycoside biosynthesis. The determinant of the specificity of Vv GT5 for UDP-glucuronic acid was found to be Arg-140, which corresponded to none of the determinants previously identified for other plant GATs in primary structures, providing another example of convergent evolution of plant GAT. We also analyzed the determinants of the sugar donor specificity of Vv GT6. Gln-373 and Pro-19 were found to play important roles in the bifunctional specificity of the enzyme. The results presented here suggest that the sugar donor specificities of these Vv GTs could be determined by a limited number of amino acid substitutions in the primary structures of protein duplicates, illustrating the plasticity of plant glycosyltransferases in acquiring new sugar donor specificities. © 2010 American Society of Plant Biologists.

Tsuruoka N.,Cerebos Pacific Ltd | Beppu Y.,Suntory Business Expert Ltd | Koda H.,Suntory Business Expert Ltd | Doe N.,Kouiken Co. | And 3 more authors.
PLoS ONE | Year: 2012

Diketopiperazines (DKPs) are naturally-occurring cyclic dipeptides with a small structure and are found in many organisms and in large amounts in some foods and beverages. We found that a chicken essence beverage, which is popular among Southeast Asians as a traditional remedy and a rich source of DKPs, inhibited the serotonin transporter (SERT) and suppressed serotonin uptake from rat brain synaptosomes, which prompted us to isolate and identify the active substance(s). We purified a SERT inhibitor from the chicken essence beverage and identified it as the DKP cyclo(L-Phe-L-Phe). Interestingly, it was a naturally occurring dual inhibitor that inhibited both SERT and acetylcholinesterase (AChE) in vitro. The DKP increased extracellular levels of the cerebral monoamines serotonin, norepinephrine, and dopamine in the medial prefrontal cortex and acetylcholine in the ventral hippocampus of freely moving rats when administered orally. Moreover, cyclo(L-Phe-L-Phe) significantly shortened escape latency in the water maze test in depressed mice previously subjected to a repeated open-space swimming task, which induces a depression-like state. Cyclo(L-Phe-L-Phe) also significantly improved accuracy rates in a radial maze test in rats and increased step-through latencies in a passive avoidance test in mice with scopolamine-induced amnesia. These animal test results suggest that cyclo(L-Phe-L-Phe), which is present abundantly in some foods such as chicken essence, may abrogate the onset of depression and, thus, contribute to preventing the development of Alzheimer's disease and other dementia, because senile depression is a risk factor for dementia. © 2012 Tsuruoka et al.

Tomimori N.,Suntory Wellness Ltd. | Nakai M.,Suntory Wellness Ltd. | Ono Y.,Suntory Wellness Ltd. | Kitagawa Y.,Suntory Wellness Ltd. | And 2 more authors.
Biological and Pharmaceutical Bulletin | Year: 2012

Episesamin is an isomer of sesamin, resulting from the refining process of non-roasted sesame seed oil. Episesamin has two methylendioxyphenyl groups on exo and endo faces of the bicyclic skeleton. The side methylendioxyphenyl group was metabolized by cytochrome-P450. Seven metabolites of episesamin were found in rat bile after treatment with glucuronidase/arylsulfatase and were identified using NMR and MS. The seven metabolites were (7α,7′β,8α, 8′α)-3,4-dihydroxy-3′,4′-methylenedioxy-7,9′: 7′,9-diepoxylignane (EC-1-1), (7α,7′β,8α, 8′α)-3,4-methylenedioxy-3′,4′-dihydroxy-7,9′: 7′,9-diepoxylignane (EC-1-2) and (7α,7′β,8α, 8′α)-3,4:3′,4′-bis(dihydroxy)-7,9′:7′, 9-diepoxylignane (EC-2), (7α,7′β,8α,8′α)-3- methoxy-4-hydroxy-3′,4′-methylenedioxy-7,9′:7′, 9-diepoxylignane (EC-1m-1), (7α,7′β,8α,8′α)- 3,4-methylenedioxy-3′-methoxy-4′-hydroxy-7,9′:7′, 9-diepoxylignane (EC-1m-2), (7α,7′β,8α,8′α)- 3-methoxy-4-hydroxy-3′,4′-dihydroxy-7,9′:7′, 9-diepoxylignane (EC-2m-1) and (7α,7′β,8α, 8′α)-3,4-dihydroxy-3′-methoxy-4′-hydroxy-7,9′: 7′,9-diepoxylignane (EC-2m-2). EC-1-1, EC-1-2 and EC-2 were also identified as metabolites of episesamin in human liver microsomes. These results suggested that similar metabolic pathways of episesamin could be proposed in rats and humans. © 2012 The Pharmaceutical Society of Japan.

Kanzaki N.,Suntory Wellness Ltd | Ono Y.,Suntory Wellness Ltd | Shibata H.,Suntory Wellness Ltd | Moritani T.,Kyoto University
Clinical Interventions in Aging | Year: 2015

Background: The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain. Methods: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. Results: In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren–Lawrence (K–L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P,0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K–L grade I. No adverse effect of treatment was identified in the safety assessment. Conclusion: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions. © 2015 Kanzaki et al.

Tateishi N.,Suntory Wellness Ltd | Kakutani S.,Suntory Wellness Ltd | Kawashima H.,Suntory Wellness Ltd | Shibata H.,Suntory Wellness Ltd | Morita I.,Tokyo Medical and Dental University
Lipids in Health and Disease | Year: 2014

Background: Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4). The effects of dietary ARA on colon maintenance are unclear because PGE2 has both mucosal protective and proinflammatory effects, and LXA4 has an anti-inflammatory role. Our objective is to clarify the effects of dietary ARA on an experimental murine colitis model. Methods. C57BL/6 mice were fed three types of ARA diet (0.075%, 0.15% or 0.305% ARA in diet), DHA diet (0.315% DHA) or control diet for 6 weeks, and were then administered dextran sodium sulphate (DSS) for 7 days to induce colitis. We evaluated colitis severity, fatty acid and lipid mediator contents in colonic tissue, and the expression of genes related to lipid mediator formation. Results: ARA composition of colon phospholipids was significantly elevated in an ARA dose-dependent manner. ARA, as well as DHA, did not affect colitis severity (body weight loss, colon shortening, diarrhea and hemoccult phenomena) and histological features. PGE2 contents in the colon were unchanged by dietary ARA, while LXA4 contents increased in an ARA dose-dependent manner. Gene expression of cyclooxygenase (COX)-1 and COX-2 was unchanged, while that of 12/15-lipoxgenase (LOX) was significantly increased by dietary ARA. ARA composition did not correlate with neither colon length nor PGE2 contents, but significantly correlated with LXA4 content. Conclusion: These results suggest that dietary ARA increases ARA and LXA4 contents in colon, but that it has no effect on severity and PGE2 content in a DSS-induced murine colitis model. © 2014 Tateishi et al.; licensee BioMed Central Ltd.

Hirota S.,Kagawa Nutrition University | Adachi N.,Kagawa Nutrition University | Gomyo T.,Kagawa Nutrition University | Kawashima H.,Suntory Wellness Ltd. | And 2 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2010

Arachidonic acid (ARA) is considered to be a minor contributor to the diet. Previous reports regarding the effect of ARA supplementation on the composition of long-chain polyunsaturated fatty acids (LCPUFA) in the blood of humans are extremely limited. In the present study, we conducted a crossover double-blind, placebo-control study. Twenty-three young Japanese women consumed one capsule containing triacylglycerol enriched with 80. mg ARA, equivalent to the amount in one egg, daily for 3 weeks. Blood samples were drawn before and after treatment periods, and the compositions of the LCPUFA in blood lipid fractions were measured. The supplementation of ARA increased the composition of ARA, but did not decrease the composition of n-3LCPUFA in erythrocyte phospholipids and plasma phospholipids, esterified cholesterol, and triacylglycerol. We found that dietary ARA increased the ARA level in all lipid fractions of the blood, even at a very low dose. © 2010 Elsevier Ltd.

Tomimori N.,Suntory Wellness Ltd. | Tanaka Y.,Suntory Business Expert Ltd. | Kitagawa Y.,Suntory Business Expert Ltd. | Fujii W.,Suntory Business Expert Ltd. | And 2 more authors.
Biopharmaceutics and Drug Disposition | Year: 2013

A single-blind, placebo-controlled, parallel-group and multiple oral dose study was conducted in 48 healthy subjects to investigate the pharmacokinetics and safety of multiple oral doses of sesame lignans (sesamin and episesamin). Subjects were randomly divided into two groups. Each subject was administered 50 mg of sesame lignans (sesamin/episesamin = 1/1) or placebo once daily for 28 days. The pharmacokinetics of the sesame lignans were investigated using 10 of the 24 subjects in the sesame lignans group. No serious adverse events were observed in this study. Sesamin was absorbed with a peak plasma concentration at 5.0 h. The plasma concentration of the main metabolite, SC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 2.4 h. Episesamin was also absorbed with a peak plasma concentration at 5.0 h and decreased with a terminal half-life of 7.1 h. The plasma concentration of the main metabolite, EC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 3.4 h. The plasma concentrations of sesamin and episesamin reached a steady state by day 7. Sesame lignans were confirmed to be safe and tolerable in healthy subjects. The results of the pharmacokinetic study demonstrate that no accumulation was observed following multiple 50 mg doses of sesame lignans. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.

Tokuda H.,Suntory Wellness Ltd. | Kontani M.,Suntory Wellness Ltd. | Kawashima H.,Suntory Wellness Ltd. | Kiso Y.,Suntory Wellness Ltd. | And 2 more authors.
Neuroscience Research | Year: 2014

Hippocampal neurogenesis affects learning and memory. We evaluated in rats effects of ingestion of arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) on age-related decreases in proliferating neural stem/progenitor cells (NSPCs) or newborn neurons (NNs). Rats were fed with ARA- and/or DHA-containing diet from 2 to 18 months old and then sacrificed 1 day or 4 weeks after 5-bromo-2-deoxyuridine (BrdU) injections at 2, 6 and 18 months. The numbers of NSPCs (SOX2+/BrdU+) and NNs (NeuN+/BrdU+) were determined immunohistochemically. The number of BrdU+ cells 1 day after BrdU injections decreased with age, but increased 65% after ARA ingestion compared to the control at 18 months. The SOX2+/BrdU+ cell ratio was unchanged by aging or ingestion of ARA or DHA. The number of NeuN+/BrdU+ cells 4 weeks after BrdU injections decreased with age, but increased 34% (yet not statistically significant) after DHA ingestion compared to the control at 18 months. These results indicate that ARA ingestion can ameliorate the age-related decrease in the number of NSPCs in rats. The functions of ARA and DHA in hippocampal neurogenesis appear to be different in aged rats; ARA may maintain an NSPC pool, whereas DHA may support NN production and/or survival. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society.

Kakutani S.,Suntory Wellness Ltd. | Kawashima H.,Suntory Wellness Ltd. | Tanaka T.,Suntory Wellness Ltd. | Shiraishi-Tateishi A.,Suntory Wellness Ltd. | Kiso Y.,Suntory Wellness Ltd.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2010

Administration of dihomo-γ-linolenic acid is useful for atopic dermatitis and atherosclerosis in mice; however, the metabolites of dihomo-γ-linolenic acid have been little studied. We employed a method which enabled simultaneous analysis of nine prostaglandins using liquid chromatography-tandem mass spectrometry, and determined the concentrations of prostaglandins in the supernatants of cultures of mouse peritoneal macrophages stimulated with lipopolysaccharide after pre-incubation with dihomo-γ-linolenic acid, arachidonic acid, or eicosapentaenoic acid. Accumulated prostaglandin concentrations from mouse macrophages with dihomo-γ-linolenic acid uptake increased in a dihomo-γ-linolenic acid concentration-dependent fashion. These increases were mainly due to prostaglandin D1 and prostaglandin E1. The order of accumulated prostaglandin concentrations was dihomo-γ-linolenic acid>arachidonic acid>eicosapentaenoic acid in supernatants with the same concentration of polyunsaturated fatty acid. Since mouse macrophages can clearly produce series-1 prostaglandins, they must be formed in vivo. These findings suggest that the effects of dihomo-γ-linolenic acid on diseases may be due to series-1 prostaglandins. © 2010 Elsevier Ltd.

Rogi T.,Suntory Wellness Ltd | Tomimori N.,Suntory Wellness Ltd | Ono Y.,Suntory Wellness Ltd | Kiso Y.,Suntory Wellness Ltd
Journal of Pharmacological Sciences | Year: 2011

Sesamin is a major lignan in sesame seed. We confirmed that ingestion of sesamin and α-tocopherol synergistically reduced the concentration of blood cholesterol in rats given a high-cholesterol diet. To elucidate the molecular mechanism behind this effect, we analyzed the gene-expression profiles in rat liver after co-ingestion of sesamin and α-tocopherol. Six-week-old male Sprague-Dawley rats were fed a 1% cholesterol diet (HC) or HC containing 0.2% sesamin, 1% α-tocopherol or sesamin + α-tocopherol for 10 days. Blood samples were collected on days 1, 3, 7, and 10 and livers were excised on day 10. The gene expressions of ATP-binding cassette, sub-family G (WHITE), members 5 (ABCG5) and 8 (ABCG8) were significantly increased, while the gene expression of apolipoprotein (Apo) A4 was significantly decreased. ABCG5 and ABCG8 form a functional heterodimer that acts as a cholesterol efflux transporter, which contributes to the excretion of cholesterol from the liver. ApoA4 controls the secretion of ApoB, which is a component of low-density-lipoprotein cholesterol. These studies indicate that the cholesterol-lowering mechanism underlying the effects of co-ingestion of sesamin and α-tocopherol might be attributable to increased biliary excretion of cholesterol and reduced ApoB secretion into the bloodstream. © The Japanese Pharmacological Society.

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