担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Food factors, such as amino acids, vitamins, and polyphenols, have been reported to exert biological effects through a system that senses food factors. However, how food and its components affect food factor sensing (FFS) systems remains largely unknown. Japanese are known for their longevity, to which the unique Japanese food is believed to contribute their health. We hypothesized that the promotion of health by Japanese food was due to the enhancement of food functionality by improving FFS systems. To examine the effect of Japanese soup stocks (katsuo-dashi and kombu-dashi) on FFS-related gene expression in mice, we performed DNA microarray analysis. Katsuo-dashi upregulated the expression of 10 FFS-related genes in the quadriceps, induced and suppressed that of nine and two FFS-related genes in the small intestine, and increased two FFS-related genes in the perirenal fat, respectively. Kombu-dashi upregulated and downregulated the expression of 30 and one FFS-related genes in the quadriceps, induced and suppressed that of one and one FFS-related genes in the small intestine, and increased and reduced that of two and one FFS-related genes in the perirenal fat, respectively. These data suggest that Japanese soup stocks mediate FFS-related gene expressions and might regulate their sensitivity to food factors.

DOI： 10.1016/j.ijgfs.2022.100573

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Isoflavone is a species of polyphenol found mainly in soy and soy products. Many studies have demonstrated its estrogen receptor (ER)-dependent action. Equol is an intestinal metabolite of a major soy isoflavone daidzein. We aimed to elucidate the mechanism for ER-independent actions of equol. Equol has been shown to inhibit proliferation of HeLa human cervical cancer cells and mouse melanoma B16 cells in an ER-independent manner. Using functional genetic screening, PAP associated domain containing 5 (PAPD5), which is a non-canonical poly(A) polymerase, was identified as an essential molecule in the ER-independent action. While peroral administration of equol inhibited tumor growth of control B16 cells subcutaneously inoculated in mice, it had little effect on the growth of PAPD5-ablated B16 cells. Intriguingly, equol progressed tumor growth of the PAPD5-ablated human breast cancer MCF-7 cells, which have high ERα expression. Equol has been found to induce polyadenylation of snoRNAs in a PAPD5-depdendent manner. Furthermore, peroral equol administration increased microRNA miR-320a expression in tumors. Together, these results suggest that equol may have a dual effect on ER-positive cancer cells, acting with, antiproliferative activity through PAPD5 and exhibiting proliferative activity via ERα and the former could be associated with miR-320a.

DOI： 10.1016/j.jnutbio.2021.108910

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

(-)-epigallocatechin-3-O-gallate (EGCG) is a bioactive polyphenol in green tea. Previous studies have demonstrated the beneficial effects of EGCG on muscle mass and muscle atrophy. In the current study, we investigated the mechanisms underlying effect of EGCG on muscle atrophy. It was demonstrated that EGCG suppressed muscle-specific ubiquitin ligase, muscle RING Finger 1 (MuRF1) expression through 67-kDa laminin receptor (67LR). Previous studies have shown that eriodictyol potentiates the anti-tumor activities of EGCG by amplifying 67LR signaling. Therefore, we investigated the effects of EGCG and eriodictyol on the MuRF1 expression in C2C12 myotubes. The combined treatment of EGCG and eriodictyol significantly suppressed MuRF1 expression in dexamethasone-treated C2C12 myotubes. Tail suspension was maintained for 10 consecutive days using C57BL6/J mice, and during this time EGCG and eriodictyol were orally administered. In the gastrocnemius muscle, the muscle mass loss was inhibited by the combination of EGCG and eriodictyol. Therefore, EGCG may prevent muscle atrophy by inducing 67LR signaling and eriodictyol amplifies this pathway.

DOI： 10.1007/s11418-020-01417-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Targeting proteins that are overexpressed in cancer cells is the major strategy of molecular imaging and drug delivery systems. The 67-kDa laminin receptor (67LR), also known as oncofetal antigen, is overexpressed in several types of cancer, including melanoma, multiple myeloma, cervical cancer and bile duct carcinoma. 67LR is involved in tumour growth, tumour metastasis and drug resistance. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) directly binds to cell-surface 67LR and induces apoptosis through the protein kinase B (Akt)/endothelial nitric oxide synthase/nitric oxide/cyclic GMP (cGMP) axis. Here we report the optimum hydroxyl group for the utilization of EGCG as a novel fluorescent EGCG-mimic imaging probe based on 67LR agonist characters, including Akt activation and inhibitory effect on viable cell number in cancer cells. 67LR specific targeting is unambiguously confirmed with the use of a non-labelled EGCG competitive assay and 67LR knockdown. Importantly, this probe strongly binds to multiple myeloma cells compared with its binding to normal cells.

DOI： 10.1016/j.bbrc.2020.03.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A majority of the potential health benefits of green tea, including the potential to prevent cognitive decline, have been attributed to epigallocatechin gallate (EGCG). Sunrouge is a green tea cultivar that contains EGCG and several other bioactive components such as quercetin, myricetin, cyanidin and delphinidin. We compared the effects of Sunrouge and Yabukita, the most popular Japanese green tea cultivar, on cognitive function in the senescence-accelerated mouse Prone8. These mice were fed an experimental diet containing Sunrouge extract (SRE) or Yabukita extract (YBE). SRE feeding significantly prevented cognitive decline, whereas YBE feeding had little effect. Moreover, SRE feeding prevented elevation of the amyloid-β42 level while improving the gene expression of neprilysin and decreasing beta-site APP-cleaving enzyme 1 in the brain. These preventive effects of SRE against cognitive decline were attributed to the characteristic composition of Sunrouge and strongly suggest that consumption of this cultivar could protect against age-related cognitive decline.

DOI： 10.1080/09168451.2018.1530093

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the major green tea catechins can inhibit the activity of carbohydrate-hydrolyzing enzymes, there is a paucity of information describing the potential of other green tea ingredients and numerous green tea cultivars. Herein, we reveled that a green tea cultivar Sunrouge significantly suppressed the postprandial blood glucose level in mice. Unlike the most representative Japanese green tea cultivar, Yabukita, the suppression by Sunrouge was observed clearly during the initial period after oral dosing of starch. Sunrouge also strongly inhibited the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase when compared with that of Yabukita and many other cultivars. Liquid chromatography-mass spectrometry (LC-MS)-based metabolic profiling (MP) of 42 Japanese green tea cultivars was performed. Multivariate statistical analysis enabled visualization of the differences among cultivars with respect to their ability to inhibit carbohydrate-hydrolyzing activities. Analysis of metabolites, contributing to the discrimination and prediction of the bioactivity of cultivars, showed that O-methylated catechins, epicatechin-3-O-(3-O-methyl) gallate (ECG3"Me) and epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me), were newly identified α-glucosidase inhibitors. Such ability was also observed in epigallocatechin-3-O-gallate (EGCG), epicatechin-3-O-gallate (ECG), delphinidin-3-O-glucoside and myricetin-3-O-glucoside. The amounts of these compounds in Sunrouge were higher than that in many other cultivars. These results suggest that Sunrouge has high potential for suppressing the elevation of the postprandial blood glucose level, and an MP approach may become a valuable strategy for evaluating the anti-hyperglycemic activity of green tea and for screening its active ingredients.

DOI： 10.1038/s41598-018-34316-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-28338-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer and the 5-year survival rate is only 5%. Several studies have suggested that cancer stem cells (CSCs) are thought to be involved in recurrence and metastasis and so it is essential to establish an approach targeting CSCs. Here we have demonstrated that cyclic guanosine monophosphate (cGMP) suppressed CD44 expression and the properties of CSCs in PDAC. Microarray analysis suggested that cGMP inhibited Forkhead box O3 (FOXO3), which is known as a tumor suppressor. Surprisingly, our data demonstrated that FOXO3 is essential for CD44 expression and the properties of CSCs. Our data also indicated that patients with high FOXO3 activation signatures had poor prognoses. This evidence suggested that cGMP induction and FOXO3 inhibition could be ideal candidates for pancreatic CSC.

DOI： 10.1038/onc.2016.426

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin- 3-O-(3-O-methyl)-gallate (EGCG3"Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3"Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor alpha in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.

DOI： 10.1074/jbc.M116.755959

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER CHEMICAL SOC  

Delphinidin, one of the major anthocyanidins, shows protective effects against a variety of pathologies, including cancer, inflammation, and muscle atrophy. The purpose of this study was to determine the preventive mechanism of delphinidin on disuse muscle atrophy. In vitro and in vivo models were used to validate the effects of delphinidin on the expression of MuRF1, miR-23a, and NFATc3. Delphinidin suppressed the upregulation of MuRF1 (1.77 +/- 0.05 vs 1.03 +/- 0.17, P < 0.05) expression and inhibited the downregulation of miR-23a (0.56 +/- 0.05 vs 0.94 +/- 0.06, P < 0.05) and NFATc3 (0.61 +/- 0.02 vs 1.02 +/- 0.08, P < 0.01) expression in dexamethasone-treated C2C12 cells. In gastrocnemius, muscle weight loss was prevented by oral administration of delphinidin. Moreover, delphinidin suppressed MuRF1 (3.35 +/- 0.13 vs 2.26 +/- 0.3, P < 0.01) expression and promoted miR-23a (0.58 +/- 0.15 vs 2.25 +/- 0.29, P < 0.001) and NFATc3 (0.85 +/- 0.17 vs 1.54 +/- 0.13, P < 0.001) expressions. Delphinidin intake may prevent disuse muscle atrophy by inducing miR-23a expression and suppressing MuRF1 expression.

DOI： 10.1021/acs.jafc.6b03661

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Delphinidin is a member of the anthocyanidin class of plant pigments. We examined the effects of delphinidin on muscle atrophy. Oral administration of delphinidin suppressed the muscle weight loss induced by mechanical unloading. Microarray analysis showed that delphinidin suppresses the upregulation of oxidative stress-related gene expression, including the expression of Cbl-b. Thus, delphinidin may prevent unloading-mediated muscle atrophy.

DOI： 10.1080/09168451.2016.1184560

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune inflammatory disease. Typical pathological findings of RA include persistent synovitis and bone degradation in the peripheral joints. Equol, a metabolite of the major soybean isoflavone daidzein, shows superior bioactivity than other isoflavones. We investigated the effects of equol administration on inflammatory response and bone erosion in mice with collagen-induced arthritis (CIA). The severity of arthritis symptoms was significantly low in the equol-administered CIA mice. In addition, equol administration improved the CIA-induced bone mineral density decline. In the inflamed area of CIA mice, equol administration suppressed the expression of interleukin-6 and its receptor. Furthermore, equol reduced the expression of genes associated with bone formation inhibition, osteoclast and immature osteoblast specificity and cartilage destruction. These results suggest that equol suppresses RA development and RA-induced bone erosion by regulating inflammation and bone metabolism. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jnutbio.2016.02.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2016.03.111

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

An epidemiological study showed that green tea consumption is associated with a reduced risk of hematopoietic malignancy. The major green tea polyphenol epigallocatechin-3-O-gallate (EGCG) is reported to have anticancer effects. Chronic myeloid leukemia (CML) is a major hematopoietic malignancy characterized by expansion of myeloid cells. In the present study, we showed EGCG-induced acid sphingomyelinase (ASM) activation and lipid raft clustering in CML cells. The ASM inhibitor desipramine significantly reduced EGCG-induced cell death. Protein kinase C delta is a well-known kinase that plays an important role in ASM activation. We observed EGCG-induced phosphorylation of protein kinase C delta at Ser664. Importantly, EGCG-induced ASM activation was significantly reduced by pretreatment of CML cells with the soluble guanylate cyclase inhibitor NS2028, suggesting that EGCG induced ASM activation through the cyclic guanosine monophosphate (cGMP)-dependent pathway. Indeed, pharmacological inhibition of a cGMP-negative regulator enhanced the anti- CML effect of EGCG. These results indicate that EGCG-induced cell death via the cGMP/ASM pathway in CML cells.

DOI： 10.3892/or.2015.4086

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (PGG) is a gallotannin isolated from various plants. In a previous study, it was reported that PGG suppressed interleukin (IL)-4 induced signal pathway in B cell which is indispensable for immunoglobulin E (IgE) production. However, the suppressive effect of PGG on IgE production in allergen-sensitized mice remains unclear. Therefore, the aim of this study was to investigate the inhibitory effect of PGG on IgE production in ovalbumin (OVA)-sensitized mice. Mice orally administered PGG showed a decrease in total and OVA-specific IgE levels in serum. Oral administration of PGG strongly suppressed production of type 2 T helper (IL-4 and IL-13), type IT helper (IFN-gamma), and pro-inflammatory cytokines (TNF-alpha and IL-6), but not anti-inflammatory cytokine (IL-10) from splenocytes of OVA-sensitized mice against OVA re-stimulation. A population of T regulatory (Treg) cells with immunosuppressive properties was increased in mesenteric lymph nodes and spleen of PGG-fed mice. PGG administration not only reduced expression levels of eotaxin, tissue inhibitors of metalloproteinases-1, and TNF-alpha, which assisted with IgE production, but also increased the expression of insulin-like growth factor binding protein-3 which inhibits IgE production. Additionally, PGG increased the levels of Treg cell-inducing factors such as IL-2, IL-10 and platelet factor-4 in serum. These data suggest that the inhibitory effect of PGG on IgE production could be partially caused by increasing a population of Treg cells in conjunction with Treg-inducing factors. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.intimp.2015.02.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE
however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid chromatography-mass spectrometry (LC-MS). Here, we revealed the polyphenol eriodictyol significantly potentiated apoptosis induction by EGCG in vitro and in a mouse tumour model by amplifying EGCG-induced activation of the 67-kDa laminin receptor (67LR)/protein kinase B/endothelial nitric oxide synthase/protein kinase C delta/acid sphingomyelinase signalling pathway. Our results show that metabolic profiling is an effective chemical-mining approach for identifying botanical drugs with therapeutic potential against multiple myeloma. Metabolic profiling-based data mining could be an efficient strategy for screening additional bioactive compounds and identifying effective chemical combinations.

DOI： 10.1038/srep09474

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The Ras/Raf/MEK/ERK pathway has been identified as a major, druggable regulator of melanoma. Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, resulting in constitutive melanoma hyperproliferation. A selective BRAF inhibitor showed remarkable clinical activity in patients with mutated BRAF. Unfortunately, most patients acquire resistance to the BRAF inhibitor, highlighting the urgent need for new melanoma treatment strategies. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibits cell proliferation independently of BRAF inhibitor sensitivity, suggesting that increased understanding of the anti-melanoma activity of EGCG may provide a novel therapeutic target. Here, by performing functional genetic screening, we identified protein phosphatase 2A (PP2A) as a critical factor in the suppression of melanoma cell proliferation. We demonstrated that tumor-overexpressed 67-kDa laminin receptor (67LR) activates PP2A through adenylate cyclase/cAMP pathway eliciting inhibitions of oncoproteins and activation of tumor suppressor Merlin. Activating 67LR/PP2A pathway leading to melanoma-specific mTOR inhibition shows strong synergy with the BRAF inhibitor PLX4720 in the drug-resistant melanoma. Moreover, SET, a potent inhibitor of PP2A, is overexpressed on malignant melanoma. Silencing of SET enhances 67LR/PP2A signaling. Collectively, activation of 67LR/PP2A signaling may thus be a novel rational strategy for melanoma-specific treatment.

DOI： 10.1074/jbc.M114.604983

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER CHEMICAL SOC  

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a powerful technique for visualizing the distribution of a wide range of biomolecules within tissue sections. However, methodology for visualizing a bioactive ellagitannin has not yet been established. This paper presents a novel in situ label-free MALDI-MSI technique for visualizing the distribution of strictinin, a bioactive ellagitannin found in green tea, within mammalian kidney after oral dosing. Among nine representative matrix candidates, 1,5-diaminonaphthalene (1,5-DAN), harmane, and ferulic acid showed higher sensitivity to strictinin spotted onto a MALDI sample plate. Of these, 1,5-DAN enables visualization of a two-dimensional image of strictinin directly spotted on mouse kidney sections with the highest sensitivity. Furthermore, 1,5-DAN-based MALDI-MSI could detect the unique distribution of orally dosed strictinin within kidney sections. This in situ label-free imaging technique will contribute to the localization analysis of strictinin and its biological mechanisms.

DOI： 10.1021/jf503143g

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

( )-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

DOI： 10.1016/j.febslet.2013.07.041

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記述言語：英語  

Strictinin has been shown to suppress interleukin (IL)-4-induced signal transducer and activator of transcription (STAT)-6 phosphorylation, which is a critical event for IgE class switching. However, it is unclear how strictinin inhibits STAT6 activation. Strictinin inhibited STAT6 phosphorylation by suppressing IL-4 receptor α (IL-4Rα) activation. Strictinin was bound to the cell surface and only localized in non-lipid raft fraction of the cells where IL-4Rα was also located. In addition, strictinin directly bound to IL-4Rα and inhibited binding of IL-4 to IL-4Rα. These results suggest that IL-4Rα locating in non-lipid raft region is a target molecule for strictinin in inhibiting STAT6 activation. © 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2014.06.069

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