75 results on '"Kumazoe M"'
Search Results
2. FOXO3 is essential for CD44 expression in pancreatic cancer cells
- Author
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Kumazoe, M, primary, Takai, M, additional, Bae, J, additional, Hiroi, S, additional, Huang, Y, additional, Takamatsu, K, additional, Won, Y, additional, Yamashita, M, additional, Hidaka, S, additional, Yamashita, S, additional, Yamada, S, additional, Murata, M, additional, Tsukamoto, S, additional, and Tachibana, H, additional
- Published
- 2016
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3. ChemInform Abstract: Photo‐Induced Conversion of Aryl(trichlorovinyl)nickel(II) Complexes (I) into Two Isomeric Mono‐organonickel(II) Complexes (II) and (III).
- Author
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WADA, M., primary, KUMAZOE, M., additional, MATSUHIRO, Y., additional, and ERABI, T., additional
- Published
- 1987
- Full Text
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4. Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies.
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Lu Z, Verginadis I, Kumazoe M, Castillo GM, Yao Y, Guerra RE, Bicher S, You M, McClung G, Qiu R, Xiao Z, Miao Z, George SS, Beiting DP, Nojiri T, Tanaka Y, Fujimura Y, Onda H, Hatakeyama Y, Nishimoto-Ashfield A, Bykova K, Guo W, Fan Y, Buynov NM, Diehl JA, Stanger BZ, Tachibana H, Gade TP, Puré E, Koumenis C, Bolotin EM, and Fuchs SY
- Subjects
- Animals, Mice, Humans, Cell Line, Tumor, Neoplasms drug therapy, Neoplasms pathology, Neoplasms blood supply, Immunity drug effects, Neovascularization, Pathologic drug therapy, Natriuretic Peptide, C-Type pharmacology, Natriuretic Peptide, C-Type therapeutic use, Tumor Microenvironment drug effects
- Abstract
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
- Published
- 2024
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5. Fustin suppressed melanoma cell growth via cAMP/PKA-dependent mechanism.
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Kumazoe M, Fujimura Y, Shimada Y, Onda H, Hatakeyama Y, and Tachibana H
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- Animals, Cell Line, Tumor, Mice, Phosphorylation drug effects, Myosin Light Chains metabolism, Cardiac Myosins metabolism, Flavonoids pharmacology, Isoquinolines pharmacology, Actins metabolism, Sulfonamides pharmacology, Humans, Melanoma pathology, Melanoma metabolism, Melanoma drug therapy, Mice, Inbred C57BL, Cyclic AMP-Dependent Protein Kinases metabolism, Cell Proliferation drug effects, Cyclic AMP metabolism, Melanoma, Experimental pathology, Melanoma, Experimental metabolism, Melanoma, Experimental drug therapy
- Abstract
Melanoma, a cancer arising from melanocytes, requires a novel treatment strategy because of the ineffectiveness of conventional therapies in certain patients. Fustin is a flavanonol found in young fustic (Cotinus coggygria). However, little is known about its antimelanoma effects. Our study demonstrates that fustin suppresses the growth of B16 melanoma cells. Phalloidin staining of cytoskeletal actin revealed that fustin induced a conformational change in the actin structure of melanoma cells, accompanied by suppressed phosphorylation of myosin regulatory light chain 2 (MLC2), a regulator of actin structure. Furthermore, the protein kinase A (cAMP-dependent protein kinase) inhibitor H89 completely attenuated fustin-induced downregulation of phosphorylated myosin phosphatase targeting subunit 1, which is involved in dephosphorylation of MLC2. In a mouse model, administration of fustin suppressed tumor growth in B16 melanoma cells without adverse effects. In conclusion, our findings suggest that fustin effectively suppresses melanoma cell growth both in vitro and in vivo., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)
- Published
- 2024
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6. Regulatory effect of Epigallocatechin-3-O-gallate on circular RNA expression in mouse liver.
- Author
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Yoshitomi R, Kumazoe M, Lee KW, Marugame Y, Fujimura Y, and Tachibana H
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- Animals, Mice, RNA genetics, RNA metabolism, Liver Cirrhosis, Gene Expression Profiling, RNA, Circular genetics, RNA, Circular metabolism, MicroRNAs genetics, Catechin analogs & derivatives
- Abstract
There are few studies on the connection between food components and circular RNA (circRNA), a type of noncoding RNA that is significant for living organisms. (-)-Epigallocatechin-3-O-gallate (EGCG) has been reported to have various biological effects, and elucidation of the molecular mechanism is important for clarifying the functionality of EGCG. In the current study, we looked at how EGCG regulates the expression of circRNA in the liver, which expresses a lot of circRNAs. Mice were given EGCG (10 mg/kg b.w.) orally for one week before circRNA microarray testing was done on their livers. The microarray analysis revealed that mice treated with EGCG had altered expression of 35 circRNAs in their livers. To clarify the function of mmu_circRNA_011775, one of the circRNAs upregulated by EGCG, mouse liver cells after the mmu_circRNA_011775 expression vector was transfected into NMuLi cells, next-generation sequencing (NGS) was used to analyze the gene expression. NGS analysis shows that the expression of the genes responsible for liver fibrosis and inflammation. Gene ontology (GO) analysis showed that mmu_circRNA_011775 changed the meaning of GO terms associated with the cardiovascular system. In the microarray, EGCG altered 35 genes expression. Among them, pre-ribosomal RNA-derived circRNA mmu_circRNA_011775 regulated the expression of various genes related to liver fibrosis and cardiovascular system., Competing Interests: Declaration of competing interests The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Neuroprotective effect of isovaleraldehyde accompanied with upregulation of BDNF and CREB phosphorylation via the PKA pathway.
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Shimada Y, Kumazoe M, Otsuka Y, Tetsuzen R, Fujimura Y, and Tachibana H
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- Humans, Cell Line, Tumor, Cacao chemistry, Plant Extracts pharmacology, Cyclic AMP-Dependent Protein Kinases metabolism, Signal Transduction drug effects, Enzyme Activation drug effects, Neuroprotective Agents pharmacology, Aldehydes pharmacology, Up-Regulation drug effects, Brain-Derived Neurotrophic Factor genetics, Cyclic AMP Response Element-Binding Protein metabolism
- Abstract
Recently, the number of patients diagnosed with dementia has increased. The World Health Organization (WHO) estimates that 50 million patients suffer from dementia. Although several therapeutic strategies have been proposed, currently, there is no curative approach for treating dementia. Neurodegeneration is an irreversible process. As this disease gradually progresses over 15-20 years, a low-cost and sustainable method for preventing these diseases is desired. Cacao nib is consumed in many countries, and a recent clinical study indicated that cocoa intake upregulates brain-derived neurotrophic factor (BDNF), which plays a significant role in memory formation and neuronal cell survival. In the present study, neural cells were treated with cacao nib extract or the 17 characteristic components of cacao nib. Treatment with Cacao nib extract upregulates BDNF mRNA expression. In addition, cacao nib extract elicits the phosphorylation of cAMP-response-element-binding protein (CREB), which regulates the transcription of BDNF. Among the 17 species screened, isovaleraldehyde (IVA), also known as an aroma component of cacao nibs extract, improved BDNF mRNA expression without SH-SY5Y cell toxicity. IVA also promoted CREB phosphorylation through a cAMP-dependent protein kinase (PKA)-dependent mechanism. In conclusion, IVA could be responsible for the BDNF upregulation effect of cacao nib, and IVA upregulated BDNF expression via the PKA-CREB axis., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)
- Published
- 2024
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8. miR-12135 ameliorates liver fibrosis accompanied with the downregulation of integrin subunit alpha 11.
- Author
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Kumazoe M, Miyamoto E, Oka C, Kondo M, Yoshitomi R, Onda H, Shimada Y, Fujimura Y, and Tachibana H
- Abstract
Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor β (TGF-β) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-β signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-β signaling in hepatic stellate cells., Competing Interests: The authors have a patent for the effect of miR12135., (© 2023 The Author(s).)
- Published
- 2023
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9. The anti-cancer effect of epigallocatechin-3-O-gallate against multiple myeloma cells is potentiated by 5,7-dimethoxyflavone.
- Author
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Bae J, Kumazoe M, Park SJ, Fujimura Y, and Tachibana H
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- Humans, Cell Line, Tumor, Apoptosis, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Catechin pharmacology
- Abstract
(-)-Epigallocatechin-3-O-gallate (EGCG) is one of the major components of green tea polyphenol. Previous studies have shown that EGCG induces cancer-specific cell death in vitro and in vivo without causing severe side effects. However, the anti-cancer effect of EGCG alone is limited. 5,7-dimethoxyflavone (5,7-DMF), one of the principal functional components of black ginger (Kaempferia parviflora), also exerts anti-cancer effects. Here, we show that 5,7-DMF synergistically enhances the anti-cancer effect of EGCG in multiple myeloma cells by potentiating EGCG-induced intracellular cyclic guanosine monophosphate (cGMP) production. Moreover, the combination of EGCG and 5,7-DMF induces apoptotic cell death in multiple myeloma cells, and this is accompanied by activation of the cGMP/acid sphingomyelinase (ASM)/cleaved caspase-3 pathway. In conclusion, we have shown that 5,7-DMF enhances the anti-cancer effect of EGCG by upregulating cGMP in multiple myeloma cells., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2023
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10. PPAR/PDK4 pathway is involved in the anticancer effects of cGMP in pancreatic cancer.
- Author
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Yamashita M, Kumazoe M, Onda H, Hiroi S, Shimada Y, Fujimura Y, and Tachibana H
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- Humans, Peroxisome Proliferator-Activated Receptors metabolism, Pancreas metabolism, Neoplastic Stem Cells pathology, Cell Line, Tumor, Pancreatic Neoplasms, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with a high mortality rate. Current treatments for PDACs often have side effects, and drug resistance in cancer stem cells (CSCs) would be also a problem. Cyclic guanosine monophosphate (cGMP) suppresses the mitochondrial function of PDACs and inhibits their CSC properties. Metabolic regulation plays a crucial role in the maintenance of CSC phenotype, and we hypothesized that cGMP induction suppresses cancer stem cell properties in the cancer cell through energy-related signaling pathways. We demonstrated that induction of cGMP upregulated the PPARα/PDK4 pathway and suppressed CSC properties in PDAC, and patients with pancreatic cancer with high PDK4 gene expression had a better prognosis than those with low gene expression. Therefore, these mechanisms may provide new therapeutic targets for the eradication of pancreatic CSCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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11. 67-kDa laminin receptor mediates oolonghomobisflavan B-induced cell growth inhibition in melanoma.
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Bae J, Kumazoe M, Lee KW, Fujimura Y, and Tachibana H
- Subjects
- Animals, Humans, Protein Phosphatase 2 metabolism, Polyphenols pharmacology, Cell Cycle, Receptors, Laminin chemistry, Receptors, Laminin metabolism, Catechin pharmacology, Melanoma, Experimental drug therapy
- Abstract
Background: Oolonghomobisflavans are unique polyphenols found in oolong teas. Oolonghomobisflavan B (OHBFB), a dimer of (-)-epigallocatechin-3-O-gallate (EGCG), is an active compound found in green tea., Purpose: OHBFB has been reported to exert an inhibitory effect on lipase enzyme activity. However, little is known regarding its intercellular signaling induction effect. Further, there are no reports describing the anti-cancer effects of OHBFB., Methods: The effect of OFBFB on B16 melanoma cells was evaluated by cell counting, and its mechanisms were determined by western blot analysis with or without protein phosphatase 2A (PP2A) inhibitor treatment. Intracellular cyclic adenosine monophosphate (cAMP) levels were evaluated by time-resolved fluorescence resonance energy transfer analysis. Quartz crystal microbalance (QCM) analysis was performed to assess the binding of OHBFB to 67LR., Results: Cell growth assay and western blot analyses showed that OHBFB inhibited melanoma cell growth, followed by myosin phosphatase target subunit 1 (MYPT1) and myosin regulatory light chain (MRLC) dephosphorylation via protein phosphatase 2A (PP2A)-dependent mechanisms. These effects are mediated by intracellular cAMP- and protein kinase A (PKA) A-dependent mechanisms. QCM analysis identified the 67-kDa laminin receptor (67LR) as an OHBFB receptor with a Kd of 3.7 µM. We also demonstrated for the first time that OHBFB intake suppresses tumor growth in vivo., Conclusions: Taken together, these results indicate that the cAMP/PKA/PP2A/MYPT1/MRLC pathway is a key mediator of melanoma cell growth inhibition following OHBFB binding to 67LR and that OHBFB suppresses tumor growth in vivo., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)
- Published
- 2023
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12. Dextran sulfate sodium-induced mild chronic colitis induced cognitive impairment accompanied by inhibition of neuronal maturation in adolescent mice.
- Author
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Lee K, Kumazoe M, Marugame Y, Fujimura Y, and Tachibana H
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- Male, Animals, Mice, Dextran Sulfate, Neuroinflammatory Diseases, Mice, Inbred C57BL, Colon metabolism, Disease Models, Animal, Neurogenesis, Colitis chemically induced, Colitis complications, Colitis metabolism, Inflammatory Bowel Diseases metabolism, Cognitive Dysfunction chemically induced, Cognitive Dysfunction metabolism, Dementia
- Abstract
Introduction: Epidemiological studies indicated that inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as its two main types, is associated with dementia. However, little is known about how adolescents with IBD will affect their cognitive ability as adults. The hippocampus, which is crucial for memory and adult neurogenesis, is closely associated with modulation of cognitive processes. Using a low kDa dextran sulfate sodium (DSS, 5 kDa)-induced chronic colitis (mild chronic colitis) mice model in adolescent mice, we investigated the effects of mild chronic colitis on cognitive functions and hippocampal neurogenesis from adolescent mice to adult mice., Methods: We induced DSS-induced mild chronic colitis in C57BL/6J male mice by multiple-cycle administration of 1%-2% DSS in autoclaved drinking water. Mice were subjected to novel-object recognition and Y-maze tests. Neurogenesis markers and neuroinflammation-related proteins in the hippocampus of mice were measured. Tight junction proteins in the colon of mice were measured., Results: Mild chronic colitis induced cognitive impairment and decreased adult neurogenesis. Notably, we found a positive correlation with the protein levels between tight junction protein, ZO-1, in the colon and mature neuron marker, NeuN, in the hippocampus. Moreover, mild chronic colitis leads to hippocampal neuroinflammation in adolescent mice., Conclusion: Our findings provide new evidence of the association between IBD and dementia risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. A gold-complex initiated functionalization of biologically active polyphenols applied to a 18 F-labeled chemical probe.
- Author
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Liu Z, Fukagawa Y, Yamano M, Tago T, Iwai K, Hirano K, Kumazoe M, Tachibana H, Toyohara J, and Tanaka H
- Subjects
- Fluorine Radioisotopes, Tea chemistry, Halogenation, Polyphenols pharmacology, Catechin pharmacology, Catechin metabolism
- Abstract
(-)-Epigallocatechin gallate (EGCG), a key component of green tea, exerts therapeutic anticancer and antiallergic properties through its binding to the 67 kDa laminin receptor. The functionalization of EGCG is a promising strategy for creating new drug candidates and chemical probes. In our study, we developed a method for effectively modifying the A ring of EGCG through an electrophilic aromatic substitution with amidomethyl 2-alkynylbenzoates initiated with a gold complex. The 2-alkynylbenzoates treated with (Ph
3 P)AuOTf under neutral conditions yielded N -acylimines. A further electrophilic aromatic substitution resulted in a mixture of EGCG substituted with acylaminomethyl groups at the 6 and 8 positions with a significant amount noted at the 6 position. We then explored the synthesis of18 F-labeled EGCG with a neopentyl labeling group, an effective labeling group for radiohalogens of not only fluorine-18 but also of astatine-211. To achieve this, we prepared precursors that possessed acid-sensitive protecting groups and base-unstable leaving groups using our established method. Substitution of EGCG with a neopentyl labeling group at either the C6 or C8 position did not affect its anticancer efficacy in U266 cells. Finally, we investigated the preparation of18 F-labeled EGCG. The18 F-fluorination of a mixture of 6- and 8-substituted precursors yielded the corresponding18 F-labeled compounds in 4.5% and 3.0% radiochemical yields (RCYs), respectively. Under acidic conditions, the18 F-labeled 8-substituted compound produced18 F-labeled EGCG in 37% RCY, which heralds the potential of our functionalization approach.- Published
- 2023
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14. Bioactivity-boosting strategy based on combination of anti-allergic O-methylated catechin with a Citrus flavanone, hesperetin.
- Author
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Fujimura Y, Yoshimoto T, Fujino K, Nezu A, Marugame Y, Bae J, Kumazoe M, and Tachibana H
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- Rats, Mice, Animals, Immunoglobulin E, Passive Cutaneous Anaphylaxis, Hesperidin, Anti-Allergic Agents pharmacology, Catechin, Flavanones
- Abstract
Many patients with allergies have anxiety about taking anti-allergic medicines due to their side effects and increased medical expenses. Thus, developing functional foods/agricultural products for allergy prevention is strongly desired. In this study, we revealed that a Citrus flavanone, hesperetin, amplified IgE/antigen-mediated degranulation-inhibitory potency of anti-allergic catechin, (-)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3''Me), in the rat basophilic/mast cell line RBL-2H3. Hesperetin also significantly elevated the activation of acid sphingomyelinase (ASM), essential for eliciting anti-allergic effect of EGCG3''Me through the cell surficial protein, 67-kDa laminin receptor (67LR). Furthermore, oral administration of the highly absorbent hesperidin, α-glucosyl hesperidin, also enhanced the inhibitory potency of EGCG3''Me-rich 'Benifuuki' green tea (Camellia sinensis L.) on passive cutaneous anaphylaxis (PCA) reaction evoked by IgE/antigen in BALB/c mice. These observations indicate that hesperetin amplifies the ability of EGCG3''Me to inhibit the IgE/antigen-mediated degranulation through activating ASM signaling., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)
- Published
- 2023
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15. Plant miRNA osa-miR172d-5p suppressed lung fibrosis by targeting Tab1.
- Author
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Kumazoe M, Ogawa F, Hikida A, Shimada Y, Yoshitomi R, Watanabe R, Onda H, Fujimura Y, and Tachibana H
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- Humans, Mice, Animals, Lung pathology, Fibrosis, Bleomycin toxicity, Bleomycin metabolism, Fibroblasts metabolism, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta1 metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, MicroRNAs metabolism, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis genetics, Idiopathic Pulmonary Fibrosis metabolism
- Abstract
Lung fibrosis, including idiopathic pulmonary fibrosis, is an intractable disease accompanied by an irreversible dysfunction in the respiratory system. Its pathogenesis involves the transforming growth factorβ (TGFβ)-induced overproduction of the extracellular matrix from fibroblasts; however, limited countermeasures have been established. In this study, we identified osa-miR172d-5p, a plant-derived microRNA (miR), as a potent anti-fibrotic miR. In silico analysis followed by an in vitro assay based on human lung fibroblasts demonstrated that osa-miR172d-5p suppressed the gene expression of TGF-β activated kinase 1 (MAP3K7) binding protein 1 (Tab1). It also suppressed the TGFβ-induced fibrotic gene expression in human lung fibroblasts. To assess the anti-fibrotic effect of osa-miR172d-5p, we established bleomycin-induced lung fibrosis models to demonstrate that osa-miR172d-5p ameliorated lung fibrosis. Moreover, it suppressed Tab1 expression in the lung tissues of bleomycin-treated mice. In conclusion, osa-miR172d-5p could be a potent candidate for the treatment of lung fibrosis, including idiopathic pulmonary fibrosis., (© 2023. The Author(s).)
- Published
- 2023
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16. (-)‑Epigallocatechin‑3‑ O ‑gallate upregulates the expression levels of miR‑6757‑3p, a suppressor of fibrosis‑related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells.
- Author
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Murata M, Marugame Y, Morozumi M, Murata K, Kumazoe M, Fujimura Y, and Tachibana H
- Abstract
As pulmonary fibrosis (PF), a severe interstitial pulmonary disease, has such a poor prognosis, the development of prevention and treatment methods is imperative. (-)-Epigallocatechin-3- O -gallate (EGCG), one of the major catechins in green tea, exerts an antifibrotic effect, although its mechanism remains unclear. Recently, it has been reported that microRNAs (miRNAs or miRs) transported by extracellular vesicles (EVs) from vascular endothelial cells (VECs) are involved in PF. In the present study, the effects of EGCG on the expression of miRNAs in EVs derived from human umbilical vein endothelial cells (HUVECs) were assessed and miRNAs with antifibrotic activity were identified. miRNA microarray analysis revealed that EGCG modulated the expression levels of 31 miRNAs (a total of 27 miRNAs were upregulated, and 4 miRNAs were downregulated.) in EVs from HUVECs. Furthermore, TargetScan analysis indicated that miR-6757-3p in particular, which exhibited the highest degree of change, may target transforming growth factor-β (TGF-β) receptor 1 (TGFBR1). To evaluate the effects of miR-6757-3p on TGFBR1 expression, human fetal lung fibroblasts (HFL-1) were transfected with an miR-6757-3p mimic. The results demonstrated that the miR-6757-3p mimic downregulated the expression of TGFBR1 as well the expression levels of fibrosis-related genes including fibronectin and α-smooth muscle actin in TGF-β-treated HFL-1 cells. In summary, EGCG upregulated the expression levels of miR-6757-3p, which may target TGFBR1 and downregulate fibrosis-related genes, in EVs derived from VECs., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Murata et al.)
- Published
- 2023
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17. Quercetin up-regulates the expression of tumor-suppressive microRNAs in human cervical cancer.
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Murata M, Komatsu S, Miyamoto E, Oka C, Lin I, Kumazoe M, Yamashita S, Fujimura Y, and Tachibana H
- Abstract
Quercetin, a flavonol present in many vegetables and fruits, has been identified as a chemoprevention agent in several cancer models. However, the molecular mechanism of quercetin's anticancer activity is not entirely understood. MicroRNAs (miRNAs), small noncoding RNAs, have been reported to play key roles in various biological processes by regulating their target genes. We hypothesized that quercetin can exert an anticancer effect through the regulation of miRNAs. To test this hypothesis, we investigated the effects of quercetin on the expression of tumor-suppressive miRNAs in cervical cancer. Quercetin up-regulated the in vivo and in vitro expression of tumor-suppressive miRNAs miR-26b, miR-126, and miR-320a. Quercetin suppressed the level of β-catenin, encoded by catenin beta 1 (CTNNB1), by up-regulating miR-320a in HeLa cells. Moreover, quercetin increased the expression of mir-26b, mir-126, and mir-320a precursors in HeLa cells. The results from this study show that quercetin has the potential to prevent cervical cancer by regulating the expression of tumor-suppressive miRNAs., (©2023 BMFH Press.)
- Published
- 2023
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18. Phosphodiesterase 5 Inhibitor Potentiates Epigallocatechin 3-O-Gallate-Induced Apoptotic Cell Death via Activation of the cGMP Signaling Pathway in Caco-2 Cells.
- Author
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Bae J, Lee K, Park JS, Jung J, Tachibana H, Fujimura Y, Kumazoe M, Lim JS, Cho YC, Lee SJ, and Park SJ
- Abstract
Epigallocatechin 3- O -gallate (EGCG) is a predominant component in green tea with various health benefits. The 67 kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that is overexpressed in various types of cancer; 67LR was identified a cell surface EGCG target that plays a pivotal role in tumor growth, metastasis, and resistance to chemotherapy. However, the plasma concentration of EGCG is limited, and its molecular mechanisms remain unelucidated in colon cancer. In this study, we found that the phosphodiesterase 5 (PDE5) inhibitor, vardenafil (VDN), potentiates EGCG-induced apoptotic cell death in colon cancer cells. The combination of EGCG and VDN induced apoptosis via activation of the endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase Cδ signaling pathway. In conclusion, the PDE5 inhibitor, VDN, may reduce the intracellular PDE5 enzyme activity that potentiates EGCG-induced apoptotic cell death in Caco-2 cells. These results suggest that PDE5 inhibitors can be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death. Therefore, EGCG may be employed as a therapeutic candidate for colon cancer.
- Published
- 2022
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19. Inflammatory markers S100A8/A9 and metabolic alteration for evaluating signs of early phase toxicity of anticancer agent treatment.
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Morikawa-Ichinose T, Fujimura Y, Kumazoe M, Onda H, Miura D, and Tachibana H
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- Animals, Mice, Cisplatin administration & dosage, Cisplatin toxicity, Docetaxel administration & dosage, Docetaxel toxicity, Doxorubicin administration & dosage, Doxorubicin toxicity, Fumarates analysis, Mice, Inbred C57BL, Tyrosine analysis, Antineoplastic Agents administration & dosage, Antineoplastic Agents toxicity, Biomarkers, Pharmacological metabolism, Calgranulin A genetics, Calgranulin A metabolism, Calgranulin B genetics, Calgranulin B metabolism, Inflammation chemically induced, Inflammation metabolism
- Abstract
Anticancer agents can cause various side effects, including tissue damages/inflammatory reactions. Drug-responsive biomarkers are essential for evaluating drug toxicity in disease processes. S100 calcium-binding proteins A8/A9 (S100A8/A9) are highly expressed in neutrophils and monocytes/macrophages accumulated at inflammatory sites and are known to be related to tissue damage/inflammation; however, their response to drug toxicity has not been reported. Herein, we investigated the effects of anticancer agents (doxorubicin, cisplatin, and docetaxel) on S100A8/A9 gene expression profiles in four representative tissues (heart, kidney, liver, and lung) in normal C57BL/6J mice. Both S100A8/A9 expression was transiently or time-dependently elevated in four tissues within 48 h after dosing of the three anticancer agents under toxicity-inducing conditions. S100A8/A9 patterns differed among agents and tissues. This result suggests that S100A8/A9 is useful for evaluating anticancer agent-induced tissue damage. Metabolomic analysis revealed that some metabolites showed temporal patterns similar to that of S100A8/A9 expression. The amounts of fumarate (doxorubicin-treated heart), tyrosine (cisplatin-treated kidney), acetylcarnosine (doxorubicin-treated liver), and 2-phosphoglycerate (docetaxel-treated lung) showed similar patterns to that of S100A8/A9 expression. Although these metabolites showed different behaviors between tissues and serum, they may be useful marker candidates for evaluating anticancer agent-induced tissue damage at an earlier stage after dosing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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20. 67-kDa Laminin Receptor-Mediated Cellular Sensing System of Green Tea Polyphenol EGCG and Functional Food Pairing.
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Fujimura Y, Kumazoe M, and Tachibana H
- Subjects
- Animals, Functional Food, Polyphenols pharmacology, Receptors, Laminin metabolism, Ribosomal Proteins, Tea, Catechin analogs & derivatives
- Abstract
The body is equipped with a "food factor-sensing system" that senses food factors, such as polyphenols, sulfur-containing compounds, and vitamins, taken into the body, and plays an essential role in manifesting their physiological effects. For example, (-)-epigallocatechin-3- O -gallate (EGCG), the representative catechin in green tea ( Camellia sinensi L.), exerts various effects, including anti-cancer, anti-inflammatory, and anti-allergic effects, when sensed by the cell surficial protein 67-kDa laminin receptor (67LR). Here, we focus on three representative effects of EGCG and provide their specific signaling mechanisms, the 67LR-mediated EGCG-sensing systems. Various components present in foods, such as eriodictyol, hesperetin, sulfide, vitamin A, and fatty acids, have been found to act on the food factor-sensing system and affect the functionality of other foods/food factors, such as green tea extract, EGCG, or its O -methylated derivative at different experimental levels, i.e., in vitro, animal models, and/or clinical trials. These phenomena are observed by increasing or decreasing the activity or expression of EGCG-sensing-related molecules. Such functional interaction between food factors is called "functional food pairing". In this review, we introduce examples of functional food pairings using EGCG.
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- 2022
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21. Myricetin improves cognitive function in SAMP8 mice and upregulates brain-derived neurotrophic factor and nerve growth factor.
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Shimada Y, Sato Y, Kumazoe M, Kitamura R, Fujimura Y, and Tachibana H
- Subjects
- Animals, Cyclic AMP Response Element-Binding Protein metabolism, Hippocampus drug effects, Hippocampus metabolism, Humans, Mice, Nerve Growth Factor metabolism, Brain-Derived Neurotrophic Factor metabolism, Cognition drug effects, Flavonoids pharmacology, Neuroblastoma metabolism
- Abstract
Introduction: Considering that neurodegeneration is an irreversible process, an efficient, low-burden approach to prevent dementia is strongly needed. Here, we show that the daily intake of myricetin normalised cognitive dysfunction in senescence-accelerated mouse prone 8 (SAMP8) mice., Methods: SAMP8 mice were fed a diet supplemented with myricetin and novel object recognition tests and Y-maze tests were performed. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brains of SAMP8 mice were measured. The phosphorylation level of cAMP-response-element-binding protein (CREB) level in brains of SAMP8 mice were evaluated. Also, SH-SY5Y cells were treated with myricetin and cAMP levels were measured., Results: In SAMP8 mice, neurotrophins, including BDNF and NGF, were downregulated relative to levels in their normal counterparts. In addition, myricetin intake upregulated the phosphorylation of CREB, the major transcription factor for BDNF and NGF. Also, myricetin induced cAMP upregulation, and CREB phosphorylation via a cAMP-dependent protein kinase-dependent manner in SH-SY5Y cells., Conclusion: Taken together, myricetin improves cognitive function in SAMP8 mice and upregulates BDNF and NGF., Competing Interests: Declaration of comepting interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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22. Metabolic Profiling for Evaluating the Dipeptidyl Peptidase-IV Inhibitory Potency of Diverse Green Tea Cultivars and Determining Bioactivity-Related Ingredients and Combinations.
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Fujimura Y, Watanabe M, Morikawa-Ichinose T, Fujino K, Yamamoto M, Nishioka S, Inoue C, Ogawa F, Yonekura M, Nakasone A, Kumazoe M, and Tachibana H
- Subjects
- Dipeptidyl Peptidase 4, Metabolomics methods, Plant Extracts chemistry, Plant Extracts pharmacology, Tea chemistry, Camellia sinensis chemistry, Dipeptidyl-Peptidase IV Inhibitors chemistry
- Abstract
There are numerous cultivars of tea ( Camellia sinensis L.), but the differences in their anti-hyperglycemic-related effects are largely unknown. The inhibition of the dipeptidyl peptidase (DPP)-IV enzyme plays an essential role in controlling hyperglycemia in diabetes by blocking the degradation of incretin hormones, which is necessary for insulin secretion. In this study, we examined the DPP-IV inhibitory activity of leaf extracts from diverse Japanese green tea cultivars. The inhibitory rates differed among tea extracts. Metabolic profiling (MP), using liquid chromatography-mass spectrometry, of all cultivars revealed compositional differences among cultivars according to their DPP-IV inhibitory capacity. Epigallocatechin-3- O -(3- O -methyl)gallate, kaempferol-3- O -rutinoside, myricetin-3- O -glucoside/galactoside, and theogallin were newly identified as DPP-IV inhibitors. The bioactivity of a tea extract was potentiated by adding these ingredients in combination. Our results show that MP is a useful approach for evaluating the DPP-IV inhibitory potency of green tea and for determining bioactivity-related ingredients and combinations.
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- 2022
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23. Retraction: Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers.
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Nojiri T, Arai M, Suzuki Y, Kumazoe M, Tokudome T, Miura K, Hino J, Hosoda H, Miyazato M, Okumura M, Kawaoka S, and Kangawa K
- Abstract
[This retracts the article DOI: 10.18632/oncotarget.18032.]., (Copyright: © 2022 Nojiri et al.)
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- 2022
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24. Fustin, a Flavanonol, Synergically Potentiates the Anticancer Effect of Green Tea Catechin Epigallocatechin-3- O -Gallate with Activation of the eNOS/cGMP Axis.
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Kumazoe M, Fujimura Y, Yoshitomi R, Shimada Y, and Tachibana H
- Subjects
- Animals, Apoptosis, Female, Flavonoids, Mice, Nitric Oxide Synthase Type III metabolism, Tea chemistry, Catechin analogs & derivatives, Catechin chemistry
- Abstract
Epigallocatechin-3- O -gallate (EGCG), a catechin present in green tea, selectively elicits apoptosis in multiple myeloma cells by activating the endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) axis. However, the effects of EGCG alone are limited. Herein, we revealed that fustin, a flavanonol, enhances the EGCG-elicited activation of the cGMP/eNOS axis in multiple myeloma cells. Isobologram analysis demonstrated that EGCG/fustin synergistically elicited cell death in multiple myeloma cells. Importantly, this chemical combination significantly promoted cell death without affecting the normal cells. To assess the effects of EGCG and fustin in vivo , female BALB/c mice were inoculated with multiple myeloma MPC11 cells and then treated with each compound. The combination of EGCG/fustin suppressed tumor growth in vivo without affecting alanine aminotransferase/aspartate aminotransferase levels, the dose-limiting toxicity of EGCG. Consistent with in vitro findings, this combination increased eNOS phosphorylation at Ser1177 in the tumor. Collectively, fustin amplified EGCG-induced activation of the eNOS/cGMP axis.
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- 2022
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25. Soy isoflavone metabolite equol inhibits cancer cell proliferation in a PAP associated domain containing 5-dependent and an estrogen receptor-independent manner.
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Yamashita S, Lin I, Oka C, Kumazoe M, Komatsu S, Murata M, Kamachi S, and Tachibana H
- Subjects
- Cell Line, Tumor, Estrogen Receptor alpha metabolism, HeLa Cells, Humans, Isoflavones pharmacology, MCF-7 Cells, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, MicroRNAs genetics, MicroRNAs metabolism, Neoplasm Transplantation, RNA, Small Nucleolar metabolism, Cell Proliferation drug effects, Equol pharmacology, Melanoma, Experimental pathology, RNA Nucleotidyltransferases metabolism, Receptors, Estrogen metabolism
- Abstract
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., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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26. Sesame lignans upregulate glutathione S-transferase expression and downregulate microRNA-669c-3p.
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Marugame Y, Takeshita N, Yamada S, Yoshitomi R, Kumazoe M, Fujimura Y, and Tachibana H
- Abstract
Oxidative stress is associated with aging and pathologies such as cardiovascular diseases, Alzheimer's disease, and cancer. Glutathione S-transferase (GST), a family of detoxification enzymes, plays a crucial role in countering oxidative stress. Therefore, there is a need for the development of physiologically functional foods and agricultural products, which enhance GST activity. Sesamin and episesamin are major lignans in refined sesame oil that exhibit beneficial properties including antioxidative stress effects. A previous study showed that sesamin upregulated GST activity. This study aimed to elucidate the mechanism underlying the GST activity enhancement elicited by sesame lignans. C57BL/6J mice were orally administered 20 mg/kg body weight sesame lignans (sesamin:episesamin=1:1) for 7 days. Oral administration of sesame lignans increased the GST activity in the mouse liver. Furthermore, the lignans upregulated GSTA1, GSTA4, and GSTM4 protein expression. Microarray analysis revealed that sesame lignans changed the expression of various microRNAs (miRNAs) (84 upregulated, 19 downregulated). We also found 16 miRNAs, including miR-669c-3p, that may negatively regulate GST expression among the 19 miRNAs with reduced expression caused by the sesame lignans. miR-669c is reportedly negatively correlated with GST. Additionally, we transfected NMuLi cells with an miR-669c-3p mimic and evaluated the effect of miR-669c-3p on GST mRNA and protein expressions. The results showed that the miR-669c-3p mimic suppressed the mRNA and protein levels of GSTA4 and GSTM4. In conclusion, sesame lignans increased GST protein expression and activity and downregulated miRNAs, including miR-669c-3p, which is a possible suppressor of GST., (©2022 BMFH Press.)
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- 2022
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27. Methylated (-)-epigallocatechin 3-O-gallate potentiates the effect of split vaccine accompanied with upregulation of Toll-like receptor 5.
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Kumazoe M, Takamatsu K, Horie F, Yoshitomi R, Hamagami H, Tanaka H, Fujimura Y, and Tachibana H
- Subjects
- Animals, Catechin chemistry, Catechin pharmacology, Drug Administration Schedule, Drug Synergism, Female, Hemagglutination, Immunity, Humoral, Influenza Vaccines, Japan, Macrophages metabolism, Methylation, Mice, Mice, Inbred BALB C, Plant Extracts chemistry, Spleen cytology, Tea, Up-Regulation, Catechin analogs & derivatives, Toll-Like Receptor 5 biosynthesis
- Abstract
Split-virus vaccine serves as a major countermeasure against influenza virus, but its effectiveness and protective action are not complete. We previously demonstrated the effect of Benifuuki, a green tea cultivar in Japan, on enhancing the split-virus vaccine-elicited immune response. However, little is known about the detail mechanisms. Here, we show that EGCG3"Me intake significantly potentiated the vaccine-elicited hemagglutination inhibition titer increase. Flow cytometry analysis revealed the increased Toll-like receptor 5 (TLR5) expression after EGCG3"Me treatment in lamina propria dendritic cells (LPDCs) and macrophages, which play crucial roles in the humoral immune system. TLR5 expression correlated with the level of interleukin-6 (IL-6)/C-C chemokine type receptor 5, which are important mediators of the humoral immunity. Taken together, In vivo and ex vivo studies showed that EGCG3"Me potentiated the split-virus vaccine-elicited immune response accompanied with the upregulation of TLR5 in intestine and splenocyte macrophages., (© 2021. The Author(s).)
- Published
- 2021
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28. The combined effect of green tea and α-glucosyl hesperidin in preventing obesity: a randomized placebo-controlled clinical trial.
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Yoshitomi R, Yamamoto M, Kumazoe M, Fujimura Y, Yonekura M, Shimamoto Y, Nakasone A, Kondo S, Hattori H, Haseda A, Nishihira J, and Tachibana H
- Subjects
- Adult, Body Mass Index, Catechin administration & dosage, Catechin therapeutic use, Female, Glucosides administration & dosage, Hesperidin administration & dosage, Hesperidin therapeutic use, Humans, Male, Middle Aged, Placebos, Catechin analogs & derivatives, Glucosides therapeutic use, Hesperidin analogs & derivatives, Obesity prevention & control, Tea chemistry
- Abstract
Green tea, a widely consumed beverage in Asia, contains green tea catechins effective against obesity, especially epigallocatechin-3-O-gallate (EGCG), but must be consumed in an impractically huge amount daily to elicit its biological effect. Meanwhile, citrus polyphenols have various physiological effects that could enhance EGCG functionality. Here we investigated the antiobesity effect of a combination of EGCG and α-glucosyl hesperidin, a citrus polyphenol, at doses that have not been previously reported to exert antiobesity effects by themselves in any clinical trial. In a randomized, placebo-controlled, double-blinded, and parallel-group-designed clinical trial, 60 healthy Japanese males and females aged 30-75 years consumed green tea combined with α-glucosyl hesperidin (GT-gH), which contained 178 mg α-glucosyl hesperidin and 146 mg EGCG, for 12 weeks. Physical, hematological, blood biochemical, and urine examinations showed that GT-gH is safe to use. At week 12, GT-gH prevented weight gain and reduced body mass index (BMI) compared with the placebo. Especially in those aged < 50 years, triglyceride and body fat percentage decreased at week 6, visceral fat level and body fat percentage decreased at week 12; body weight, BMI, and blood LDL/HDL ratio also decreased. In conclusion, taking GT-gH prevents weight gain, and the antiobesity effect of GT-gH was more pronounced in people aged < 50 years., (© 2021. The Author(s).)
- Published
- 2021
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29. Glucosyl-hesperidin enhances the cyclic guanosine monophosphate-inducing effect of a green tea polyphenol EGCG.
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Kumazoe M, Tanaka Y, Yoshitomi R, Marugame Y, Lee KW, Onda H, Fujimura Y, Yonekura M, Shimamoto Y, and Tachibana H
- Subjects
- Animals, Guanosine Monophosphate, Polyphenols pharmacology, Tea, Catechin analogs & derivatives, Catechin pharmacology, Hesperidin
- Abstract
Animal and clinical studies have revealed that (-)-epigallocatechin-3-O-gallate (EGCG), one of the major bioactive polyphenols in green tea, showed several pharmacological effects including anti-obesity effect and anti-inflammatory effect. We previously reported that the second messenger cyclic guanosine monophosphate (cGMP) mediates its anti-inflammatory and anti-cancer properties. Here we demonstrated that glucosyl-hesperidin, enhances the cGMP-inducing effects of green tea extract in vivo. Moreover, glucosyl-hesperidin intake potentiated the green tea-elicited upregulation of the anti-inflammatory factor, toll-interacting protein., (© 2021. The Japanese Society of Pharmacognosy.)
- Published
- 2021
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30. Eriodictyol-Amplified 67-kDa Laminin Receptor Signaling Potentiates the Antiallergic Effect of O -Methylated Catechin.
- Author
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Fujimura Y, Fujino K, Yoshimoto T, Nezu A, Marugame Y, Bae J, Kumazoe M, and Tachibana H
- Subjects
- Animals, Camellia sinensis chemistry, Cell Line, Female, Mast Cells drug effects, Mice, Inbred BALB C, Rats, Signal Transduction drug effects, Tea, Mice, Anti-Allergic Agents pharmacology, Catechin pharmacology, Flavanones pharmacology, Receptors, Laminin metabolism
- Abstract
(-)-Epigallocatechin-3- O -(3- O -methyl) gallate ( 1 , EGCG3″Me), an antiallergic O -methylated catechin, is present in high quantities in the green tea cultivar "Benifuuki" ( Camellia sinensis L.). Previous studies have shown that EGCG3″Me inhibited basophil degranulation mediated through the cell-surface 67-kDa laminin receptor (67LR), but the mechanisms are not fully elucidated. This study aimed to investigate the mechanisms underlying the inhibitory effect of EGCG3″Me on IgE/antigen (Ag)-mediated degranulation and the combined effect of EGCG3″Me with eriodictyol ( 2 ), a bioactive flavanone. EGCG3″Me inhibited β-hexosaminidase release from the rat basophilic/mast cell line RBL-2H3 stimulated by IgE/Ag and induced acid sphingomyelinase (ASM) activity. This induction was inhibited by anti-67LR antibody treatment. The ASM-specific inhibitor desipramine inhibited EGCG3″Me-induced suppression of degranulation. The soluble guanylate cyclase (sGC) inhibitor NS2028 weakened the potency of EGCG3″Me, and the sGC activator BAY41-2272 suppressed degranulation. The ability of EGCG3″Me to induce ASM activity and inhibit degranulation was amplified by eriodictyol. Furthermore, oral administration of the lemon-peel-derived eriodyctiol-7- O -glucoside ( 3 ) potentiated the suppressive effect of EGCG3″Me-rich "Benifuuki" green tea on the IgE/Ag-induced passive cutaneous anaphylaxis (PCA) reaction in BALB/c mice. These results suggest that EGCG3″Me inhibits IgE/Ag-mediated degranulation by inducing the 67LR/sGC/ASM signaling pathway, and eriodictyol amplifies this signaling.
- Published
- 2021
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31. Src Mediates Epigallocatechin-3- O -Gallate-Elicited Acid Sphingomyelinase Activation.
- Author
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Kumazoe M, Kadomatsu M, Bae J, Otsuka Y, Fujimura Y, and Tachibana H
- Subjects
- Catechin metabolism, Cell Death drug effects, Cell Line, Tumor, Cell Survival, Enzyme Activation, Focal Adhesion Kinase 1 metabolism, Humans, Models, Biological, Phosphorylation, Protein Binding, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Mas, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, src-Family Kinases antagonists & inhibitors, Catechin analogs & derivatives, Sphingomyelin Phosphodiesterase metabolism, src-Family Kinases metabolism
- Abstract
Epigallocatechin-3- O -gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM) axis via targeting its receptor 67-kDa laminin receptor (67LR), which is overexpressed in cancer. However, little is known about upstream mechanisms of EGCG-elicited ASM activation. In this study we show that the proto-oncogene tyrosine-protein kinase Src, also known as c-src, plays a crucial role in the anticancer effect of EGCG. We showed that EGCG elicits phosphorylation of Src at Tyr 416, a crucial phosphorylation site for its activity, and that the pharmacological inhibition of Src impedes the upstream events in EGCG-induced cell death signaling including upregulation of Akt activity, increase in cGMP levels, and activation of ASM. Moreover, focal adhesion kinase (FAK), which is involved in the phosphorylation of Src, is colocalized with 67LR. EGCG treatment enhanced interaction of FAK and 67LR. Consistent with these findings, pharmacological inhibition of FAK significantly neutralized EGCG-induced upregulation of Akt activity and activation of ASM. Taken together, FAK/Src play crucial roles in the upstream signaling of EGCG.
- Published
- 2020
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32. EGCG down-regulates MuRF1 expression through 67-kDa laminin receptor and the receptor signaling is amplified by eriodictyol.
- Author
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Murata M, Shimizu Y, Marugame Y, Nezu A, Fujino K, Yamada S, Kumazoe M, Fujimura Y, and Tachibana H
- Subjects
- Animals, Catechin chemistry, Down-Regulation, Mice, Signal Transduction, Catechin analogs & derivatives, Flavanones metabolism, Muscle Proteins metabolism, Plants chemistry, Receptors, Laminin metabolism, Tripartite Motif Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
(-)-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.
- Published
- 2020
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33. Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3.
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Yoshitomi R, Nakayama K, Yamashita S, Kumazoe M, Lin TA, Mei CY, Marugame Y, Fujimura Y, Maeda-Yamamoto M, Kuriyama S, and Tachibana H
- Subjects
- Carrier Proteins blood, Cohort Studies, Dietary Supplements, Female, Folic Acid administration & dosage, HEK293 Cells, Homocysteine toxicity, Humans, Male, Middle Aged, Neurotoxicity Syndromes etiology, Neurotoxicity Syndromes pathology, Carrier Proteins metabolism, Folic Acid metabolism, Homocysteine blood
- Abstract
Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy), a risk factor of Alzheimer's disease, thrombosis, neuropsychiatric illness and fractures. While several studies have reported that FOLR1 and FOLR2 import folic acid into cells, the role of FOLR3 remains unknown. In this study, we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity. To reveal the role of FOLR3, we constructed FOLR3-overexpressed HEK293 cells (FOLR3
+ cells) and evaluated cell growth, folic acid intake and Hcy-induced neurotoxicity. Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine. The ectopic expression of FOLR3 enhanced cell growth, and the enhanced effect was neutralised by folic acid-deficient media. The Western blot analysis revealed that FOLR3 is secreted into cell supernatant. The folic acid intake of FOLR3+ cells was higher than that of wild-type cells. Supernatant from FOLR3+ cells showed a protective effect on Hcy-induced cytotoxicity. FOLR3 expression in plasma is negatively correlated with plasma homocysteine. Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other.- Published
- 2020
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34. Cancer cell selective probe by mimicking EGCG.
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Kumazoe M, Hiroi S, Tanimoto Y, Miyakawa J, Yamanouchi M, Suemasu Y, Yoshitomi R, Murata M, Fujimura Y, Takahashi T, Tanaka H, and Tachibana H
- Subjects
- Animals, Catechin chemistry, Catechin pharmacology, Cell Line, Tumor, Fluorescence, Gene Knockdown Techniques, Humans, Mice, Multiple Myeloma genetics, Protein Binding, Proto-Oncogene Proteins c-akt metabolism, Receptors, Laminin agonists, Receptors, Laminin genetics, Signal Transduction drug effects, Signal Transduction genetics, Anticarcinogenic Agents pharmacology, Antioxidants pharmacology, Catechin analogs & derivatives, Multiple Myeloma metabolism, Receptors, Laminin metabolism
- Abstract
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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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35. Procyanidin C1 Inhibits Melanoma Cell Growth by Activating 67-kDa Laminin Receptor Signaling.
- Author
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Bae J, Kumazoe M, Murata K, Fujimura Y, and Tachibana H
- Subjects
- Animals, Cell Proliferation drug effects, Cell Proliferation physiology, Cyclic AMP-Dependent Protein Kinases metabolism, Cytoskeleton metabolism, Intracellular Signaling Peptides and Proteins metabolism, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Mice, Inbred C57BL, Muscle Proteins metabolism, Myosin Light Chains metabolism, Phosphorylation drug effects, Protein Phosphatase 2 metabolism, Antineoplastic Agents, Phytogenic pharmacology, Flavonoids pharmacology, Melanoma, Experimental drug therapy, Receptors, Laminin metabolism
- Abstract
Scope: Procyanidin C1 (PC1) is an epicatechin trimer found mainly in grapes that is reported to provide several health benefits. However, little is known about the molecular mechanisms underlying these benefits. The aim of this study is to demonstrate the molecular mechanisms by which PC1 operates., Methods and Results: A 67-kDa laminin receptor (67LR) is identified as a cell surface receptor of PC1, with a Kd value of 2.8 µm. PC1 induces an inhibitory effect on growth, accompanied by dephosphorylation of the C-kinase potentiated protein phosphatase-1 inhibitor protein of 17 kDa (CPI17) and myosin regulatory light chain (MRLC) proteins, followed by actin cytoskeleton remodeling in melanoma cells. These actions are mediated by protein kinase A (PKA) and protein phosphatase 2A (PP2A) activation once PC1 is bound to 67LR., Conclusion: It is demonstrated that PC1 elicits melanoma cell growth inhibition by activating the 67LR/PKA/PP2A/CPI17/MRLC pathway., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2020
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36. Epigallocatechin-3-O-gallate induces acid sphingomyelinase activation through activation of phospholipase C.
- Author
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Bae J, Kumazoe M, Takeuchi C, Hidaka S, Fujimura Y, and Tachibana H
- Subjects
- Apoptosis drug effects, Catechin pharmacology, Cell Line, Tumor, Humans, Multiple Myeloma metabolism, Phosphorylation, Signal Transduction drug effects, Catechin analogs & derivatives, Cyclic GMP metabolism, Enzyme Activation drug effects, Gene Expression Regulation, Neoplastic, Sphingomyelin Phosphodiesterase metabolism, Type C Phospholipases metabolism
- Abstract
Epigallocatechin-3-O-gallate (EGCG)-induced cyclic guanosine monophosphate (cGMP) plays a crucial role in EGCG-induced cell death in various types of cancer cells. However, little is known regarding the early molecular events after cGMP induction. In this study, we showed that cGMP induction is sufficient to induce the phosphorylation of protein kinase C delta (PKCδ) at Ser664, the crucial kinase for EGCG-induced activation of acid sphingomyelinase (ASM). Using a chemical inhibitor library, we revealed that the inhibitors of the negative regulators of diacylglycerol strongly increase the effect of EGCG. We also showed that EGCG treatment increased phospholipase C (PLC) activity, and the same results were obtained with cGMP inducer treatment. EGCG-induced ASM activation was completely suppressed by pharmacological inhibition of PLC. Collectively, EGCG-induced cGMP activated the cGMP/PLC/PKCδ/ASM signaling axis in multiple myeloma cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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37. Alteration of specific cytokine expression patterns in patients with breast cancer.
- Author
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Kawaguchi K, Sakurai M, Yamamoto Y, Suzuki E, Tsuda M, Kataoka TR, Hirata M, Nishie M, Nojiri T, Kumazoe M, Saito K, and Toi M
- Subjects
- Cytokines genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Models, Theoretical, Neoplasm Metastasis, Breast Neoplasms immunology, Cytokines metabolism
- Abstract
Systemic inflammation has been associated with aggressive tumor growth, invasion, and metastasis. Here we performed a comprehensive analysis of 26 kinds of inflammatory cytokine expression patterns among 185 patients with breast cancer and 54 healthy volunteers followed by chemometric analysis. We identified the specific cytokine expression patterns of breast cancer patients compared to healthy volunteers with (1) VEGF, IL-9, GM-CSF, IL-13, IL-4, and IFNγ, (2) IL-8, IL-10, IL-12, IL-5, IL-7, IL-1α, GCSF, IL-1β, and TNFα and (3) IL-2, Eotaxin, MIP1β, MIP1α, IL-17, and bFGF. Among the patients with breast cancer, we identified the specific cytokine signature of metastatic patients compared to non-metastatic patients. We also established a mathematical model for distinguishing patients with breast cancer from healthy volunteers and metastatic patients from non-metastatic patients. This cytokine network analysis could provide new insights into early intervention and effective therapeutic strategy for patients with breast cancer.
- Published
- 2019
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38. Diallyl disulfide potentiates anti-obesity effect of green tea in high-fat/high-sucrose diet-induced obesity.
- Author
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Bae J, Kumazoe M, Fujimura Y, and Tachibana H
- Subjects
- 3T3-L1 Cells, Adipocytes drug effects, Adipocytes metabolism, Adipose Tissue drug effects, Adipose Tissue metabolism, Animals, Body Weight drug effects, Catechin analogs & derivatives, Catechin pharmacology, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, Gene Expression Regulation drug effects, Lipid Metabolism drug effects, Lipid Metabolism genetics, Male, Mice, Mice, Inbred C57BL, Peroxisome Proliferator-Activated Receptors metabolism, Sucrose adverse effects, Allyl Compounds pharmacology, Anti-Obesity Agents pharmacology, Diet, High-Fat adverse effects, Disulfides pharmacology, Tea
- Abstract
Obesity is a major problem in developed countries and a burden on social health care systems. Several epidemiological studies showed the protective effects of green tea against obesity-related diseases. Cyclic guanosine monophosphate (cGMP) acts as a mediator for the physiological effects of (-)-epigallocatechin-3-O-gallate, the major constituent of green tea. Here, we showed that the level of phosphodiesterase 5, a negative regulator of cGMP, was up-regulated in adipose tissues of high-fat/high-sucrose (HF/HS) diet-fed mice and that this up-regulation was ameliorated by diallyl disulfide (DADS), the major organosulfur in garlic. A green tea extract (GT) and DADS in combination attenuated HF/HS diet-induced adipose increase and triglyceride accumulation in the liver. In these mechanisms, the combination regimen suppressed the HF/HS diet-induced up-regulation of fatty acid synthesis-related enzymes including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, and stearoyl-CoA desaturase-1. Moreover, this combination diet up-regulated thermogenesis-related genes including peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha and uncoupling proteins in both white and brown adipose tissues. In conclusion, we identified DADS as an enhancer of the anti-obesity effect of GT accompanied by the suppression of SREBP-1 and activation of PPAR axis. The combination diet is a novel and easily applicable approach against obesity-related diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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39. Saturated fatty acid attenuates anti-obesity effect of green tea.
- Author
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Yamashita S, Hirashima A, Lin IC, Bae J, Nakahara K, Murata M, Yamada S, Kumazoe M, Yoshitomi R, Kadomatsu M, Sato Y, Nezu A, Hikida A, Fujino K, Murata K, Maeda-Yamamoto M, and Tachibana H
- Subjects
- Adipose Tissue, White pathology, Animals, Catechin pharmacology, Diet, High-Fat, Male, Meat adverse effects, Mice, Mice, Inbred C57BL, Olive Oil adverse effects, PPAR gamma metabolism, Weight Gain drug effects, Catechin analogs & derivatives, Fatty Acids adverse effects, Obesity drug therapy, Plant Extracts pharmacology, Tea chemistry
- Abstract
Green tea and its major polyphenol epigallocatechin-3-O-gallate (EGCG) have suppressive effect on dietary obesity. However, it remains unsolved what type of diet on which they exhibit high or low anti-obesity effect. In the present study, we investigated whether anti-obesity effect of green tea differs depending on composition of fats or fatty acids that consist high-fat (HF) diet in mouse model. Green tea extract (GTE) intake dramatically suppressed weight gain and fat accumulation induced by olive oil-based HF diet, whereas the effects on those induced by beef tallow-based HF diet were weak. GTE also effectively suppressed obesity induced by unsaturated fatty acid-enriched HF diet with the stronger effect compared with that induced by saturated fatty acid-enriched HF diet. These differences would be associated with the increasing action of GTE on expression of PPARδ signaling pathway-related genes in the white adipose tissue. Expressions of genes relating to EGCG signaling pathway that is critical for exhibition of physiological effects of EGCG were also associated with the different effects of GTE. Here, we show that anti-obesity effect of GTE differs depending on types of fats or fatty acids that consist HF diet and could be attenuated by saturated fatty acid.
- Published
- 2018
- Full Text
- View/download PDF
40. Correction: Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression.
- Author
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Kumazoe M, Yamashita M, Nakamura Y, Takamatsu K, Bae J, Yamashita S, Yamada S, Onda H, Nojiri T, Kangawa K, and Tachibana H
- Published
- 2018
- Full Text
- View/download PDF
41. Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression.
- Author
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Kumazoe M, Yamashita M, Nakamura Y, Takamatsu K, Bae J, Yamashita S, Yamada S, Onda H, Nojiri T, Kangawa K, and Tachibana H
- Subjects
- Animals, Catechin chemistry, Catechin pharmacology, Cyclic GMP genetics, Cyclic GMP immunology, DNA-Binding Proteins genetics, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Mice, Inbred BALB C, Nuclear Proteins genetics, Protein Phosphatase 2 genetics, Protein Phosphatase 2 immunology, Second Messenger Systems genetics, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 immunology, Transcription Factors genetics, Catechin analogs & derivatives, DNA-Binding Proteins immunology, Intracellular Signaling Peptides and Proteins immunology, Nuclear Proteins immunology, Second Messenger Systems immunology, Tea chemistry, Transcription Factors immunology, Up-Regulation immunology
- Abstract
TLR signaling is critical to innate immune system regulation; however, aberrant TLR signaling is involved in several diseases, including insulin resistance, Alzheimer's disease, and tumor metastasis. Moreover, a recent study found that TLR-4 signaling pathway inhibition might be a target for the suppression of chronic inflammatory disorders. In this article, we show that the green tea polyphenol epigallocatechin-3- O -gallate (EGCG) increases the expression of Toll interacting protein, a strong inhibitor of TLR4 signaling, by suppressing the expression of E74-like ETS transcription factor 1 (Elf-1). A mechanistic study revealed that EGCG suppressed Elf-1 expression via protein phosphatase 2A/cyclic GMP (cGMP)-dependent mechanisms. We also confirmed that orally administered EGCG and a cGMP inducer upregulated Toll interacting protein expression, increased intracellular levels of cGMP in macrophages, and suppressed Elf-1 expression. These data support EGCG and a cGMP inducer as potential candidate suppressors of TLR4 signaling., (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Published
- 2017
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42. Hydrogen sulphide donors selectively potentiate a green tea polyphenol EGCG-induced apoptosis of multiple myeloma cells.
- Author
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Bae J, Kumazoe M, Yamashita S, and Tachibana H
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Catechin pharmacology, Catechin therapeutic use, Cell Line, Tumor, Humans, Hydrogen Sulfide therapeutic use, Mice, Multiple Myeloma metabolism, Multiple Myeloma physiopathology, Tea chemistry, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis, Catechin analogs & derivatives, Hydrogen Sulfide pharmacology, Multiple Myeloma drug therapy, Signal Transduction
- Abstract
Hydrogen sulphide (H
2 S) is a colourless gas with the odour of rotten eggs and has recently been recognized as a signal mediator in physiological activities related with the regulation of homeostasis, the vascular system and the inflammatory system. Here we show that H2 S donors, including sodium hydrogen sulphide (NaHS), GYY 4137 and diallyltrisulfide (DATS), synergistically enhanced the anti-cancer effect of a green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) against multiple myeloma cells without affecting normal cells. NaHS significantly potentiated the anti-cancer effect of EGCG and prolonged survival in a mouse xenograft model. In this mechanism, H2 S enhanced apoptotic cell death through cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase pathway induced by EGCG. Moreover, NaHS reduced the enzyme activity of cyclic nucleotide phosphodiesterase that is known as cGMP negative regulator. In conclusion, we identified H2 S as a gasotransmitter that potentiates EGCG-induced cancer cell death.- Published
- 2017
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- View/download PDF
43. SphK1 inhibitor potentiates the anti-cancer effect of EGCG on leukaemia cells.
- Author
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Tsukamoto S, Kumazoe M, Huang Y, Lesnick C, Kay NE, Shanafelt TD, and Tachibana H
- Subjects
- Catechin pharmacology, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Drug Synergism, Gene Expression, Humans, Leukemia genetics, Leukemia metabolism, Leukemia pathology, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Antineoplastic Agents pharmacology, Catechin analogs & derivatives, Enzyme Inhibitors pharmacology, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors
- Published
- 2017
- Full Text
- View/download PDF
44. The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma.
- Author
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Kumazoe M, Takai M, Hiroi S, Takeuchi C, Kadomatsu M, Nojiri T, Onda H, Bae J, Huang Y, Takamatsu K, Yamashita S, Kangawa K, and Tachibana H
- Subjects
- Animals, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carrier Proteins genetics, Cell Line, Tumor, Female, Forkhead Box Protein O3 genetics, Humans, Male, Mice, Knockout, Neoplasm Proteins genetics, Neoplastic Stem Cells, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, RNA-Binding Proteins, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal metabolism, Carrier Proteins metabolism, Forkhead Box Protein O3 metabolism, Neoplasm Proteins metabolism, Pancreatic Neoplasms metabolism, Signal Transduction
- Abstract
In 95% of patients with pancreatic ductal adenocarcinoma, recurrence is observed following chemotherapy. Findings from several studies have indicated that cancer stem cells (CSCs) are resistant to anticancer agents and may be involved in cancer recurrence and metastasis. The CD44 protein is a major CSC marker, and CD44 also plays an indispensable role in the CSC properties in several cancers, including pancreatic cancer; however, no clinical approach exists to inhibit CD44 activity. Here, we have performed knock-in/knockdown experiments, and we demonstrate that the forkhead box O3 (FOXO3)/liver kinase B1 (LKB1)/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ co-activator-1β (PGC-1β)/pyruvate dehydrogenase-A1 pathway is essential for CD44 expression and CSC properties. We observed that patients exhibiting high pyruvate dehydrogenase-A1 expression have a poor prognosis. Systemic PGC-1β knock-out mice are fertile and viable and do not exhibit an overt phenotype under normal conditions. This suggests that cGMP induction and PGC-1β inhibition represent potential strategies for treating patients with pancreatic ductal adenocarcinoma., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
45. Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers.
- Author
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Nojiri T, Arai M, Suzuki Y, Kumazoe M, Tokudome T, Miura K, Hino J, Hosoda H, Miyazato M, Okumura M, Kawaoka S, and Kangawa K
- Abstract
Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied in vivo . On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche., Competing Interests: CONFLICTS OF INTEREST T. Nojiri, H. Hosoda, M. Okumura, and K. Kangawa have the filed patent related to ANP for the treatment of cancer metastasis with Shionogi & Co., Ltd., which has a part of the right to apply for the patent transferred from one of the original applicants, Daiichi-Sankyo Pharmaceutical Inc. (PCT/JP2012/054841). The other authors have no competing interests.
- Published
- 2017
- Full Text
- View/download PDF
46. PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma.
- Author
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Kumazoe M, Takai M, Hiroi S, Takeuchi C, Yamanouchi M, Nojiri T, Onda H, Bae J, Huang Y, Takamatsu K, Yamashita S, Yamada S, Kangawa K, Takahashi T, Tanaka H, and Tachibana H
- Subjects
- Animals, Biomarkers, Tumor, Catechin chemistry, Catechin pharmacology, Cell Line, Tumor, Cyclic GMP metabolism, Cyclic Nucleotide Phosphodiesterases, Type 3 genetics, Cyclic Nucleotide Phosphodiesterases, Type 3 metabolism, Disease Models, Animal, Drug Synergism, Fluorescent Antibody Technique, Gene Expression, Humans, Mice, Phosphodiesterase 3 Inhibitors chemistry, Xenograft Model Antitumor Assays, Carcinoma, Pancreatic Ductal metabolism, Catechin analogs & derivatives, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Phosphodiesterase 3 Inhibitors pharmacology
- Abstract
Recurrence following chemotherapy is observed in the majority of patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that cancer stem cells (CSCs) may be involved in PDAC recurrence and metastasis. However, an efficient approach to targeting pancreatic CSCs remains to be established. Here we show that in cancer cells overexpressing the 67-kDa laminin receptor (67LR)-dependent cyclic GMP (cGMP) inducer, epigallocatechin-3-O-gallate (EGCG) and a phosphodiesterase 3 (PDE3) inhibitor in combination significantly suppressed the Forkhead box O3 and CD44 axis, which is indispensable for the CSC properties of PDAC. We confirmed that the EGCG and PDE3 inhibitor in combination strongly suppressed tumour formation and liver metastasis in vivo. We also found that a synthesized EGCG analog capable of inducing strong cGMP production drastically suppressed the CSC properties of PDAC and extended the survival period in vivo. In conclusion, the combination treatment of EGCG and a PDE3 inhibitor as a strong cGMP inducer could be a potential treatment candidate for the eradication of CSCs of PDAC.
- Published
- 2017
- Full Text
- View/download PDF
47. Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216.
- Author
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Kumazoe M, Nakamura Y, Yamashita M, Suzuki T, Takamatsu K, Huang Y, Bae J, Yamashita S, Murata M, Yamada S, Shinoda Y, Yamaguchi W, Toyoda Y, and Tachibana H
- Subjects
- Animals, Catechin pharmacology, Cells, Cultured, Hyperinsulinism metabolism, Hyperinsulinism prevention & control, Hypertriglyceridemia metabolism, Hypertriglyceridemia prevention & control, Inflammation etiology, Inflammation prevention & control, Lipopolysaccharides pharmacology, Macrophages, Peritoneal cytology, Macrophages, Peritoneal metabolism, Male, Mice, Mice, Inbred C57BL, NF-kappa B genetics, NF-kappa B metabolism, Obesity etiology, Obesity prevention & control, Receptors, Laminin agonists, Receptors, Laminin genetics, Signal Transduction drug effects, Toll-Like Receptor 4 genetics, Transcriptional Activation, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Ubiquitin-Protein Ligases genetics, Up-Regulation, Catechin analogs & derivatives, Gene Expression Regulation drug effects, Macrophages, Peritoneal drug effects, Receptors, Laminin metabolism, Tea chemistry, Toll-Like Receptor 4 metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
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 α 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., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
48. Oligomer formation of a tea polyphenol, EGCG, on its sensing molecule 67 kDa laminin receptor.
- Author
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Huang Y, Sumida M, Kumazoe M, Sugihara K, Suemasu Y, Yamada S, Yamashita S, Miyakawa J, Takahashi T, Tanaka H, Fujimura Y, and Tachibana H
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Antioxidants chemistry, Antioxidants metabolism, Catechin antagonists & inhibitors, Catechin chemistry, Catechin pharmacology, Cell Death drug effects, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Hep G2 Cells, Humans, Molecular Structure, Peptides chemistry, Peptides pharmacology, Receptors, Laminin chemistry, Surface Plasmon Resonance, Thermodynamics, Antineoplastic Agents pharmacology, Antioxidants pharmacology, Catechin analogs & derivatives, Receptors, Laminin metabolism, Tea chemistry
- Abstract
Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) has been attributed to the activation of its cell surface sensing receptor 67 kDa laminin receptor (67LR). However, the action of EGCG to activate 67LR remains unknown. Here we show that EGCG undergoes oligomer formation on its surface receptor 67LR.
- Published
- 2017
- Full Text
- View/download PDF
49. Green tea cultivar 'Benifuuki' potentiates split vaccine-induced immunoglobulin A production.
- Author
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Won YS, Kumazoe M, Takamatsu K, Shinoda Y, Sonoda S, Okada K, Okamoto T, and Tachibana H
- Subjects
- Animals, Female, Influenza Vaccines administration & dosage, Mice, Mice, Inbred BALB C, Models, Animal, Immunoglobulin A metabolism, Plant Extracts chemistry, Tea chemistry
- Abstract
Influenza is a widespread disease caused by infection with the influenza virus. Vaccination is considered to be the main countermeasure against influenza. A split vaccine is widely used to avoid severe adverse events, and it induces strong humoral immunity. However, the split vaccine alone cannot elicit mucosal immunity, including IgA production, and its preventative effects are limited. Here, we show that the green tea cultivar 'Benifuuki' extract enhanced the effect of a split vaccine on mucosal immunity. The frequency of IgA
+ cells was increased in lung and Peyer's patch that received Benifuuki diet. Secretion of hemagglutinin-specific mucosal IgA, which is closely linked to the prevention of viral infection, was significantly increased in the bronchoalveolar lavage fluid of split vaccine-immunized BALB/c mice that were administered green tea Benifuuki extract. Our findings suggest that Benifuuki intake enhanced the effects of the split vaccine on mucosal immunity.- Published
- 2017
- Full Text
- View/download PDF
50. The Synthesis of trans-Flavan-3-ol Gallates by Regioselective Oxidative Etherification and Their Cytotoxicity Mediated by 67 LR.
- Author
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Shiraishi N, Kumazoe M, Fuse S, Tachibana H, and Tanaka H
- Subjects
- Antineoplastic Agents pharmacology, Catechin analogs & derivatives, Catechin chemical synthesis, Cell Line, Tumor, Cell Survival drug effects, Cyclization, Epichlorohydrin chemistry, Epoxy Compounds pharmacology, Flavonoids pharmacology, Gallic Acid pharmacology, Humans, Molecular Structure, Oxidation-Reduction, Phenols chemistry, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Epoxy Compounds chemical synthesis, Flavonoids chemical synthesis, Gallic Acid chemical synthesis
- Abstract
We report on a chiral pool approach for the synthesis of trans-flavan-3-ol gallates from epichlorohydrin. The trans-flavan-3-ol gallates were prepared by the cycloetherification of the phenol at the C2 benzylic position of 2-acylozyl-1,3-diarylpropane during regioselective C-H oxidation. The 1,3-diarylpropanes were prepared starting from epichlorohydrin by epoxide opening with A and B ring precursors, followed by acylation of the resultant alcohol with galloyl chloride. The availability of both the enantiomers of epichlorohydrin allowed the preparation of the corresponding enantiomer using the same procedure. The cytotoxicity of the compounds against U266 cells was tested, in which 5-deoxy-7,3'-O-dimethyl gallocatechin gallate exhibited cytotoxicity that was more than ten times stronger than natural (-)-EGCG. In addition, the absolute configuration of the derivatives did not critically affect the biological activity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
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