70 results on '"Miyamoto, L."'
Search Results
2. Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet
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Kusakabe, T., Tanioka, H., Ebihara, K., Hirata, M., Miyamoto, L., Miyanaga, F., Hige, H., Aotani, D., Fujisawa, T., Masuzaki, H., Hosoda, K., and Nakao, K.
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- 2009
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3. PO304 AICAR STIMULATION MIMICS METABOLOMIC EFFECTS OF ELECTRICAL CONTRACTION IN ISOLATED RAT EPITROCHLEARIS MUSCLE
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Miyamoto, L., primary, Egawa, T., additional, Oshima, R., additional, Kurogi, E., additional, Tsuchiya, K., additional, and Hayashi, T., additional
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- 2014
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4. PO362 A HYDROPHILIC DERIVATIVE OF PROBUCOL AMELIORATES GLUCOSE TOLERANCE AND INSULIN SENSITIVITY IN HFD-FED MICE
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Takenokuma, K., primary, Miyamoto, L., additional, Tomida, Y., additional, Tsuchihashi, Y., additional, Matsushita, T., additional, Hattori, H., additional, Nemoto, H., additional, and Tsuchiya, K., additional
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- 2014
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5. An Adipose Tissue-Independent Insulin-Sensitizing Action of Telmisartan: a Study in Lipodystrophic Mice
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Rong, X., primary, Li, Y., additional, Ebihara, K., additional, Zhao, M., additional, Aini, W., additional, Kusakabe, T., additional, Hirata, M., additional, Miyamoto, L., additional, Murray, M., additional, and Nakao, K., additional
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- 2009
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6. Measurement And Simulation Of Debris Production From A Laser-plasma X-ray Source
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Daido, E.L., primary, Sharma, L.B., additional, Kate, Y., additional, Yabe, T., additional, Ohmura, E., additional, Fukumoto, I., additional, Tanaka, H., additional, Nishi, N., additional, and Miyamoto, L., additional
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- 1997
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7. Measurement And Simulation Of Debris Production From A Laser-plasma X-ray Source
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Daido, E., primary, Sharma, L.B., additional, Kate, Y., additional, Yabe, T., additional, Ohmura, E., additional, Fukumoto, I., additional, Tanaka, H., additional, Nishi, N., additional, and Miyamoto, L., additional
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8. Morus alba leaf extract stimulates 5'-AMP-activated protein kinase in isolated rat skeletal muscle.
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Ma X, Iwanaka N, Masuda S, Karaike K, Egawa T, Hamada T, Toyoda T, Miyamoto L, Nakao K, and Hayashi T
- Abstract
AIM OF THE STUDY: Morus alba (mulberry) leaf is a natural therapeutic agent that has been shown to have an antidiabetic effect. We explored the possibility that 5'-AMP-activated protein kinase (AMPK) is involved in metabolic enhancement by the Morus alba leaf. MATERIALS AND METHODS: Isolated rat epitrochlearis muscle was incubated in a buffer containing Morus alba leaf hot water extract (MLE) and the AMPK activation and related events were examined. RESULTS: In response to MLE treatment, the Thr(172) phosphorylation of the catalytic alpha subunit of AMPK, an essential step for full kinase activation increased in a dose- and time-dependent manner. Ser(79) phosphorylation of acetyl CoA carboxylase, an intracellular substrate of AMPK, increased similarly. Analysis of isoform-specific AMPK activity revealed that MLE activated both the alpha1 and alpha2 isoforms of the catalytic subunit. This increase in enzyme activity was associated with an increased rate of 3-O-methyl-D-glucose transport in the absence of insulin and with phosphorylation of AS160, a signaling intermediary leading to glucose transporter 4 translocation. The intracellular energy status, estimated from the ATP and phosphocreatine concentrations, was not affected by MLE. CONCLUSION: MLE stimulates skeletal muscle AMPK activity acutely without changing the intracellular energy status. [ABSTRACT FROM AUTHOR]
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- 2009
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9. Dauferulins A-L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities.
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Yoshino Y, Imanishi M, Miyamoto L, Tsuji D, Akagi R, Tsuchiya K, Kashiwada Y, and Tanaka N
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- Humans, Animals, Mice, Molecular Structure, Plant Roots chemistry, Ferula chemistry, Carcinoma, Hepatocellular drug therapy, Sesquiterpenes chemistry, Liver Neoplasms
- Abstract
Phytochemical study on the roots of a medicinal plant Ferula communis L. (Apiaceae) resulted in the isolation of 20 sesquiterpenes including 12 previously undescribed compounds, dauferulins A-L (1-12). The detailed spectroscopic analysis revealed 1-12 to be daucane-type sesquiterpenes with a p-methoxybenzoyloxy group at C-6. The absolute configurations of 1-12 were deduced by analysis of the ECD spectra. Dauferulins A-L (1-12), known sesquiterpenes (13-20), and analogues (14a-14l) derived from 6-O-p-methoxybenzoyl-10α-angeloyloxy-jeaschkeanadiol (14) were evaluated for their effects on AMPK phosphorylation in human hepatoma HepG2 cells as well as inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and IL-1β production from LPS-treated murine microglial cells., Competing Interests: Declaration of competing interest [Dauferulins A–L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities]. The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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10. Indigo Leaves-Induced Pulmonary Arterial Remodeling without Right Ventricular Hypertrophy in Rats.
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Tsunematsu H, Imanishi M, Uemura Y, Higaki Y, Morisaki M, Katsura A, Miyamoto L, Funamoto M, Ichimura-Shimizu M, Horinouchi Y, Ikeda Y, Tsuneyama K, and Tsuchiya K
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- Animals, Male, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary metabolism, Rats, Endothelial Cells drug effects, Endothelial Cells metabolism, Lung drug effects, Lung pathology, Lung metabolism, Plant Leaves, Pulmonary Artery drug effects, Pulmonary Artery metabolism, Pulmonary Artery pathology, Endothelin-1 metabolism, Vascular Remodeling drug effects, Hypertrophy, Right Ventricular metabolism, Hypertrophy, Right Ventricular physiopathology, Rats, Sprague-Dawley
- Abstract
Indigo naturalis (IN), derived from the leaves of the indigo plant, is a traditional Chinese medicine that has historically been used for its anti-inflammatory properties in the treatment of various diseases, including ulcerative colitis (UC). However, long-term use of IN in UC patients is incontrovertibly associated with the onset of pulmonary arterial hypertension (PAH). To investigate the mechanisms by which IN induces PAH, we focused on the raw material of IN, indigo leaves (IL). Only the condition of long-term chronic (6 months) and high-dose (containing 5% IL in the control diet) administration of IL induced medial thickening in the pulmonary arteries without right ventricular hypertrophy in our rat model. IL administration for a month did not induce pulmonary arterial remodeling but increased endothelin-1 (ET-1) expression levels within endothelial cell (EC) layers in the lungs. Gene Expression Omnibus analysis showed that ET-1 is a key regulator of PAH and that the IL component indican and its metabolite IS induced ET-1 mRNA expression via reactive oxygen species-dependent mechanism. We identified the roles of indican and IS in ET-1 expression in ECs, which were linked to pulmonary arterial remodeling in an animal model.
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- 2024
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11. Changes in intestinal microbiota and biochemical parameters in patients with inflammatory bowel disease and irritable bowel syndrome induced by the prolonged addition of soluble fibers to usual drug therapy.
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Watanabe H, Inoue T, Miyamoto L, Ono Y, Matsumoto K, Takeda M, and Tsuchiya K
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- Humans, Male, Female, Adult, Middle Aged, Inflammatory Bowel Diseases drug therapy, Feces microbiology, Feces chemistry, Fatty Acids, Volatile analysis, Fatty Acids, Volatile metabolism, Gastrointestinal Microbiome drug effects, Irritable Bowel Syndrome drug therapy, Irritable Bowel Syndrome microbiology, Dietary Fiber administration & dosage, Mannans administration & dosage, Plant Gums administration & dosage, Galactans administration & dosage
- Abstract
Objectives: Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber;in addition to improving bowel movements, it maintains intestinal health by producing short-chain fatty acids. However, majority of clinical studies on PHGG have been concluded within a month and excluded usual drug therapy. Hence, this study aimed to determine the effects of long-term consumption of PHGG, in combination with drug therapy, on gut bacteria ratios, laboratory values for inflammatory response, and fecal characteristics., Methods and Results: The study was performed in patients with irritable bowel syndrome (IBS), Crohn's disease (CD), and ulcerative colitis (UC), by the administration of PHGG for six months while they continued their usual treatment. PHGG treatment caused significant changes in patients with IBS, including an increase in the abundance of short-chain fatty acid-producing bacteria, a significant decrease in Bacteroides abundance, and normalization of the Bristol scale of stool. In patients with UC, non-significant normalization of soft stools and decrease in fecal calprotectin were observed. Adverse events were not observed in any of the groups., Conclusion: Thus, it would be beneficial to include PHGG in the usual drug therapies of patients with IBS. J. Med. Invest. 71 : 121-128, February, 2024.
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- 2024
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12. CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses.
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Imanishi M, Inoue T, Fukushima K, Yamashita R, Nakayama R, Nojima M, Kondo K, Gomi Y, Tsunematsu H, Goto K, Miyamoto L, Funamoto M, Denda M, Ishizawa K, Otaka A, Fujino H, Ikeda Y, and Tsuchiya K
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- Humans, Carbonic Anhydrase IX genetics, Carbonic Anhydrase IX metabolism, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Antigens, Neoplasm therapeutic use, Hypoxia metabolism, RNA, Small Interfering, Computational Biology, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics
- Abstract
A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
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- 2023
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13. Role of ferroptosis in cisplatin-induced acute nephrotoxicity in mice.
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Ikeda Y, Hamano H, Horinouchi Y, Miyamoto L, Hirayama T, Nagasawa H, Tamaki T, and Tsuchiya K
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- Animals, Ferritins, Iron metabolism, Lipid Peroxidation, Mice, Cisplatin toxicity, Ferroptosis
- Abstract
Background: Cisplatin is widely used as an antitumor drug for the treatment of solid tumors. However, its use has been limited owing to nephrotoxicity, a major side effect. The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN., Methods: We evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model., Results: Cisplatin increased the protein expressions of transferrin receptor-1 and ferritin, and iron content in the kidney of mice. In addition, treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and increased inflammatory cytokine expression; these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. The expression of the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE), increased with cisplatin administration, and decreased with the administration of Fer-1. By contrast, cisplatin-induced apoptosis and necroptosis were inhibited by treatment with Fer-1. Moreover, deferoxamine, an iron chelator, also inhibited CIN, with a decrease in the expression of COX-2 and 4-HNE., Conclusion: Ferroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN., (Copyright © 2021 Elsevier GmbH. All rights reserved.)
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- 2021
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14. Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity.
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Hamano H, Ikeda Y, Goda M, Fukushima K, Kishi S, Chuma M, Yamashita M, Niimura T, Takechi K, Imanishi M, Zamami Y, Horinouchi Y, Izawa-Ishizawa Y, Miyamoto L, Ishizawa K, Fujino H, Tamaki T, Aihara KI, and Tsuchiya K
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- Animals, Apoptosis, Cisplatin toxicity, Diphenhydramine metabolism, Diphenhydramine pharmacology, Diphenhydramine therapeutic use, Humans, Kidney metabolism, Mice, Oxidative Stress, Retrospective Studies, Acute Kidney Injury chemically induced, Acute Kidney Injury drug therapy, Acute Kidney Injury prevention & control, Antineoplastic Agents toxicity
- Abstract
Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes kidney toxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced kidney toxicity is currently available. Here, based on a repositioning analysis of the Food and Drug Administration Adverse Events Reporting System, we found that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced kidney toxicity. To confirm this, the actual efficacy of diphenhydramine was evaluated in in vitro and in vivo experiments. Diphenhydramine inhibited cisplatin-induced cell death in kidney proximal tubular cells. Mice administered cisplatin developed kidney injury with significant dysfunction (mean plasma creatinine: 0.43 vs 0.15 mg/dl) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and MAPKs activation. However, most of these symptoms were suppressed by treatment with diphenhydramine. Furthermore, the concentration of cisplatin in the kidney was significantly attenuated in diphenhydramine-treated mice (mean platinum content: 70.0 vs 53.4 μg/g dry kidney weight). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. In a selected cohort of 98 1:1 matched patients from a retrospective database of 1467 patients showed that patients with malignant cancer who had used diphenhydramine before cisplatin treatment exhibited significantly less acute kidney injury compared to ones who did not (6.1 % vs 22.4 %, respectively). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced kidney toxicity., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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15. Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice.
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Ikeda Y, Watanabe H, Shiuchi T, Hamano H, Horinouchi Y, Imanishi M, Goda M, Zamami Y, Takechi K, Izawa-Ishizawa Y, Miyamoto L, Ishizawa K, Aihara KI, Tsuchiya K, and Tamaki T
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- Animals, Apoferritins genetics, Diabetes Mellitus etiology, Male, Mice, Mice, Knockout, Obesity etiology, Random Allocation, Apoferritins metabolism, Diabetes Mellitus metabolism, Diabetes Mellitus therapy, Diet, High-Fat adverse effects, Macrophages metabolism, Obesity metabolism, Obesity therapy
- Abstract
Aims/hypothesis: Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron-storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes., Methods: Conditional macrophage-specific H-ferritin (Fth, also known as Fth1) knockout (LysM-Cre Fth KO) mice were used and divided into four groups: wild-type (WT) and LysM-Cre Fth KO mice with normal diet (ND), and WT and LysM-Cre Fth KO mice with high-fat diet (HFD). These mice were analysed for characteristics of obesity and diabetes, tissue iron content, inflammation, oxidative stress, insulin sensitivity and metabolic measurements. RAW264.7 macrophage cells were used for in vitro experiments., Results: Iron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from LysM-Cre Fth KO mice. HFD-induced obesity was lower in LysM-Cre Fth KO mice than in WT mice at 12 weeks (body weight: KO 34.6 ± 5.6 g vs WT 40.1 ± 5.2 g). mRNA expression of inflammatory cytokines and infiltrated macrophages and oxidative stress increased in the adipose tissue of HFD-fed WT mice, but was not elevated in HFD-fed LysM-Cre Fth KO mice. However, WT mice fed an HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre Fth KO mice fed an HFD (adipose tissue [μmol Fe/g protein]: KO 1496 ± 479 vs WT 2316 ± 866; spleen [μmol Fe/g protein]: KO 218 ± 54 vs WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre Fth KO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and lipopolysaccharide-induced Tnf-α (also known as Tnf) mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA., Conclusions/interpretation: Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes.
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- 2020
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16. Novel Hydrophilic Camptothecin Derivatives Conjugated to Branched Glycerol Trimer Suppress Tumor Growth without Causing Diarrhea in Murine Xenograft Models of Human Lung Cancer.
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Tsuchihashi Y, Abe S, Miyamoto L, Tsunematsu H, Izumi T, Hatano A, Okuno H, Yamane M, Yasuoka T, Ikeda Y, and Tsuchiya K
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- A549 Cells, Animals, Camptothecin chemistry, Cell Line, Tumor, Disease Models, Animal, Heterografts drug effects, Humans, Hydrophobic and Hydrophilic Interactions, Irinotecan pharmacology, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver drug effects, Rats, Sprague-Dawley, Xenograft Model Antitumor Assays methods, Antineoplastic Agents, Phytogenic pharmacology, Camptothecin adverse effects, Camptothecin pharmacology, Diarrhea prevention & control, Glycerol chemistry, Lung Neoplasms drug therapy
- Abstract
Camptothecin possesses broad antitumor spectra on various cancers. In spite of its marked tumor-suppressing potency, camptothecin is too hydrophobic to be solved in water and therefore not currently in clinical use. CPT-11 (irinotecan) is one of the hydrophilic analogues of camptothecin and widely prescribed. However, its water solubility is still low and furthermore evokes severe diarrhea. Therefore, we designed and synthesized novel highly hydrophilic camptothecin derivatives by conjugating SN38 with branched glycerol trimer (SN38-BGL), which we have been developing as a unique strategy to endow hydrophobic molecule with much hydrophilicity, to maximize the benefit of CPT-11 and minimize the adverse effects. The SN38-BGLs exhibited equivalent or slightly stronger tumor-suppressing effects in murine xenograft human lung cancer models compared to CPT-11. However, neither early- nor late-onset diarrhea was observed when SN38-BGL was administered. Heights of villi in jejunum and ileum were bigger than those from CPT-11-treated mice, indicating that SN38-BGL is less harmful than CPT-11. Ex vivo digestion by liver microsome did not yield SN38 but a couple of other molecules against our expectations, which suggests the involvement of other active metabolites than SN38 and may explain the differences. Hence, SN38-BGLs can be a novel hydrophilic camptothecin derivative without causing severe diarrhea.
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- 2020
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17. [Preface].
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Miyamoto L and Okuyama S
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- 2020
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18. [Conjugation to Branched Glycerol Oligomers, a Novel Strategy for Extremely Hydrophobic Agents].
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Miyamoto L, Abe S, Nemoto H, and Tsuchiya K
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- Fibric Acids, Polyethylene Glycols chemistry, Polymers, Solubility, Water, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Glycerol chemistry, Hydrophobic and Hydrophilic Interactions
- Abstract
Ascertaining the absorption, distribution, metabolism, and excretion (ADME) profile of drugs is one of the most crucial factors in the process of drug discovery. Since it is important to combine water solubility and cell permeability within the compound to achieve the desired ADME properties, an appropriate balance between lipophilicity and hydrophilicity is required. It is often necessary to facilitate hydrophilicity of very hydrophobic candidates, because quite lipophobic molecules are rarely hit as positive in molecular-targeted or cell-based screenings. For that purpose, it has been popular to conjugate hydrophobic molecules with polyethylene glycol (PEG). However, PEG is a polymer, and PEG-conjugated molecules are not uniform. Besides, the dosage should be much increased compared with the original molecule due to the increase in molecular weight. Therefore we have been developing alternative ways to endow hydrophobic compounds with extra hydrophilicity by conjugating with symmetrically branched glycerol oligomers. This technology is versatile and easily applicable to various hydrophobic compounds. Water-solubility of fenofibrate, one of the most hydrophobic medicines in clinical use, was facilitated by a factor of more than 2000, and its lipid-lowering effect in vivo improved more than ten-fold, by simply conjugating with branched glycerol trimer, for instance. Here we will briefly introduce the basic concepts and our successful experiences of applying branched glycerol oligomers including antitumor agents in terms of water-solubility, pharmacological effects, and pharmacokinetics, and merits and current issues will be discussed in this review.
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- 2020
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19. Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway.
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Hamano H, Niimura T, Horinouchi Y, Zamami Y, Takechi K, Goda M, Imanishi M, Chuma M, Izawa-Ishizawa Y, Miyamoto L, Fukushima K, Fujino H, Tsuchiya K, Ishizawa K, Tamaki T, and Ikeda Y
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- Anemia, Iron-Deficiency blood, Anemia, Iron-Deficiency physiopathology, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Cation Transport Proteins metabolism, Duodenum metabolism, Duodenum physiopathology, Hep G2 Cells, Hepatocytes metabolism, Histamine H2 Antagonists toxicity, Humans, Iron Deficiencies, Male, Mice, Inbred C57BL, Receptors, Aryl Hydrocarbon genetics, Anemia, Iron-Deficiency chemically induced, Basic Helix-Loop-Helix Transcription Factors metabolism, Duodenum drug effects, Hepatocytes drug effects, Hepcidins metabolism, Intestinal Absorption drug effects, Iron blood, Proton Pump Inhibitors toxicity, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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20. [Metabolic beneficial effects of Citrus Sudachi].
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Miyamoto L and Tsuchiya K
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- Diet, Fruit, Health Promotion, Humans, Japan, Citrus
- Abstract
Sudachi (Citrus Sudachi) is a sour fruit and is a popular seasoning for Japanese dishes, Washoku. It can grow only in Tokushima and the surrounding areas for some reason, and therefore, Sudachi is a specialty of Tokushima prefecture in Japan. We usually use only its juice, and the size of the fruit is so small that a huge amount of pomace has been an industrial problem of the region. Therefore, we undertook exploratory studies of the Sudachi peel in terms of health promotion with making a kind of collaborative consortium for the study of acid citruses. Our recent activities on Sudachi research including the consortium were shared and discussed in the symposium, and the metabolic effects of Sudachi peel will be briefly introduced in the current manuscript.
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- 2020
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21. [State-of-the-art Technologies Innovative to the World of Pharmaceutical Sciences].
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Miyamoto L and Sato H
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- Animals, Drug Delivery Systems, Drug Design, Genetic Engineering methods, Genetic Engineering trends, Humans, Metabolomics methods, Metabolomics trends, Molecular Imaging methods, Molecular Imaging trends, Biopharmaceutics methods, Biopharmaceutics trends, Drug Development methods, Drug Development trends, Technology, Pharmaceutical trends
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- 2020
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22. Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress.
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Ikeda Y, Satoh A, Horinouchi Y, Hamano H, Watanabe H, Imao M, Imanishi M, Zamami Y, Takechi K, Izawa-Ishizawa Y, Miyamoto L, Hirayama T, Nagasawa H, Ishizawa K, Aihara KI, Tsuchiya K, and Tamaki T
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- Animals, Blotting, Western, Cell Line, Cell Survival physiology, Hydroxyl Radical metabolism, MAP Kinase Signaling System physiology, Male, Mice, Mice, Inbred C57BL, Muscle Development physiology, Thiobarbituric Acid Reactive Substances metabolism, Iron metabolism, Muscle, Skeletal metabolism, Oxidative Stress physiology, RNA, Messenger metabolism
- Abstract
Skeletal muscle atrophy is caused by disruption in the homeostatic balance of muscle degeneration and regeneration under various pathophysiological conditions. We have previously reported that iron accumulation induces skeletal muscle atrophy via a ubiquitin ligase-dependent pathway. However, the potential effect of iron accumulation on muscle regeneration remains unclear. To examine the effect of iron accumulation on myogenesis, we used a mouse model with cardiotoxin (CTX)-induced muscle regeneration in vivo and C2C12 mouse myoblast cells in vitro . In mice with iron overload, the skeletal muscles exhibited increased oxidative stress and decreased expression of satellite cell markers. Following CTX-induced muscle injury, these mice also displayed delayed muscle regeneration with a decrease in the size of regenerating myofibers, reduced expression of myoblast differentiation markers, and decreased phosphorylation of MAPK signaling pathways. In vitro , iron overload also suppressed the differentiation of C2C12 myoblast cells but the suppression could be reversed by superoxide scavenging using tempol. Excess iron inhibits myogenesis via oxidative stress, leading to an imbalance in skeletal muscle homeostasis.-Ikeda, Y., Satoh, A., Horinouchi, Y., Hamano, H., Watanabe, H., Imao, M., Imanishi, M., Zamami, Y., Takechi, K., Izawa-Ishizawa, Y., Miyamoto, L., Hirayama, T., Nagasawa, H., Ishizawa, K., Aihara, K.-I., Tsuchiya, K., Tamaki, T. Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress.
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- 2019
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23. Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis.
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Horinouchi Y, Ikeda Y, Fukushima K, Imanishi M, Hamano H, Izawa-Ishizawa Y, Zamami Y, Takechi K, Miyamoto L, Fujino H, Ishizawa K, Tsuchiya K, and Tamaki T
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- Animals, Cells, Cultured, Humans, Inflammation pathology, Inflammation prevention & control, Kidney Diseases pathology, Macrophages metabolism, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Nephritis, Interstitial pathology, Ureteral Obstruction pathology, Databases, Factual, Factor Xa Inhibitors pharmacology, Kidney Diseases prevention & control, Macrophages drug effects, Nephritis, Interstitial drug therapy, Pyridines pharmacology, Thiazoles pharmacology, Ureteral Obstruction drug therapy
- Abstract
Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis.
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- 2018
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24. The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease.
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Hamano H, Ikeda Y, Watanabe H, Horinouchi Y, Izawa-Ishizawa Y, Imanishi M, Zamami Y, Takechi K, Miyamoto L, Ishizawa K, Tsuchiya K, and Tamaki T
- Subjects
- Adenine toxicity, Animals, Disease Models, Animal, Hep G2 Cells, Hepcidins genetics, Humans, Male, Mice, Mice, Inbred C57BL, Oxidative Stress drug effects, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic pathology, Gene Expression Regulation drug effects, Hepcidins metabolism, Indican pharmacology, Iron metabolism, Renal Insufficiency, Chronic metabolism
- Abstract
Background: Hepcidin secreted by hepatocytes is a key regulator of iron metabolism throughout the body. Hepcidin concentrations are increased in chronic kidney disease (CKD), contributing to abnormalities in iron metabolism. Levels of indoxyl sulfate (IS), a uremic toxin, are also elevated in CKD. However, the effect of IS accumulation on iron metabolism remains unclear., Methods: We used HepG2 cells to determine the mechanism by which IS regulates hepcidin concentrations. We also used a mouse model of adenine-induced CKD. The CKD mice were divided into two groups: one was treated using AST-120 and the other received no treatment. We examined control mice, CKD mice, CKD mice treated using AST-120 and mice treated with IS via drinking water., Results: In the in vitro experiments using HepG2 cells, IS increased hepcidin expression in a dose-dependent manner. Silencing of the aryl hydrocarbon receptor (AhR) inhibited IS-induced hepcidin expression. Furthermore, IS induced oxidative stress and antioxidant drugs diminished IS-induced hepcidin expression. Adenine-induced CKD mice demonstrated an increase in hepcidin concentrations; this increase was reduced by AST-120, an oral adsorbent of the uremic toxin. CKD mice showed renal anemia, decreased plasma iron concentration, increased plasma ferritin and increased iron content in the spleen. Ferroportin was decreased in the duodenum and increased in the spleen. These changes were ameliorated by AST-120 treatment. Mice treated by direct IS administration showed hepatic hepcidin upregulation., Conclusions: IS affects iron metabolism in CKD by participating in hepcidin regulation via pathways that depend on AhR and oxidative stress.
- Published
- 2018
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25. [Lifestyle Inspires Future Pharmacotherapy and Drug Discovery].
- Author
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Miyamoto L and Nishida M
- Subjects
- AMP-Activated Protein Kinases physiology, Cardiovascular Diseases prevention & control, Energy Metabolism genetics, Forecasting, Humans, Sarcopenia prevention & control, Drug Discovery trends, Drug Therapy trends, Life Style
- Published
- 2018
- Full Text
- View/download PDF
26. Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate.
- Author
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Tsuda K, Miyamoto L, Hamano S, Morimoto Y, Kangawa Y, Fukue C, Kagawa Y, Horinouchi Y, Xu W, Ikeda Y, Tamaki T, and Tsuchiya K
- Subjects
- Antimalarials pharmacology, Antipyrine analogs & derivatives, Antipyrine pharmacology, Artesunate, Cell Survival drug effects, Edaravone, Free Radical Scavengers pharmacology, Hep G2 Cells, Humans, Hydrogen-Ion Concentration, Oxidation-Reduction, Antineoplastic Agents pharmacology, Artemisinins pharmacology, Iron pharmacology, Oxygen pharmacology, Reactive Oxygen Species metabolism
- Abstract
Artemisinin was discovered in 1971 as a constituent of the wormwood genus plant (Artemisia annua). This plant has been used as an herbal medicine to treat malaria since ancient times. The compound artemisinin has a sesquiterpene lactone bearing a peroxide group that offers its biological activity. In addition to anti-malarial activity, artemisinin derivatives have been reported to exert antitumor activity in cancer cells, and have attracted attention as potential anti-cancer drugs. Mechanisms that might explain the antitumor activities of artemisinin derivatives reportedly induction of apoptosis, angiogenesis inhibitory effects, inhibition of hypoxia-inducible factor-1α (HIF-1α) activation, and direct DNA injury. Reactive oxygen species (ROS) generation is involved in many cases. However, little is known about the mechanism of ROS formation from artemisinin derivatives and what types of ROS are produced. Therefore, we investigated the iron-induced ROS formation mechanism by using artesunate, a water-soluble artemisinin derivative, which is thought to be the underlying mechanism involved in artesunate-mediated cell death. The ROS generated by the coexistence of iron(II), artesunate, and molecular oxygen was a hydroxyl radical or hydroxyl radical-like ROS. Artesunate can reduce iron(III) to iron(II), which enables generation of ROS irrespective of the iron valence. We found that reduction from iron(III) to iron(II) was activated in the acidic rather than the neutral region and was proportional to the hydrogen ion concentration.
- Published
- 2018
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27. [AMPK as a Metabolic Intersection between Diet and Physical Exercise].
- Author
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Miyamoto L
- Subjects
- Aminoimidazole Carboxamide analogs & derivatives, Biphenyl Compounds, Drug Discovery, Exercise Therapy, Humans, Hypoglycemic Agents, Isoenzymes metabolism, Metabolic Diseases genetics, Metformin, Muscle Contraction genetics, Muscle Contraction physiology, Pyrones, Ribonucleosides, Thiophenes, AMP-Activated Protein Kinases metabolism, AMP-Activated Protein Kinases physiology, Diet, Eating genetics, Eating physiology, Exercise physiology, Metabolic Diseases metabolism, Metabolic Diseases therapy, Molecular Targeted Therapy
- Abstract
Physical exercise is well known to be beneficial to our health. Therapeutic exercise is widely applicable to metabolic disorders, including obesity and diabetes. In addition, recent studies have suggested its potential benefit in the treatment of more various diseases such as mental disorders and cancer. 5'AMP-activated protein kinase (AMPK), which is an intracellular central metabolic sensor as well as a regulator, has been demonstrated to play significant roles in the contracting skeletal muscles, suggesting that AMPK should be one of the key molecules mediating metabolic effects during physical exercise. Therefore, AMPK is a desirable therapeutic target for drug discovery. In the symposium S41 held in the 137th Annual Meeting of the Pharmaceutical Society of Japan, our data on the molecular mechanisms of isoform-specific postprandial suppression of AMPK activity were shared, and we discussed potential roles of AMPK as an intersection where metabolic signals by physical exercise and feeding status crosstalk. Here, I would like to introduce basic knowledge related to AMPK and recent findings regarding how AMPK activity is regulated in response to physiological and pharmacological stimulation.
- Published
- 2018
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28. Molecular Pathogenesis of Familial Wolff-Parkinson-White Syndrome.
- Author
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Miyamoto L
- Subjects
- AMP-Activated Protein Kinases genetics, Animals, Humans, Wolff-Parkinson-White Syndrome genetics, AMP-Activated Protein Kinases physiology, Glycogen metabolism, Mutation, Myocardium metabolism, Wolff-Parkinson-White Syndrome etiology
- Abstract
Familial Wolff-Parkinson-White (WPW) syndrome is an autosomal dominant inherited disease and consists of a small percentage of WPW syndrome which exhibits ventricular pre-excitation by development of accessory atrioventricular pathway. A series of mutations in PRKAG2 gene encoding gamma2 subunit of 5'AMP-activated protein kinase (AMPK) has been identified as the cause of familial WPW syndrome. AMPK is one of the most important metabolic regulators of carbohydrates and lipids in many types of tissues including cardiac and skeletal muscles. Patients and animals with the mutation in PRKAG2 gene exhibit aberrant atrioventricular conduction associated with cardiac glycogen overload. Recent studies have revealed "novel" significance of canonical pathways leading to glycogen synthesis and provided us profound insights into molecular mechanism of the regulation of glycogen metabolism by AMPK. This review focuses on the molecular basis of the pathogenesis of cardiac abnormality due to PRKAG2 mutation and will provide current overviews of the mechanism of glycogen regulation by AMPK. J. Med. Invest. 65:1-8, February, 2018.
- Published
- 2018
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- View/download PDF
29. [Sodium-Glucose Transporters as a Therapeutic Target for Diabetes from the Viewpoint of Drug Discovery and Pharmacotherapy].
- Author
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Miyamoto L and Tsuchiya K
- Subjects
- Body Weight drug effects, Carbonates pharmacology, Carbonates therapeutic use, Energy Metabolism drug effects, Glucosides pharmacology, Glucosides therapeutic use, Humans, Phloretin pharmacology, Phloretin therapeutic use, Phlorhizin pharmacology, Phlorhizin therapeutic use, Sodium-Glucose Transporter 2 Inhibitors, Diabetes Mellitus drug therapy, Diabetes Mellitus genetics, Drug Discovery, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Molecular Targeted Therapy, Sodium-Glucose Transporter 2
- Abstract
Sodium-glucose transporter (SGLT)-2 inhibitors, which are currently in clinical use in most of the world, are unique as their hypoglycemic effects are completely independent of insulin action. Potential benefits and indications for the treatment of other diseases like circulatory and renal disorders are attracting attention. SGLT2 inhibitors not only reduce blood glucose levels but also alter the whole-body energy balance to lower body weight, which should result in the amelioration of multiple metabolic disorders like metabolic syndrome. In the symposium, we briefly introduced the physiological as well as biological functions of SGLTs and discussed strategies for drug design by looking back at the history of drug discovery for SGLT2 inhibitors. We also shared our recent data on their combined usage with other hypoglycemic agents and effects on glucagon secretion, which are current clinical topics relevant to SGLT2 inhibitors. Among those topics, strategies for drug discovery of SGLT2 inhibitors are discussed in this review.
- Published
- 2018
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30. Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells.
- Author
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Xu W, Miyamoto L, Aihara H, Yamaoka T, Tanaka N, Tsuchihashi Y, Ikeda Y, Tamaki T, Kashiwada Y, and Tsuchiya K
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Cell Line, Humans, Hypolipidemic Agents isolation & purification, Hypolipidemic Agents pharmacology, Methanol, Mice, Models, Biological, PPAR alpha metabolism, Phytotherapy, Plant Extracts isolation & purification, Signal Transduction drug effects, Sirtuin 1 metabolism, Triglycerides metabolism, Citrus chemistry, Lipid Metabolism drug effects, Plant Extracts pharmacology
- Abstract
Ectopic fat accumulation is associated with insulin resistance and type 2 diabetes mellitus. Citrus sudachi is an evergreen tree that is found mainly in Tokushima Prefecture in Japan. Previously, it was demonstrated that Citrus sudachi could inhibit the rising trend of blood glucose and fatty acid in human subjects. In the current study, we illustrated the function of methanol extracts from sudachi peel and investigated the mechanism of this effect. We got the five kinds of methanol extracts by using diaion HP-20, and those were named by hydrophobicity from M-F1 to M-F5. Among the 5 kinds of sudachi methanol extracts, only M-F4 significantly decreased the intracellular triglyceride of C2C12 cells. It augmented the AMPK activity and increased the transcription of PPARα and its downstream targets CPT-1b and UCP2. In conclusion, M-F4 improved the lipid metabolism possibly through AMPK, PPARα and their downstream targets like CPT-1b and UCP2. Furthermore, this extract may be useful for preventing obesity and diabetes related diseases. J. Med. Invest. 65:225-230, August, 2018.
- Published
- 2018
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31. Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice.
- Author
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Ikeda Y, Horinouchi Y, Hamano H, Hirayama T, Kishi S, Izawa-Ishizawa Y, Imanishi M, Zamami Y, Takechi K, Miyamoto L, Ishizawa K, Aihara KI, Nagasawa H, Tsuchiya K, and Tamaki T
- Subjects
- Acute Kidney Injury diet therapy, Acute Kidney Injury pathology, Animals, Biomarkers, Cytokines metabolism, Disease Models, Animal, Immunohistochemistry, Inflammasomes metabolism, Inflammation Mediators metabolism, Kidney Function Tests, Male, Mice, NADPH Oxidases metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nephritis, Interstitial diet therapy, Nephritis, Interstitial pathology, Oxidative Stress, Serum Albumin, Bovine administration & dosage, Serum Albumin, Bovine adverse effects, Acute Kidney Injury etiology, Acute Kidney Injury metabolism, Iron metabolism, Iron, Dietary, Nephritis, Interstitial etiology, Nephritis, Interstitial metabolism, Proteinuria complications, Proteinuria metabolism
- Abstract
Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22
phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.- Published
- 2017
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32. Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation.
- Author
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Oshima K, Ikeda Y, Horinouchi Y, Watanabe H, Hamano H, Kihira Y, Kishi S, Izawa-Ishizawa Y, Miyamoto L, Hirayama T, Nagasawa H, Ishizawa K, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Erythropoietin analysis, Ferric Compounds pharmacology, Ferric Oxide, Saccharated, Fibroblasts, Glucaric Acid pharmacology, Hep G2 Cells, Humans, Kidney drug effects, Kidney metabolism, Mice, Up-Regulation drug effects, Ureteral Obstruction, Basic Helix-Loop-Helix Transcription Factors metabolism, Erythropoietin metabolism, Iron pharmacology, Oxidative Stress drug effects
- Abstract
Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment. Anemia-induced increase in renal EPO and HIF-2α expression was inhibited by iron treatment. In in vitro experiments using EPO-producing HepG2 cells, iron stimulation reduced the expression of the EPO gene, as well as HIF-2α. Moreover, iron treatment augmented oxidative stress, and iron-induced reduction of EPO and HIF-2α expression was restored by tempol, an antioxidant compound. HIF-2α interaction with the Epo promoter was inhibited by iron treatment, and was restored by tempol. These findings suggested that iron supplementation reduced EPO gene expression via an oxidative stress-HIF-2α-dependent signaling pathway.
- Published
- 2017
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33. Nitrite Activates 5'AMP-Activated Protein Kinase-Endothelial Nitric Oxide Synthase Pathway in Human Glomerular Endothelial Cells.
- Author
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Miyamoto L, Yamane M, Tomida Y, Kono M, Yamaoka T, Kawasaki A, Hatano A, Tsuda K, Xu W, Ikeda Y, Tamaki T, and Tsuchiya K
- Subjects
- Cell Line, Endothelial Cells drug effects, Humans, Kidney Glomerulus cytology, Kidney Glomerulus drug effects, Nitric Oxide metabolism, Phosphorylation, AMP-Activated Protein Kinases metabolism, Endothelial Cells metabolism, Nitric Oxide Synthase Type III metabolism, Nitrites pharmacology, Protective Agents pharmacology, Signal Transduction drug effects
- Abstract
Recent studies have shown that orally supplied nitrates, which substantially exist in our daily diets, are reduced into nitrites and become significant sources of nitric oxide (NO) especially in hypoxic tissues. However, physiological significance of nitrites in normal tissues has not been elucidated though our serum concentrations of nitrites reach as high as micromolar levels. We investigated effects of nitrite on endothelial NO synthase (eNOS) using human glomerular endothelial cells to reveal potential glomerular-protective actions of nitrites with its underlying molecular mechanism. Here we demonstrate that nitrite stimulation evokes eNOS activation which is dependent on 5'AMP-activated protein kinase (AMPK) activation in accordance with ATP reduction. Thus, nitrites should facilitate AMPK-eNOS pathway in an energy level-dependent manner in endothelial cells. The activation of AMPK-eNOS signals is suggested to be involved in vascular and renal protective effects of nitrites and nitrates. Nitrites may harbor beneficial effects on metabolic regulations as AMPK activators.
- Published
- 2017
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34. Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.
- Author
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Abe S, Kaneko MK, Tsuchihashi Y, Izumi T, Ogasawara S, Okada N, Sato C, Tobiume M, Otsuka K, Miyamoto L, Tsuchiya K, Kawazoe K, Kato Y, and Nishioka Y
- Subjects
- Animals, Antibody-Dependent Cell Cytotoxicity immunology, Cell Line, Tumor, Complement System Proteins immunology, Cytotoxicity, Immunologic, Disease Models, Animal, Drug Therapy, Combination, Humans, Immunotherapy, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Male, Mesothelioma drug therapy, Mesothelioma pathology, Mesothelioma, Malignant, Mice, Pemetrexed pharmacology, Pleural Neoplasms drug therapy, Pleural Neoplasms pathology, Rats, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Lung Neoplasms immunology, Lung Neoplasms metabolism, Membrane Glycoproteins antagonists & inhibitors, Mesothelioma immunology, Mesothelioma metabolism, Pleural Neoplasms immunology, Pleural Neoplasms metabolism
- Abstract
Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2016
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35. Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3-E3 ubiquitin ligase-dependent pathway.
- Author
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Ikeda Y, Imao M, Satoh A, Watanabe H, Hamano H, Horinouchi Y, Izawa-Ishizawa Y, Kihira Y, Miyamoto L, Ishizawa K, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Body Weight drug effects, Cell Line, Ferritins blood, Iron Overload metabolism, Mice, Inbred C57BL, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal pathology, Muscle Proteins genetics, Muscular Atrophy blood, Organ Size drug effects, Oxidative Stress drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, SKP Cullin F-Box Protein Ligases genetics, Signal Transduction drug effects, Signal Transduction genetics, Tripartite Motif Proteins genetics, Ubiquitin-Protein Ligases genetics, Forkhead Box Protein O3 metabolism, Iron adverse effects, Muscle Proteins metabolism, Muscle, Skeletal pathology, Muscular Atrophy chemically induced, Proto-Oncogene Proteins c-akt metabolism, SKP Cullin F-Box Protein Ligases metabolism, Tripartite Motif Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Skeletal muscle wasting or sarcopenia is a critical health problem. Skeletal muscle atrophy is induced by an excess of iron, which is an essential trace metal for all living organisms. Excessive amounts of iron catalyze the formation of highly toxic hydroxyl radicals via the Fenton reaction. However, the molecular mechanism of iron-induced skeletal muscle atrophy has remained unclear. In this study, 8-weeks-old C57BL6/J mice were divided into 2 groups: vehicle-treated group and the iron-injected group (10 mg iron day(-1)mouse(-1)) during 2 weeks. Mice in the iron-injected group showed an increase in the iron content of the skeletal muscle and serum and ferritin levels in the muscle, along with reduced skeletal muscle mass. The skeletal muscle showed elevated mRNA expression of the muscle atrophy-related E3 ubiquitin ligases, atrogin-1 and muscle ring finger-1(MuRF1), on days 7 and 14 of iron treatment. Moreover, iron-treated mice showed reduced phosphorylation of Akt and forkhead box O3 (FOXO3a) in skeletal muscles. Inhibition of FOXO3a using siRNA in vitro in C2C12 myotube cells inhibited iron-induced upregulation of atrogin-1 and MuRF1 and reversed the reduction in myotube diameters. Iron-load caused oxidative stress, and an oxidative stress inhibitor abrogated iron-induced muscle atrophy by reactivating the Akt-FOXO3a pathway. Iron-induced skeletal muscle atrophy is suggested to involve the E3 ubiquitin ligase mediated by the reduction of Akt-FOXO3a signaling by oxidative stress., (Copyright © 2016 Elsevier GmbH. All rights reserved.)
- Published
- 2016
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36. Can food factors provide Us with the similar beneficial effects of physical exercise?
- Author
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Miyamoto L
- Abstract
Metabolic diseases have got global health issues. Physical exercise as well as diet therapy is a potent strategy for fighting against the diseases. However, it is often difficult to continue to keep exercise regularly enough to take sufficient effect. Thus, good substitutes for the therapeutic exercise would be greatly beneficial. Recent studies have suggested that 5'AMP-activated protein kinase (AMPK) play important roles in the metabolic alterations by muscle contraction. The notion that AMPK mediates broad effects of physical exercise has been widely accepted, though it has been challenged by observations in some genetically AMPK-disrupted animals. We have demonstrated metabolome-wide significance of AMPK activation in contracting muscles. Thus, pharmacological activation of AMPK can be a promising way to obtain similar effects of the exercise. The relevance of AMPK will be introduced, and possible strategies for obtaining similar effects to the exercise from food factors will be discussed in the current review.
- Published
- 2016
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37. Novel Strategies for Treating Lifestyle-related Diseases Using Various Approaches.
- Author
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Miyamoto L
- Subjects
- AMP-Activated Protein Kinases physiology, Diet Therapy, Drug Design, Drug Discovery, Exercise Therapy, Glycerol, Humans, Hydrophobic and Hydrophilic Interactions, Metabolic Syndrome prevention & control, Metabolome, Muscle Contraction, Muscle, Skeletal physiology, Polymers, Prodrugs, Life Style, Metabolic Syndrome etiology, Metabolic Syndrome therapy
- Abstract
The number of patients with metabolic disorders is dramatically increasing all over the world. The diseases often exhibit multiple metabolic disturbances including diabetes, hyperlipidemia, and obesity, and so on, recognized as a concept of metabolic syndrome. It is important to consider the common underlying pathophysiological bases of such metabolic diseases at the suggestion of the teachings of a parable, "The blind men and an elephant," whereby each blind man investigates a different part of the elephant. The lesson could even be applicable to each aspect of the disorders. Physical exercise as well as dietetics harbor versatile preventive and therapeutic potency against diverse metabolic diseases. Thus further investigation into molecular and physiological mechanisms underlying beneficial effects of therapeutic exercise and diet will provide us with significant clues to the elephant behind the disorders. Moreover, it could be of great benefit if such non-drug treatments, which may be hard to achieve for most patients, were replaced with medication. Recently, we demonstrated evidence that activators of 5'AMP-activated protein kinase (AMPK) could be satisfactory exercise mimetics in terms of metabolome. In this review, metabolomic analysis on the significant roles of AMPK in contracting skeletal muscles is described. In addition, our novel prodrug strategy providing extremely hydrophobic agents with marked hydrophilicity by conjugation with branched glycerol oligomers, which can be widely applicable in general to drug design for good pharmacokinetic properties in drug discovery, is introduced.
- Published
- 2016
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38. Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice.
- Author
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Tajima S, Ikeda Y, Enomoto H, Imao M, Horinouchi Y, Izawa-Ishizawa Y, Kihira Y, Miyamoto L, Ishizawa K, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Biomarkers blood, Bone Morphogenetic Protein 6 genetics, Bone Morphogenetic Protein 6 metabolism, CCAAT-Enhancer-Binding Proteins genetics, CCAAT-Enhancer-Binding Proteins metabolism, Cation Transport Proteins genetics, Cation Transport Proteins metabolism, Down-Regulation, Duodenum metabolism, Ferritins blood, Hepcidins genetics, Kidney drug effects, Kidney metabolism, Liver drug effects, Liver metabolism, Male, Mice, Mice, Inbred C57BL, RNA, Messenger genetics, RNA, Messenger metabolism, Spleen drug effects, Spleen metabolism, Transcription Factors genetics, Angiotensin II pharmacology, Duodenum drug effects, Hepcidins blood, Iron metabolism, Transcription Factors metabolism
- Abstract
Purpose: Angiotensin II (ANG II) has been shown to affect iron metabolism through alteration of iron transporters, leading to increased cellular and tissue iron contents. Serum ferritin, a marker of body iron storage, is elevated in various cardiovascular diseases, including hypertension. However, the associated changes in iron absorption and the mechanism underlying increased iron content in a hypertensive state remain unclear., Methods: The C57BL6/J mice were treated with ANG II to generate a model of hypertension. Mice were divided into three groups: (1) control, (2) ANG II-treated, and (3) ANG II-treated and ANG II receptor blocker (ARB)-administered (ANG II-ARB) groups., Results: Mice treated with ANG II showed increased serum ferritin levels compared to vehicle-treated control mice. In ANG II-treated mice, duodenal divalent metal transporter-1 and ferroportin (FPN) expression levels were increased and hepatic hepcidin mRNA expression and serum hepcidin concentration were reduced. The mRNA expression of bone morphogenetic protein 6 and CCAAT/enhancer-binding protein alpha, which are regulators of hepcidin, was also down-regulated in the livers of ANG II-treated mice. In terms of tissue iron content, macrophage iron content and renal iron content were increased by ANG II treatment, and these increases were associated with reduced expression of transferrin receptor 1 and FPN and increased expression of ferritin. These changes induced by ANG II treatment were ameliorated by the administration of an ARB., Conclusions: Angiotensin II (ANG II) altered the expression of duodenal iron transporters and reduced hepcidin levels, contributing to the alteration of body iron distribution.
- Published
- 2015
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39. Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia.
- Author
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Miyamoto L, Yagi Y, Hatano A, Kawazoe K, Ishizawa K, Minakuchi K, Tomita S, and Tsuchiya K
- Subjects
- Caco-2 Cells, Cell Proliferation, Cellular Reprogramming, Humans, Phosphorylation, Cell Hypoxia, Extracellular Signal-Regulated MAP Kinases physiology, MAP Kinase Signaling System physiology, Mitogen-Activated Protein Kinase Kinases physiology
- Abstract
Background: Oxygen is important for common eukaryotic cells to generate ATP. Pathophysiological conditions such as ischemic diseases cause tissue hypoxia. In addition, oxygen availability in deep tissues is supposed to be far lower than surrounding atmosphere even in healthy animals, and the oxygen partial pressures in most normal tissues are estimated to be around 40-50mmHg, so-called mild hypoxia. Recent studies have demonstrated that mild hypoxia has distinct effects on living cells from severe hypoxia. For instance, mild hypoxia was reported to promote cell reprogramming. Although severe hypoxia is known to inhibit cell proliferation, mild hypoxia has been paradoxically demonstrated to increase cell proliferation. However, it has not been clarified by which molecular mechanisms mild hypoxia evokes the discontinuous increment of cell proliferation., Methods: We established experimental conditions showing the opposite influences of mild and severe hypoxia on cell proliferation using undifferentiated Caco2 human colon carcinoma cells in order to clarify the underlying molecular mechanism., Results: The basal activity of Erk, which is a typical mediator of mitogenic signals, is spontaneously increased specifically in cells exposed to mild hypoxia, and inhibition of MEK, an upstream kinase of the Erk, completely inhibited the mild hypoxia-induced enhancement of cell proliferation., Conclusions: Spontaneous hyperactivation of the MEK-Erk pathway by mild hypoxia should be the plausible molecular mechanism of the paradoxical promotion of cell proliferation., General Significance: Our findings will provide clues to the molecular basis of mild hypoxia-evoked phenomena such as cell reprogramming., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
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40. A long-term high-fat diet changes iron distribution in the body, increasing iron accumulation specifically in the mouse spleen.
- Author
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Yamano N, Ikeda Y, Sakama M, Izawa-Ishizawa Y, Kihira Y, Ishizawa K, Miyamoto L, Tomita S, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Cation Transport Proteins genetics, Cation Transport Proteins metabolism, Diabetes Mellitus, Type 2 etiology, Dietary Fats adverse effects, Duodenum metabolism, Ferritins blood, Hemoglobins metabolism, Intestinal Absorption genetics, Male, Mice, Inbred C57BL, Obesity etiology, Obesity metabolism, Oxidative Stress, RNA, Messenger metabolism, Diabetes Mellitus, Type 2 metabolism, Diet, High-Fat adverse effects, Dietary Fats administration & dosage, Iron metabolism, Iron, Dietary metabolism, Spleen metabolism
- Abstract
Although iron is an essential trace metal, its presence in excess causes oxidative stress in the human body. Recent studies have indicated that iron storage is a risk factor for type 2 diabetes mellitus. Dietary iron restriction or iron chelation ameliorates symptoms of type 2 diabetes in mouse models. However, whether iron content in the body changes with the development of diabetes is unknown. Here, we investigated the dynamics of iron accumulation and changes in iron absorption-related genes in mice that developed obesity and diabetes by consuming a high-fat diet (HFD-fed mice). HFD-fed mice (18-20 wk) were compared with control mice for hematologic features, serum ferritin levels, and iron contents in the gastrocnemius muscle, heart, epididymal fat, testis, liver, duodenum, and spleen. In addition, the spleen was examined histologically. Iron absorption-related gene expression in the liver and duodenum was also examined. Hemoglobin and serum ferritin levels were increased in HFD-fed mice. The HFD-fed mice showed iron accumulation in the spleen, but not in the heart or liver. Increased percentages of the splenic red pulp and macrophages were observed in HFD-fed mice and iron accumulation in the spleen was found mainly in the splenic red pulp. The HFD-fed mice also showed decreased iron content in the duodenum. The mRNA expression of divalent metal transporter-1 (DMT-1), an iron absorption-related gene, was elevated in the duodenum of HFD-fed mice. These results indicate that iron accumulation (specifically accumulation in the spleen) is enhanced by the development of type 2 diabetes induced by HFD.
- Published
- 2015
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41. Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.
- Author
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Ikeda Y, Ozono I, Tajima S, Imao M, Horinouchi Y, Izawa-Ishizawa Y, Kihira Y, Miyamoto L, Ishizawa K, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Blotting, Western, Fibrosis, Immunohistochemistry, Kidney Diseases etiology, Mice, Signal Transduction drug effects, Transforming Growth Factor beta metabolism, Chelation Therapy methods, Deferoxamine pharmacology, Iron Chelating Agents pharmacology, Kidney Diseases pathology, Kidney Diseases prevention & control, Ureteral Obstruction complications
- Abstract
Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox) expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.
- Published
- 2014
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42. Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.
- Author
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Ishizawa K, Izawa-Ishizawa Y, Yamano N, Urushihara M, Sakurada T, Imanishi M, Fujii S, Nuno A, Miyamoto L, Kihira Y, Ikeda Y, Kagami S, Kobori H, Tsuchiya K, and Tamaki T
- Subjects
- Animals, Cell Line, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nifedipine therapeutic use, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III metabolism, Oxidative Stress drug effects, Antioxidants therapeutic use, Diabetic Nephropathies drug therapy, Diabetic Nephropathies metabolism, Nifedipine analogs & derivatives, Nitroso Compounds therapeutic use
- Abstract
Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.
- Published
- 2014
- Full Text
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43. AICAR stimulation metabolome widely mimics electrical contraction in isolated rat epitrochlearis muscle.
- Author
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Miyamoto L, Egawa T, Oshima R, Kurogi E, Tomida Y, Tsuchiya K, and Hayashi T
- Subjects
- AMP-Activated Protein Kinases metabolism, Aminoimidazole Carboxamide pharmacology, Animals, Cell Line, Electric Stimulation, Factor Analysis, Statistical, Glucose metabolism, Glutathione metabolism, Male, Metabolome, Muscle Contraction physiology, Muscle, Skeletal physiology, Principal Component Analysis, Random Allocation, Rats, Rats, Sprague-Dawley, Transcriptome, Aminoimidazole Carboxamide analogs & derivatives, Hypoglycemic Agents pharmacology, Muscle Contraction drug effects, Muscle, Skeletal drug effects, Ribonucleotides pharmacology
- Abstract
Physical exercise has potent therapeutic and preventive effects against metabolic disorders. A number of studies have suggested that 5'-AMP-activated protein kinase (AMPK) plays a pivotal role in regulating carbohydrate and lipid metabolism in contracting skeletal muscles, while several genetically manipulated animal models revealed the significance of AMPK-independent pathways. To elucidate significance of AMPK and AMPK-independent signals in contracting skeletal muscles, we conducted a metabolomic analysis that compared the metabolic effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR) stimulation with the electrical contraction ex vivo in isolated rat epitrochlearis muscles, in which both α1- and α2-isoforms of AMPK and glucose uptake were equally activated. The metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry detected 184 peaks and successfully annotated 132 small molecules. AICAR stimulation exhibited high similarity to the electrical contraction in overall metabolites. Principal component analysis (PCA) demonstrated that the major principal component characterized common effects whereas the minor principal component distinguished the difference. PCA and a factor analysis suggested a substantial change in redox status as a result of AMPK activation. We also found a decrease in reduced glutathione levels in both AICAR-stimulated and contracting muscles. The muscle contraction-evoked influences related to the metabolism of amino acids, in particular, aspartate, alanine, or lysine, are supposed to be independent of AMPK activation. Our results substantiate the significance of AMPK activation in contracting skeletal muscles and provide novel evidence that AICAR stimulation closely mimics the metabolomic changes in the contracting skeletal muscles.
- Published
- 2013
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44. A novel prodrug strategy for extremely hydrophobic agents: conjugation to symmetrically branched glycerol trimer improves pharmacological and pharmacokinetic properties of fenofibrate.
- Author
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Miyamoto L, Watanabe M, Taoka C, Kono M, Tomida Y, Matsushita T, Kamiya M, Hattori H, Ishizawa K, Abe S, Nemoto H, and Tsuchiya K
- Subjects
- Fenofibrate chemistry, Glycerol chemistry, Hydrophobic and Hydrophilic Interactions, Fenofibrate analogs & derivatives, Prodrugs chemistry
- Abstract
Management of a lipophilic-hydrophilic balance is a key element in drug design to achieve desirable pharmacokinetic characters. Therefore we have created unique modular molecules, symmetrically branched oligoglycerols (BGL), as an alternative way to endow hydrophobic molecules with sufficient hydrophilicity. We have successfully demonstrated amelioration of the water solubility and thermal stability of several hydrophobic agents by covalent conjugation to BGL so far. However, it has not been clarified whether the molecular modification by BGL also improves the pharmacological and/or pharmacokinetic properties indeed. Recently, we synthesized a novel BGL-prodrug derivative of fenofibrate, which is an antihyperlipidemic agent and one of the most hydrophobic medicinal compounds currently used clinically, by conjugating fenofibric acid to symmetrically branched glycerol trimer (BGL003), the simplest BGL. We have previously demonstrated that the hydrophilicity and water solubility of fenofibrate are improved more than 2000 times just by conjugation to the BGL003. To verify our hypothesis that the prodrug strategy with BGL should improve pharmacological efficacy and pharmacokinetic properties of extremely hydrophobic agents such as fenofibrate by the rise in hydrophilicity, we evaluated the BGL003-prodrug derivative of fenofibrate (FF-BGL) using rodent models. Here we demonstrate that the lipid-lowering effects of fenofibrate are much potentiated by chemical conjugation to BGL003 without exhibiting significant toxicity. Plasma concentration of fenofibric acid, an active metabolite of fenofibrate, after single oral administration of FF-BGL was more than 3 times higher than that of fenofibrate, in accordance. In fasting rats, plasma concentration of fenofibric acid after fenofibrate administration was curtailed into less than half of that in ad libitum-fed rats, while FF-BGL showed about the same plasma level even in the starving rats. This is the first report showing that BGL-prodrug improves pharmacological and pharmacokinetic properties as well as hydrophilicity of highly hydrophobic compounds. Furthermore, prodrug strategy using BGL suggests the possibility of diminishing the food-drug interaction effects, which should be advantageous for promoting drug compliance. BGL will be a suitable prodrug strategy to ameliorate physical, pharmacological, and pharmacokinetic characteristics of extremely hydrophobic compounds.
- Published
- 2013
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45. Leptin activates hepatic 5'-AMP-activated protein kinase through sympathetic nervous system and α1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin.
- Author
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Miyamoto L, Ebihara K, Kusakabe T, Aotani D, Yamamoto-Kataoka S, Sakai T, Aizawa-Abe M, Yamamoto Y, Fujikura J, Hayashi T, Hosoda K, and Nakao K
- Subjects
- AMP-Activated Protein Kinases genetics, Animals, Cells, Cultured, Fatty Liver drug therapy, Fatty Liver genetics, Fatty Liver metabolism, Female, Hepatocytes enzymology, Hepatocytes metabolism, Humans, Leptin therapeutic use, Lipodystrophy drug therapy, Lipodystrophy genetics, Lipodystrophy metabolism, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal enzymology, Muscle, Skeletal metabolism, Rats, Rats, Wistar, Receptors, Adrenergic, alpha-1 genetics, Sympathetic Nervous System metabolism, AMP-Activated Protein Kinases metabolism, Fatty Liver enzymology, Leptin metabolism, Lipodystrophy enzymology, Receptors, Adrenergic, alpha-1 metabolism, Sympathetic Nervous System enzymology
- Abstract
Background: AMPK activation promotes glucose and lipid metabolism., Results: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the α-adrenergic effect., Conclusion: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems., Significance: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin. Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin-resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5'-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and α-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down-regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin.
- Published
- 2012
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46. Synthesis of highly water-soluble fibrate derivatives via BGLation.
- Author
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Nemoto H, Kamiya M, Nakamoto A, Matsushita T, Matsumura K, Hattori H, Kawamura T, Taoka C, Abe S, Ishizawa K, Miyamoto L, and Tsuchiya K
- Subjects
- Animals, Bezafibrate blood, Bezafibrate chemical synthesis, Bezafibrate pharmacology, Clofibrate blood, Clofibrate chemical synthesis, Clofibrate pharmacology, Fenofibrate blood, Fenofibrate chemical synthesis, Fenofibrate pharmacology, Hypolipidemic Agents blood, Hypolipidemic Agents chemical synthesis, Hypolipidemic Agents pharmacology, Male, Rats, Rats, Sprague-Dawley, Solubility, Triglycerides blood, Water chemistry, Bezafibrate chemistry, Clofibrate chemistry, Fenofibrate chemistry, Hypolipidemic Agents chemistry
- Abstract
Three water-soluble fibrates (fenofibrate, bezafibrate and chlofibrate) conjugated with a symmetrically branched glyceryl trimer (BGL003) were synthesized, and an evaluation of the fenofibrate-BGL003 conjugate as a candidate for anti-hyperlipemia drug was carried out using rats. The water-solubility of the fenofibrate-BGL003 conjugate was several thousand times greater than that of the original fenofibrate. The lipid-lowering effects of the fenofibrate-BGL003 conjugate were as strong as those of the same grams of fenofibrate. The actual active species of fenofibrate, fenofibric acid, was detected in rats' blood, but neither the fenofibrate-BGL003 conjugate nor fenofibrate was detected, probably due to enzymatic hydrolysis of the ester bond. The plasma concentration of fenofibric acid derived from the fenofibrate-BGL003 conjugate was five times higher than that derived from fenofibrate 4h after administration., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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47. Synthesis of paclitaxel-BGL conjugates.
- Author
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Nemoto H, Katagiri A, Kamiya M, Kawamura T, Matsushita T, Matsumura K, Itou T, Hattori H, Tamaki M, Ishizawa K, Miyamoto L, Abe S, and Tsuchiya K
- Subjects
- Animals, Antineoplastic Agents, Phytogenic chemistry, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Conformation, Molecular Weight, Solubility, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents, Phytogenic chemical synthesis, Antineoplastic Agents, Phytogenic pharmacology, Glycerol chemistry, Glycerol pharmacology, Neoplasms, Experimental drug therapy, Paclitaxel chemistry, Paclitaxel pharmacology
- Abstract
Four kinds of symmetrically branched oligoglyceryl trimeric (BGL003)-paclitaxel conjugates and a corresponding heptameric (BGL007) conjugate were synthesized. Molecular weights of all the compounds were less than two times that of paclitaxel. The anti-tumor activity of the most water-soluble BGL003 conjugate was examined and found to be preserved in spite of the chemical modification that is displacement of the N3'-debenzoyl residue with the BGL003 succinyl residue., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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48. Development of a reduction-responsive amino acid that induces peptide bond cleavage in hypoxic cells.
- Author
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Shigenaga A, Ogura K, Hirakawa H, Yamamoto J, Ebisuno K, Miyamoto L, Ishizawa K, Tsuchiya K, and Otaka A
- Subjects
- Amides chemistry, Cell Hypoxia physiology, Fluorescence Resonance Energy Transfer, Molecular Structure, Oxidation-Reduction, Peptides chemistry, Prodrugs metabolism, Amino Acids chemistry, Peptides chemical synthesis, Prodrugs chemistry
- Abstract
Hypoxia-responsive amino acids are indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. In this paper, the design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
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49. Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice.
- Author
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Kusakabe T, Ebihara K, Sakai T, Miyamoto L, Aotani D, Yamamoto Y, Yamamoto-Kataoka S, Aizawa-Abe M, Fujikura J, Hosoda K, and Nakao K
- Subjects
- Animals, Anti-Obesity Agents administration & dosage, Delayed-Action Preparations administration & dosage, Delayed-Action Preparations therapeutic use, Diabetes Mellitus, Type 2 etiology, Diet, High-Fat adverse effects, Drug Resistance, Drug Therapy, Combination, Energy Intake drug effects, Energy Metabolism drug effects, Hypoglycemic Agents administration & dosage, Insulin blood, Islet Amyloid Polypeptide administration & dosage, Leptin administration & dosage, Liver drug effects, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Obesity etiology, Obesity metabolism, Obesity physiopathology, Triglycerides metabolism, Weight Loss drug effects, Anti-Obesity Agents therapeutic use, Diabetes Mellitus, Type 2 prevention & control, Hypoglycemic Agents therapeutic use, Insulin Resistance, Islet Amyloid Polypeptide therapeutic use, Leptin therapeutic use, Obesity drug therapy
- Abstract
Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg⁻¹·day⁻¹), amylin (A; 100 μg·kg⁻¹·day⁻¹), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.
- Published
- 2012
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50. Angiotensin II receptor blocker improves tumor necrosis factor-α-induced cytotoxicity via antioxidative effect in human glomerular endothelial cells.
- Author
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Izawa-Ishizawa Y, Ishizawa K, Sakurada T, Imanishi M, Miyamoto L, Fujii S, Taira H, Kihira Y, Ikeda Y, Hamano S, Tomita S, Tsuchiya K, and Tamaki T
- Subjects
- Cell Survival drug effects, Cells, Cultured, Endothelial Cells metabolism, Humans, Intercellular Adhesion Molecule-1 metabolism, Kidney Glomerulus cytology, Reactive Oxygen Species metabolism, Angiotensin II Type 1 Receptor Blockers pharmacology, Apoptosis drug effects, Endothelial Cells drug effects, Imidazoles pharmacology, Tetrazoles pharmacology, Tumor Necrosis Factor-alpha
- Abstract
Background/aims: Tumor necrosis factor-α (TNF-α) is known to involve the progression of renal dysfunction through its cytotoxicity and proinflammatory effects such as the induction of intercellular adhesion molecule (ICAM)-1 expression in vascular endothelial cells (ECs). Olmesartan, one of the angiotensin II type 1 receptor blockers (ARBs), has been reported to show protective effects on injured ECs by some causal factors of renal disorder other than angiotensin II. However, the effects of olmesartan on TNF-α-induced glomerular EC damage have not been investigated. In the present study, we investigated the effects of RNH-6270, an active metabolite of olmesartan, on TNF-α-induced human glomerular EC (HGEC) damage to clarify the renoprotective mechanisms of ARBs., Methods: Cultured HGECs were stimulated by TNF-α, and then cell viability and cytotoxicity were measured by MTT assay and lactate dehydrogenase release assay, respectively. TNF-α-induced oxidative stress was estimated by dihydroethidium assay and lucigenin chemiluminescence assay. ICAM-1 expression and the phosphorylations of mitogen-activated protein kinases were measured using Western blotting assay., Results: RNH-6270 suppressed cell death and the increase in ICAM-1 expression induced by TNF-α via the inhibition of reactive oxygen species in HGECs., Conclusion: Our findings suggested that olmesartan might have protective effects against TNF-α-induced glomerular EC dysfunction., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2012
- Full Text
- View/download PDF
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