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Articles by M Ito
Total Records ( 13 ) for M Ito
  D. S De Silva , R. M Wilson , C Hutchinson , P. C Ip , A. G Garcia , S Lancel , M Ito , D. R Pimentel and F. Sam

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 µM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 µM)—a selective inhibitor of c-Jun NH2-terminal kinase (JNK)—inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 µM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg·kg body wt–1·day–1) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR) ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.

  S Tada , A Kitanaka , Y Kubota , M Ito and T. Taminato

We have previously reported an ultrasensitive fluorometric assay for measuring cellular cholesterol. Although this technique is reliable, the use of the assay has limitations due to the requirement for special equipment. It is therefore difficult to apply this assay for the routine determination of cellular cholesterol.


A colorimetric assay to measure cellular cholesterol was established that utilizes reagents widely used for the measurement of cholesterol in blood samples in conjunction with a random access chemistry analyser ARCHITECT c8000 that is also common in clinical laboratories.


This colorimetric assay showed excellent linearity and recovery. The within-run coefficients of variation were less than 2.5%. The sensitivity of this method, with its detection limit of 1.29 µmol/L, was found to be superior to that of the fluorometric assay we have developed previously. In platelets obtained from patients with diabetes, both the free cholesterol and cholesterol ester content were significantly increased.


Using this technique, measurement of cellular cholesterol could be performed routinely without the requirement for special reagents and equipment.

  K Kawaguchi , H Murakami , T Taniguchi , M Fujii , S Kawata , T Fukui , Y Kondo , H Osada , N Usami , K Yokoi , Y Ueda , Y Yatabe , M Ito , Y Horio , T Hida and Y. Sekido

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although expression and activation of receptor tyrosine kinases (RTKs), including MET, have been reported in most MPM, specific RTK inhibitors showed less than the expected response in MPM cells. To determine whether the lack of response of MET inhibitors was due to cooperation with other RTKs, we determined activation status of MET and other RTKs, including epidermal growth factor receptor (EGFR) family of 20 MPM cell lines, and tested whether dual RTK inhibition is an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%) cell lines, but treatment with MET-specific inhibitors showed weak or modest effect of suppression in most of the cell lines. Phospho-RTK array analysis revealed that MET was simultaneously activated with other RTKs, including EGFR, ErbB2, ErbB3 and platelet-derived growth factor receptor-β. Combination of MET and EGFR inhibitors triggered stronger inhibition on cell proliferation and invasion of MPM cells than that of each in vitro. These results indicated that coactivation of RTKs was essential in mesothelioma cell proliferation and/or survival, thus suggesting that simultaneous inhibition of RTKs may be a more effective strategy for the development of molecular target therapy for MPM.

  G. O Osoata , T Hanazawa , C Brindicci , M Ito , P. J Barnes , S Kharitonov and K. Ito

Peroxynitrite (PN) formed by the reaction of nitric oxide and superoxide is a powerful oxidant/nitrosant. Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (< 1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release.


PN was measured using oxidation of 2',7'-dichlorofluorescein (DCDHF) in exhaled breath condensate (EBC) collected in high pH and sputum cells. The PN scavenging effect was also evaluated by the same system as PN-induced bovine serum albumin (BSA) nitration.


The mean (± SD) PN levels in EBC of COPD patients (7.9 ± 3.0 nmol/L; n = 10) were significantly higher than those of healthy volunteers (2.0 ± 1.1 nmol/L; p < 0.0001; n = 8) and smokers (2.8 ± 0.9 nmol/L; p = 0.0017; n = 6). There was a good correlation between PN level and disease severity (FEV1) in COPD (p = 0.0016). Fudosteine (FDS), a unique mucolytic antioxidant, showed a stronger scavenging effect of PN than N-acetyl-cysteine on DCDHF oxidation in vitro and in sputum macrophages, and also on PN-induced BSA nitration. FDS (0.1 mmol/L) reduced PN-enhanced interleukin (IL)-1β-induced IL-8 release and restored corticosteroid sensitivity defected by PN more potently than those induced by H2O2 in A549 airway epithelial cells.


This noninvasive PN measurement in EBC may be useful for monitoring airway nitrative stress in COPD. Furthermore, FDS has the potential to inhibit PN-induced events in lung by its scavenging effect.

  H Uto Kondo , M Ayaori , M Ogura , K Nakaya , M Ito , A Suzuki , S. i Takiguchi , E Yakushiji , Y Terao , H Ozasa , T Hisada , M Sasaki , F Ohsuzu and K. Ikewaki

Rationale: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL).

Objective: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo.

Methods and Results: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting [3H]cholesterol-labeled acetyl low-density lipoprotein-loaded RAW264.7 cells into mice, then monitoring appearance of 3H tracer in plasma, liver, and feces. Supporting in vitro and ex vivo data, ferulic acid was found to significantly increase the levels of 3H tracer in feces.

Conclusions: Coffee intake might have an antiatherogenic property by increasing ABCG1 and SR-BI expression and enhancing HDL-mediated cholesterol efflux from the macrophages via its plasma phenolic acids.

  H Itoh , T Sakaguchi , W. G Ding , E Watanabe , I Watanabe , Y Nishio , T Makiyama , S Ohno , M Akao , Y Higashi , N Zenda , T Kubota , C Mori , K Okajima , T Haruna , A Miyamoto , M Kawamura , K Ishida , I Nagaoka , Y Oka , Y Nakazawa , T Yao , H Jo , Y Sugimoto , T Ashihara , H Hayashi , M Ito , K Imoto , H Matsuura and M. Horie

Background— Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.

Methods and Results— Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.

Conclusions— dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

  Y Tani , T Funatsu , H Ashida , M Ito , S Itonori , M Sugita and K. Yamamoto

Hirsutella rhossiliensis, a nematophagous fungus belonging to the Ascomycota, is resistant to aureobasidin A (AbA). In this fungus, the biosynthetic pathway leading to mannosylinositolphosphoceramides, which is inhibited by AbA, was not detected. Instead, this fungus contains neutral complex glycosphingolipids (GSLs) and monoglycosylceramides. Except for monoglycosylceramides, neutral GSLs share a neogala-series core structure, Galβ1–6Galβ1-Cer. Among the GSLs of H. rhossiliensis, three novel GSLs with terminal Man and Glc residues on the sugar chain were elucidated. We analyzed GSL structure using compositional sugar, fatty acid, and sphingoid analyses, methylation analysis, matrix-assisted laser desorption ionization time-of-flight/mass spectrometry (MALDI-TOF MS), and 1H nuclear magnetic resonance spectroscopy (NMR). The following structures were determined: Man1–3Galβ1–6Galβ1–6Galβ1-Cer; Glc1–2Galβ1–6Galβ1–6Galβ1-Cer; and Man1–3Galβ1–6(Glc1–4)Galβ1–6Galβ1-Cer. In the ceramides, the fatty acids were predominantly saturated h24:0-acids and the sphingoids were predominately t18:0- or t18:1-sphingoids. In contrast, the ceramides of Glcβ1-Cer contained d18:2- and d19:2-sphingoids. These findings indicate the presence of a novel biosynthetic pathway of neogala-series GSLs in fungi.

  Y Watanabe , T Takahashi , A Okajima , M Shiokawa , N Ishii , I Katano , R Ito , M Ito , M Minegishi , N Minegishi , S Tsuchiya and K. Sugamura

‘Humanized mice’ are anticipated to be a valuable tool for studying the human immune system, but the reconstituted human immune cells have not yet been well characterized. Here, we extensively investigated the differentiation and functions of human B and T cells in a supra-immunodeficient mouse strain, NOD/shi-scid/cnull (NOG) reconstituted with CD34+ hematopoietic stem cells obtained from umbilical cord blood. In these hu-HSC NOG mice, the development of human B cells was partially blocked, and a significant number of B-cell progenitors accumulated in the spleen. The mature CD19+IgM+IgD+ human B cells of the hu-HSC NOG mice could produce IgG in vivo and in vitro by antigenic stimulation. In contrast, although human T cells with an apparently normal phenotype developed, most of them could neither proliferate nor produce IL-2 in response to antigenic stimulation by anti-CD3 and anti-CD28 antibodies in vitro. The positive selection of human T cells in the thymus was sufficiently functional, if not complete, and mainly mediated by mouse class II, suggesting that the human T cells lost their function in the periphery. We found that multiple mechanisms were involved in the T-cell abnormalities. Collectively, our results demonstrate that further improvements are necessary before humanized mice with a functional human immune system are achieved.

  M Ito , K Miyado , K Nakagawa , M Muraki , M Imai , N Yamakawa , J Qin , Y Hosoi , H Saito and Y. Takahashi

p38 MAPK (p38) plays pivotal roles in aging and reproductive physiology. Nevertheless, involvement of p38 in female reproductive aging is uncertain. To improve knowledge of the role of p38 in age-associated reproductive failure, the expression and subcellular localization of phosphorylated p38 was investigated in human granulosa cells. p38 was 7-fold more activated in cells from older subjects than in those from younger subjects. Similar results were obtained in human granulosa-like KGN cells treated with hydrogen peroxide (H2O2). Interestingly, phosphorylated p38 was detected in the nucleus less frequently in older cells than in younger cells (Younger: 58.6%; Older: 29.8%, P< 0.01). Similarly cytoplasmic localization of phosphorylated p38 in KGN cells was observed after treatment with H2O2. The activation and cytoplasmic localization of p38 in H2O2-treated KGN cells were blocked by N-acetylcysteine and SB203580. Although the p38 activators, FSH and tumor necrosis factor-, induced a similar localization of phosphorylated p38 in KGN cells, the expression and localization patterns of p38 were distinct from those in older granulosa cells and H2O2-treated KGN cells. These results indicate that the characteristic localization of p38 in older granulosa cells is induced by oxidative stress.

  N Adachi , N Akanuma , M Ito , M Kato , T Hara , Y Oana , M Matsuura , Y Okubo and T. Onuma


Age at the first psychotic episode and an interval between the onset of epilepsy and that of psychosis reflect developmental processes of interictal psychosis. However, factors relating to these indices remain unknown.


To identify clinical variables that are associated with the timing of the development of interictal psychosis.


In 285 adults with epilepsy with interictal psychosis, effects of epileptic (epilepsy type), organic (intellectual functioning) and genetic (family history of psychosis) variables on timing of the development of psychosis were examined.


The mean interval between the onset of epilepsy and that of psychosis was 14.4 years. Some psychosis occurred within a few years of the first seizure. Generalised epilepsy, normal intellectual function and a positive family history of psychosis were associated with early onset of psychosis.


Early development of interictal psychosis in people with epilepsy may reflect other individual vulnerabilities to psychosis rather than epilepsy-related damage.

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