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Articles by M. Mori
Total Records ( 5 ) for M. Mori
  M. Negishi , K. Shimomura , P. Proks , M. Mori and Y. Shimomura
  Background  Disopyramide, an antiarrhythmia drug, has been reported to cause hypoglycaemia. Pre-existing factors that increase the concentration of the drug in the blood increase the risk of hypoglycaemia. Furthermore, other factors can also increase the risk of hypoglycaemia even when disopyramide levels are in the therapeutic range. It has been proposed that disopyramide-induced hypoglycaemia is caused by inhibition of the pancreatic B-cell KATP channels.

Case report  We report a case of severe disopyramide-induced hypoglycaemia in a 62-year-old woman with Type 2 diabetes taking low-dose glimepiride treatment. She had not experienced hypoglycaemia prior to the start of disopyramide therapy. No further hypoglycaemic episodes occurred following withdrawal of disopyramide therapy.

Functional study  Current recordings of KATP channels expressed in Xenopus oocytes showed that at their estimated therapeutic concentrations, disopyramide and glimepiride inhibited KATP channels by about 50-60%. However, when both drugs were applied together, KATP channels were almost completely closed (~95%). Such dramatic inhibition of KATP channels is sufficient to cause B-cell membrane depolarization and stimulate insulin secretion.

Conclusions  Disopyramide therapy is not recommended for patients treated with KATP channel inhibitors.

  T. Ando , S. Okada , Y. Niijima , K. Hashimoto , H. Shimizu , T. Tsuchiya , M. Yamada , K. Ohshima , M. Mori and K. Ono
  Aims  The study aimed to investigate early-stage atherosclerosis in patients with impaired fasting glucose compared with patients with impaired glucose tolerance.

Methods  Body mass index, systolic blood pressure, fasting plasma glucose, lipid variables, ankle-brachial pressure index and brachial-ankle pulse wave velocity were measured in 2842 subjects from Takasaki city located approximately 100 km north of Tokyo in Japan. The subjects were divided into the following five groups based on a 75-g oral glucose tolerance test: (i) normal fasting plasma glucose/normal glucose tolerance group, (ii) impaired fasting glucose group, (iii) impaired glucose tolerance group, (iv) combined glucose intolerance group and (v) diabetic glucose intolerance group.

Results  In comparison with fasting plasma glucose levels (r = 0.269, P < 0.0001), 2-h post-challenge glucose levels were more closely correlated with pulse wave velocity values (r = 0.300, P < 0.0001). The groups with impaired glucose tolerance, combined glucose intolerance and diabetic glucose intolerance had significantly higher pulse wave velocity values compared with the groups with normal glucose tolerance and impaired fasting glucose. Multiple regression analyses showed an independent association of age, systolic blood pressures, total cholesterol, fasting and 2h plasma glucose with pulsewave velocityvalues. Furthermore, pulse wave velocity was not significantly correlated with fasting plasma glucose, but was correlated with increased 2h plasma glucose.

Conclusions  Groups with impaired glucose tolerance and combined glucose intolerance had significantly higher brachio-ankle pulse wave velocity values compared with the group with normal glucose tolerance. Although the group with impaired fasting glucose showed a marginal increase in pulse wave velocity values compared with the group with normal glucose tolerance, the difference was not significant. Thus impaired glucose tolerance, but not impaired fasting glucose, is a risk factor for early-stage atherosclerosis.

  T Satoh , T Ishizuka , T Tomaru , S Yoshino , Y Nakajima , K Hashimoto , N Shibusawa , T Monden , M Yamada and M. Mori

The 26S proteasome, which degrades ubiquitinated proteins, appears to contribute to the cyclical loading of androgen receptor (AR) to androgen response elements of target gene promoters; however, the mechanism whereby the 26S proteasome modulates AR recruitment remains unknown. Using yeast two-hybrid screening, we previously identified Tat-binding protein-1 (TBP-1), an adenosine triphosphatase of 19S regulatory particles of the 26S proteasome, as a transcriptional coactivator of thyroid hormone receptor. Independently, TBP-1-interacting protein (TBPIP) was also identified as a coactivator of several nuclear receptors, including AR. Here, we investigated whether TBP-1 could interact with and modulate transcriptional activation by AR cooperatively with TBPIP. TBP-1 mRNA was ubiquitously expressed in human tissues, including the testis and prostate, as well as in LNCaP cells. TBP-1 directly bound TBPIP through the amino-terminal domain possessing the leucine zipper structure. AR is physically associated with TBP-1 and TBPIP in vitro and in LNCaP cells. TBP-1 similarly and additively augmented AR-mediated transcription upon coexpression with TBPIP, and the ATPase domain, as well as leucine zipper structure in TBP-1, was essential for transcriptional enhancement. Overexpression of TBP-1 did not alter AR protein and mRNA levels. In the chromatin immunoprecipitation assay, TBP-1 was transiently recruited to the proximal androgen response element of the prostate-specific antigen gene promoter in a ligand-dependent manner in LNCaP cells. These findings suggest that a component of 19S regulatory particles directly binds AR and might participate in AR-mediated transcriptional activation in cooperation with TBPIP.

  K Hashimoto , E Ishida , S Matsumoto , S Okada , M Yamada , T Satoh , T Monden and M. Mori

The molecular mechanism of thyroid hormone (TH) effects to fatty acid metabolism in liver is yet to be clear. The carbohydrate response element-binding protein (ChREBP) as well as sterol response element-binding protein (SREBP)-1c plays a pivotal role in hepatic lipogenesis. Both SREBP-1c and ChREBP are target genes of liver X receptors (LXRs). Because LXRs and TH receptors (TRs) cross talk mutually in many aspects of transcription, we examined whether TRs regulate the mouse ChREBP gene expression. In the current study, we demonstrated that TH up-regulated mouse ChREBP mRNA and protein expression in liver. Run-on and luciferase assays showed that TH and TR-β1 positively regulated the ChREBP gene transcription. The mouse ChREBP gene promoter contains two direct repeat-4 sites (LXRE1 and LXRE2) and EMSAs demonstrated that LXR- and TR-β1 prefer to bind LXRE1 and LXRE2, respectively. The direct repeat-4 deletion and LXRE2 mutants of the promoter deteriorate the positive regulation by TR-β1, indicating that LXRE2 is functionally important for the regulation. We also showed that human ChREBP gene expression and promoter activities were up-regulated by TH. These data suggest that ChREBP mRNA expression is positively regulated by TR-β1 and TH at the transcriptional level in mammals. This novel observation indicates that TH fine-tunes hepatic lipogenesis via regulating SREBP-1c and ChREBP gene expression reciprocally.

  R Umezawa , M Yamada , K Horiguchi , S Ishii , K Hashimoto , S Okada , T Satoh and M. Mori

We reported a novel mutation of thyroid hormone receptor (TR)-β, F455S, in a patient with pituitary resistance to thyroid hormone (RTH), who showed impaired release of nuclear receptor corepressor and abnormal histone deacetylation. In the present study, we further analyzed the histone modifications and the dynamics of TR and RNA polymerase II on the TRH gene. The lysine residues 9 (H3K9) and 14 (K14) of the histone H3 were acetylated in the absence of thyroid hormone (TH), and addition of TH caused a temporary deacetylation of both residues. Although H3K4 was di- and trimethylated in the absence of T3, no methylation of H3K9 or K27 was detected. Long-term incubation with T3 decreased the level of trimethylated H3K4, the amount of TR, and the level of phosphorylated RNA polymerase II but not dimethylated H3K4. Treatment with an inhibitor for H3K4 methyltransferase, 5'-deoxy-5'-methylthioadenosine, decreased basal promoter activity but did not affect the repression by TH. Conversely, overexpression of MLL, an H3K4-specific methyltransferase, caused an increase in basal activity. In the presence of F455S, methylation of H3K4 and the dynamics of TR were intact, but both H3K9 and H3K14 were hyperacetylated, and T3-induced deacetylation was impaired, resulting in a high transcriptional level. These findings demonstrated that 1) negative regulation of the TRH gene by TH involves both the acetylation and methylation of specific residues of histone tails and changing the amount of TR, and 2) the major impairment to histone modifications in F455S was hyperacetylation of the specific histone tails.

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