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Articles by T Wada
Total Records ( 5 ) for T Wada
  T Wada , S Hori , M Sugiyama , E Fujisawa , T Nakano , H Tsuneki , K Nagira , S Saito and T. Sasaoka
 

Maternal insulin resistance is essential for efficient provision of glucose to the fetus. Although elevation of placental hormones is known to relate to the development of insulin resistance, the precise underlying mechanism of maternal insulin resistance is unknown. Therefore, we examined the molecular mechanisms of progesterone causing insulin resistance in 3T3-L1 adipocytes. Progesterone at 10–4 M, but not 10–5 M, reduced the amount of IRS-1. As a result, insulin-induced phosphorylation of IRS-1, the association of IRS-1 with p85, and subsequent phosphorylation of Akt1 and -2 was decreased moderately by 10–4 M progesterone. Subsequently, insulin-induced translocation of GLUT4 to the plasma membrane evaluated by immunostaining on the plasma membrane sheet by confocal laser microscope was also decreased by 10–4 M progesterone. In contrast, 2-[3H]deoxyglucose (2DG) uptake was markedly inhibited by both 10–5 and 10–4 M progesterone in a dose-dependent manner. Surprisingly, 2DG uptake elicited by adenovirus-mediated expression of constitutive-active mutant of PI 3-kinase (myr-p110) and Akt (myr-Akt) was suppressed by progesterone. Interestingly, insulin-induced tyrosine phosphorylation of Cbl and activation of TC10 were inhibited by progesterone at 10–5 M. These results indicate that progesterone is implicated in insulin resistance during pregnancy by inhibiting the PI 3-kinase pathway at the step of 1) IRS-1 expression and 2) distal to Akt and 3) by suppressing the PI 3-kinase-independent pathway of TC10 activation by affecting Cbl phosphorylation.

  T Torii , K Kanemitsu , T Wada , S Itoh , K Kinugawa and A. Hagiwara
  Background

Short-chain fatty acids such as lactic acid produced by the intestinal bacterial flora have various physiological actions involved in health, and it is important to determine the concentrations of faecal short-chain fatty acids and evaluate their relationship with large intestinal diseases. In this study, we evaluated the highly selective and sensitive simultaneous measurement of both volatile and non-volatile short-chain fatty acid hydrazides using high-performance liquid chromatography (HPLC).

Materials and methods

Faeces treated with ethanol were used as analytic samples. Short-chain fatty acids were measured as fatty acid hydrazides by HPLC.

Results

For 12 types of short-chain fatty acid, the results regarding linearity, recovery tests and reproducibility were favourable. Faeces treated with ethanol could be stored at room temperature.

Discussion

The stability of short-chain fatty acids in faeces at room temperature was statistically analysed. Faeces stored without treatment with ethanol showed increases/decreases in the concentrations of short-chain fatty acids, which may be due to assimilation by intestinal bacteria. However, specimen in 70% ethanol and stored in room temperature exhibited no substantial changes in concentrations of short-chain fatty acids up to seven days.

  Y Kodama , M Takita , S Kawagoe , S Hirahara , Y Kimura , S Onozawa , T Wada , K Nakano , M Kami , T Matsumura and K. Yuji
  Objective

There is a lack of sufficient information on the employment of home care for the treatment of hematologic malignancies.

Methods

We provided home care to 580 patients from 1 January through 31 October 2007. Patients with hematologic malignancies were selected from these 580 patients; subsequently, by reviewing their medical records.

Results

The main clinical condition in 15 (2.6%) of 580 patients was hematologic malignancies. The median age of the patients was 78 years (range, 64–92). Of the 15 patients, 12 showed a performance status (PS) of 3–4, and the condition of 6 patients was complicated with dementia. Food intake via the oral route was possible in 14 patients. These patients were administered palliative care. Among the seven patients who required pain control, four had been opioid users; however, none had used anticancer drugs for pain relief. Furthermore, three patients received blood transfusion. Although three patients developed severe complications (acute appendicitis, pneumonia and hyperglycemia), we were able to treat all cases adequately. Eight patients died at home due to aggravation of the primary diseases. The remaining seven patients were transferred to other hospitals for the treatment of complications or for the convenience of their respective families.

Conclusions

Even patients with hematologic malignancies could be candidates for home care if their underlying diseases are slowly progressive, and they can sustain themselves by oral intakes. Dementia and poor PS are not contraindicated to it.

  L Jin , D Martynowski , S Zheng , T Wada , W Xie and Y. Li
 

The retinoic acid-related orphan receptor (ROR) has important roles in development and metabolic homeostasis. Although the biological functions of ROR have been studied extensively, no ligands for ROR have been identified, and no structure of ROR has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by ROR using biochemical assays. We also report the crystal structures of the ROR ligand-binding domain bound with hydroxycholesterols. The structures reveal the binding modes of various hydroxycholesterols in the ROR pocket, with the receptors all adopting the canonical active conformation. Mutations that disrupt the binding of hydroxycholesterols abolish the constitutive activity of ROR. Our observations suggest an important role for the endogenous hydroxycholesterols in modulating ROR-dependent biological processes.

  Y Soeda , H Tsuneki , H Muranaka , N Mori , S Hosoh , Y Ichihara , S Kagawa , X Wang , N Toyooka , Y Takamura , T Uwano , H Nishijo , T Wada and T. Sasaoka
 

Impairment of insulin and IGF-I signaling in the brain is one of the causes of dementia associated with diabetes mellitus and Alzheimer’s disease. However, the precise pathological processes are largely unknown. In the present study, we found that SH2-containing inositol 5'-phosphatase 2 (SHIP2), a negative regulator of phosphatidylinositol 3,4,5-trisphosphate-mediated signals, is widely expressed in adult mouse brain. When a dominant-negative mutant of SHIP2 was expressed in cultured neurons, insulin signaling was augmented, indicating physiological significance of endogenous SHIP2 in neurons. Interestingly, SHIP2 mRNA and protein expression levels were significantly increased in the brain of type 2 diabetic db/db mice. To investigate the impact of increased expression of SHIP2 in the brain, we further employed transgenic mice overexpressing SHIP2 and found that increased amounts of SHIP2 induced the disruption of insulin/IGF-I signaling through Akt. Neuroprotective effects of insulin and IGF-I were significantly attenuated in cultured cerebellar granule neurons from SHIP2 transgenic mice. Consistently, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay demonstrated that the number of apoptosis-positive cells was increased in cerebral cortex of the transgenic mice at an elderly age. Furthermore, SHIP2 transgenic mice exhibited impaired memory performance in the Morris water maze, step-through passive avoidance, and novel-object-recognition tests. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that SHIP2 is a potent negative regulator of insulin/IGF-I actions in the brain, and excess amounts of SHIP2 may be related, at least in part, to brain dysfunction in insulin resistance with type 2 diabetes.

 
 
 
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