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Articles by H Sato
Total Records ( 5 ) for H Sato
  T Masamune , H Sato , K Okuyama , Y Imai , H Iwashita , T Ishiyama , T Oguchi , D. I Sessler and T. Matsukawa

BACKGROUND: JM-1232(–) is a novel isoindoline derivative which shows sedative and hypnotic activities through the benzodiazepine site of -aminobutyric acid type A (GABAA) receptors. Typical doses of midazolam, another GABAA receptor agonist, slightly reduce the shivering threshold in humans. We thus determined the extent to which JM-1232(–) decreases the shivering threshold.

METHODS: Eighteen rabbits, lightly anesthetized with isoflurane 0.2 minimum alveolar anesthetic concentration (MAC), were randomly assigned to infusions of 1) saline (control), 2) 0.01 mg · kg–1 · min–1 JM-1232(–), or 3) 0.1 mg · kg–1 · min–1 JM-1232(–). Body temperature was reduced at a rate of 2-3°C/h by perfusing water at 10°C though a U-shaped plastic tube positioned in the colon. Cooling continued until shivering was observed by an investigator blinded to treatment, or until core temperature reached 34°C. Core temperatures were recorded from the distal esophagus, and core temperature at the onset of shivering defined the threshold. Data were analyzed by one-way analysis of variance with Student-Newman-Keuls tests. Results are presented as means ± sd; P < 0.05 was considered statistically significant.

RESULTS: The rabbits given a saline infusion shivered at 36.5 ± 0.3°C. Five of the six rabbits given JM-1232(–) at a rate of 0.01 mg · kg–1 · min–1 shivered at 35.7 ± 0.8°C, and one of these rabbits failed to shiver at 34.0°C. None of the rabbits given JM-1232(–) at a rate of 0.1 mg · kg–1 · min–1 shivered before reaching the 34.0°C cutoff temperature.

CONCLUSION: A low dose of JM-1232(–) reduced the shivering threshold in rabbits approximately 0.8°C which is similar to the effects in humans given premedication doses of midazolam. In contrast, a 10-fold larger dose reduced the threshold more than 2.5°C. This is a substantial decrement and might facilitate induction of therapeutic hypothermia.

  T Shimizu , T Tanaka , T Iso , H Doi , H Sato , K Kawai Kowase , M Arai and M. Kurabayashi

Objective— Vascular calcification is closely correlated with cardiovascular morbidity and mortality. Here, we demonstrate the role of Notch signaling in osteogenic differentiation and mineralization of vascular smooth muscle cells (SMCs).

Methods and Results— The Msx2 gene, a key regulator of osteogenesis, was highly induced by coculture with Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) in human aortic SMCs (HASMCs). Furthermore, the Notch1 intracellular domain (N1-ICD) overexpression markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2 mediated N1-ICD–induced osteogenic conversion of HASMCs. Interestingly, Msx2 induction by N1-ICD was independent of bone morphogenetic protein–2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by N1-ICD overexpression. The RBP-Jk binding element within the Msx2 promoter was critical to Notch-induced Msx2 gene expression. Correspondingly, N1-ICD overexpression did not induce the Msx2 expression in RBP-Jk–deficient fibroblasts. Immunohistochemistry of human carotid artery specimens revealed localization of Notch1, Jagged1 and Msx2 to fibrocalcific atherosclerotic plaques.

Conclusion— These results imply a new mechanism for osteogenic differentiation of vascular SMCs in which Notch/RBP-Jk signaling directly induces Msx2 gene expression and suggest its crucial role in mediating vascular calcification.

  K Kinouchi , A Ichihara , M Sano , G. H Sun Wada , Y Wada , A Kurauchi Mito , K Bokuda , T Narita , Y Oshima , M Sakoda , Y Tamai , H Sato , K Fukuda and H. Itoh

Rationale: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H+-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2.

Objective: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes.

Methods and Results: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the VO subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes.

Conclusions: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.

  N Hosono , M Kato , K Kiyotani , T Mushiroda , S Takata , H Sato , H Amitani , Y Tsuchiya , K Yamazaki , T Tsunoda , H Zembutsu , Y Nakamura and M. Kubo

Background: Cytochrome P450 2D6 (CYP2D6), one of the most important drug-metabolizing enzymes, has been reported to possess variation in the encoding CYP2D6 gene (cytochrome P450, family 2, subfamily D, polypeptide 6) that affects enzymatic activity. For the pharmacogenetic study of CYP2D6, accurate measurement of the dosage of the functional gene is essential; however, current genotyping techniques are insufficient because of their inability to provide the exact copy number of functional CYP2D6 genes.

Methods: We developed 3 quantitative real-time PCR (qPCR) assays for estimating the total copy number of the CYP2D6 gene, as well as 24-multiplex PCR-based real-time Invader assays (mPCR-RETINAs) for estimating the allele ratio at each variation locus. After determining the allele copy number at each locus, we estimated the frequencies of CYP2D6 alleles in a population and the diplotype in each individual by a CNVphaser (copy number variation phaser). The qPCR assays and RETINAs used for HapMap Japanese and Chinese samples were applied to 455 Japanese individuals.

Results: Forty-two individuals (9.2%) had one CYP2D6 gene copy, 207 (45.5%) had 2 copies, 161 (35.4%) had 3 copies, 40 (8.8%) had 4 copies, and 5 (1.1%) had 5 copies of the CYP2D6 gene. We found 16 different CYP2D6 alleles, with frequencies similar to those described in previous reports. In the diplotype analysis, we observed that CYP2D6*1/*1 and *1/*10-*36 were the most common diplotypes (approximately 20%) in our population.

Conclusions: Our method is the first to determine the exact number of functional CYP2D6 gene copies. We believe our method will facilitate and accelerate the detailed pharmacogenetic analysis of CYP2D6.

  H Sato , N Usuda , M Kuroda , S Hashimoto , M Maruta and K. Maeda

Interaction of CA19-9 with E-selectin is involved in initiation of hematogenous metastases. We investigated whether serum concentrations of E-selectin and CA19-9 are good predictors of hematogenous metastases and prognosis in colorectal cancer.


Pre-operative serum samples were obtained from 152 patients with colorectal cancer, and from 28 healthy volunteers. Correlation between serum E-selectin and CA19-9 was studied in terms of clinically detected hematogenous metastases and prognosis of patients.


Low serum concentration of E-selectin was defined as <50 U/ml in healthy volunteers, and on that basis, 20.4% of all patients belonged to the high E-selectin group. Several distinctive characteristics were observed in the clinical course of patients with high serum concentrations of both CA19-9 and E-selectin. The rate of Dukes’ D cancer was significantly higher, and curative surgery was performed less frequently in patients with high serum concentrations of both CA19-9 and E-selectin (60 and 40%) than in others. However, there was no significant difference in the frequency of recurrence after curative surgery between patients with high serum concentrations of both CA19-9 and E-selectin (25.0%) and others. Overall the 5-year survival rate was significantly lower in patients with high serum concentrations of both CA19-9 and E-selectin (34.3%) than in other patients. Even if the serum concentration of CA19-9 was high, prognosis was not poor in patients with low serum concentration of E-selectin.


These results suggested that it was useful to measure both CA19-9 and E-selectin as markers of hematogenous metastases and as predictors of prognosis in colorectal cancer.

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