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T Asano

Publications and source records attributed to T Asano.

At least 127 records · Page 7Linked to original sources
PubMed2000

Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats.

3-(Benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-(6-O-methoxycarbonyl)-bet a-D -glucopyranoside (T-1095) is a derivative of phlorizin, a potent inhibitor of Na(+)-glucose cotransporters. We determined the antidiabetic effect of T-1095 in neonatally streptozotocin-treated diabetic rats. Orally administered T-1095 is metabolized to an active form, 3-(benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-beta-D-glucopyranoside (T-1095A), which inhibits renal Na(+)-glucose cotransporters as potently as phlorizin in vitro. A single oral administration of T-1095 (30 and 100 mg/kg, p.o.) markedly lowered blood glucose levels with a concomitant increase in urinary glucose excretion; whereas the effect on blood glucose levels in non-diabetic rats was minimal. Continuous administration of T-1095 to diabetic rats for 6 weeks (0.1% in diet) improved not only hyperglycemia, but also the elevation of plasma free fatty acid and plasma ketone body levels. In addition, oral glucose tolerance testing clearly illustrated the improvement of glucose tolerance and insulin secretion with T-1095. In fact, amelioration of impaired insulin sensitivity in diabetic rats was demonstrated by the increase of whole-body and skeletal-muscle insulin-mediated glucose utilization with normalization of muscle glucose transporter (GLUT)4 content, and decrease of the hepatic glucose production rate. Consequently, polyuria and glucosuria were also improved in the T-1095-treated group. Therefore, T-1095 has a therapeutic potential as a means of ameliorating abnormal glucose metabolism via diminished glucose toxicity.

Animals↗
PubMed2000

The N-terminal 34 residues of the 55 kDa regulatory subunits of phosphoinositide 3-kinase interact with tubulin.

There are five regulatory subunit isoforms of phosphoinositide 3-kinase (PI 3-kinase), which are classified into three groups: proteins of 85 kDa (p85alpha and p85beta), 55 kDa (p55alpha and p55gamma) and 50 kDa (p50alpha). Structural differences between the three groups reside in the N-terminus. To elucidate the unique functional role of the 55 kDa regulatory subunits, GST (glutathione S-transferase) fusion proteins containing a unique N-terminal portion consisting of a 34-amino-acid sequence of p55alpha or p55gamma (GST-p55alpha/gammaN(1-34)) were used as affinity matrices to screen rat brain cell extracts for proteins to which this portion binds specifically. A protein that bound was identified as beta-tubulin by protein sequencing. In addition, not only the beta isoform of tubulin, but also the alpha and gamma isoforms, were detected in the protein absorbed from cell lysates with GST-p55gammaN(1-34) and GST-p55alphaN(1-34) by immunoblotting. Indeed, the only regulatory subunit present in the purified microtubule assembly from rat brain was the 55 kDa isoform; neither 85 kDa nor 50 kDa subunits were detected. These results indicate endogenous binding of 55 kDa regulatory subunits of PI 3-kinase to tubulin in the brain. Finally, we measured tubulin-associated PI 3-kinase activity in CHO/IR cells overexpressing each of the five regulatory subunit isoforms. Only in cells expressing p55alpha or p55gamma was there a significant elevation of tubulin-associated PI 3-kinase activity in response to insulin. These results suggest that the p55alpha and p55gamma regulatory subunits have important roles in regulating PI 3-kinase activity, particularly for microtubules at the cell periphery.

Amino Acid Sequence↗
PubMed2000

Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts.

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-kappaB) pathways on osteoclast survival and activation, we constructed adenovirus vectors carrying various mutants of signaling molecules: dominant negative Ras (Ras(DN)), constitutively active MEK1 (MEK(CA)), dominant negative IkappaB kinase 2 (IKK(DN)), and constitutively active IKK2 (IKK(CA)). Inhibiting ERK activity by Ras(DN) overexpression rapidly induced the apoptosis of osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEK(CA) remarkably lengthened their survival by preventing spontaneous apoptosis. Neither inhibition nor activation of ERK affected the bone-resorbing activity of OCLs. Inhibition of NF-kappaB pathway with IKK(DN) virus suppressed the pit-forming activity of OCLs and NF-kappaB activation by IKK(CA) expression upregulated it without affecting their survival. Interleukin 1alpha (IL-1alpha) strongly induced ERK activation as well as NF-kappaB activation. Ras(DN) virus partially inhibited ERK activation, and OCL survival promoted by IL-1alpha. Inhibiting NF-kappaB activation by IKK(DN) virus significantly suppressed the pit-forming activity enhanced by IL-1alpha. These results indicate that ERK and NF-kappaB regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-kappaB regulates osteoclast activation for bone resorption.

Adenoviridae↗
PubMed2000

G protein betagamma subunits induce stress fiber formation and focal adhesion assembly in a Rho-dependent manner in HeLa cells.

In fibroblasts, the G protein alpha subunits Galpha(12) and Galpha(13) stimulate Rho-dependent stress fiber formation and focal adhesion assembly, whereas G protein betagamma subunits instead exert a disruptive influence. We show here that the latter can, however, stimulate the formation of stress fibers and focal adhesions in epithelial-like HeLa cells. Transient expression of beta(1) with gamma(2), gamma(5), gamma(7), and gamma(12) in quiescent HeLa cells induced stress fiber formation and focal adhesion assembly as did expression of the constitutively active Galpha(12). Co-expression of betagamma with Galpha(i2) and the C-terminal fragment of the beta-adrenergic receptor kinase, both of which are known to bind and sequester free betagamma, blocked betagamma-induced stress fiber and focal adhesion formation. Inhibition was also noted with co-expression of a dominant negative mutant of Rho. Botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho, and a Rho-associated protein kinase inhibitor, Y-27632, similarly inhibited betagamma-induced stress fiber and focal adhesion assembly. These results indicate that G protein betagamma subunits regulate Rho-dependent actin polymerization in HeLa cells.

3T3 Cells↗
PubMed2000

Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1.

Spinal cord injury in adult mammals results in little axonal regeneration, although the mechanism of regeneration failure still remains elusive. Recent research has revealed that activation of the extracellular-signal-regulated kinases (ERKs) plays an important role in the neurite outgrowth. In the present study, we constructed a replication-defective adenovirus vector carrying mutated form of MEK1 (CA-MEK virus), which constitutively activate ERK pathway, and investigated its effect on thoracic spinal cord injury model in young adult rats as well as neurite outgrowth in vitro. In rat pheocromocytoma cell line PC12 cells, CA-MEK virus infection induced sustained activation of ERKs and stimulated neurite outgrowth in the absence of neurotrophic factors. In rat spinal cord transection model, injection of CA-MEK virus into the completely transected spinal cord efficiently activated ERKs in the supraspinal neurons and induced axonal regeneration across the transection site, which was confirmed by anterograde labeling with wheat-germ-agglutinin conjugated peroxidase (WGA-HRP). Spinal cord evoked potentials (SCEP) showed that these regenerated axons were electroconductive. Most importantly, CA-MEK virus-treated rats showed significant recovery of hind limb function 2 weeks after operation compared to the control rats treated with no virus or LacZ virus. These results suggest that adenovirus-mediated CA-MEK gene transduction offers a novel strategy for the gene therapy of spinal cord injury.

Adenoviridae↗
PubMed2000

Inferior head resection of the pancreas for intraductal papillary mucinous tumors.

BACKGROUND: Patients with intraductal papillary mucinous tumor have a favorable prognosis after surgical treatment. When this neoplasm is located in the head of the pancreas, resection has conventionally required pancreatoduodenectomy. Although pancreatoduodenectomy can now be performed with a low mortality rate, morbidity still occurs frequently. METHODS: Between November 1982 and January 1999, 38 intraductal papillary mucinous tumors of the pancreas were resected at the Chiba University Hospital. Seven patients (18%) underwent inferior head resection of the pancreas. In this preliminary study, the operative technique is presented, and its efficacy in improvement of quality of life is evaluated. RESULTS: Patients with intraductal papillary mucinous tumor underwent resection with no perioperative mortality. After discharge from hospital, 6 patients who underwent inferior head resection were still alive without recurrent disease after a median follow-up of 3 years. However, 1 patient developed peritoneal dissemination and died 18 months after inferior head resection. Patients had regained 98% of preoperative weight 1 year after inferior head resection. N-benzoyl-L-tyrosyl-p-amino-benzoic acid (BT-PABA) excretion test showed the same value before (73%) and after (73%) inferior head resection (n = 7). Pancreatic fistulas occurred more frequently after inferior head resection (38%), but the incidence of major complications was similar between inferior head resection and other types of pancreatic head resection. CONCLUSIONS: Pancreatic function was well preserved, and patients regained 98% of preoperative weight after inferior head resection of the pancreas. The authors concluded that the limited involvement of intraductal papillary mucinous tumors enables the surgeons to perform inferior head resection of the pancreas.

Adenocarcinoma, Mucinous↗
PubMed2000

Troglitazone enhances glycolysis and improves intracellular glucose metabolism in rat mesangial cells.

To clarify the action of the new antidiabetic agent, troglitazone, on rat mesangial cells, we assessed its effect on the uptake and intracellular metabolism of glucose. Troglitazone increased the uptake of 2-deoxyglucose (2DOG) in a dose-dependent manner with an upregulation of glucose transporter 1 (GLUT1) mRNA, whereas it had no effect on the uptake of alpha-methyl glucoside (AMG). This troglitazone-induced glucose uptake was not suppressed by phlorizin. In 5 mmol/L glucose, 2 microg/mL (4.5 micromol/L) troglitazone increased glucose consumption 2.9-fold, similar to that in 20 mmol/L glucose. Troglitazone increased the production of pyruvate and lactate as a consequence of the increase in glycolysis, but did not increase the cellular ATP content. Troglitazone improved the high-glucose-induced accumulation of intracellular sorbitol and fructose and elevation of the cellular redox potential. These data suggest that troglitazone enhances glucose uptake through GLUT1 with an acceleration of glycolysis, and improves the abnormal intracellular glucose metabolism under high-glucose conditions in rat mesangial cells.

Adenosine Triphosphate↗
PubMed2000

Effect of Zena F-III, a liquid nutritive and tonic drug, on the neurochemical changes elicited by physical fatigue in mice.

The effects of a liquid nutritive and tonic drug (NTD) on the neurochemical changes elicited by physical fatigue in mice were investigated in terms of the calcium-dependent dopamine synthesizing function of the brain. In this study, Zena F-III (Taisho Pharmaceutical Co., Ltd., Japan), one of the most popular NTDs in Japan, containing 15 crude drug extracts together with taurine, caffeine, and vitamins, and formulated based on the precepts of traditional Chinese medicine, was used. Male mice were forced to walk for 0-6 h at a speed of 3 m/min using a programmed motor-driven wheel cage. The serum and brain calcium levels in the mice were significantly increased following forced walking. The increase in brain calcium level began later and was more gradual than that in the serum calcium level, and reached its maximum value following forced walking for 3 h. The neostriatal dopamine level was also significantly increased, and locomotor activity significantly decreased following forced walking for 3 h. Prior oral administration of F-III (10 ml/kg) attenuated the increases in the serum and brain calcium levels, the increase in the brain dopamine levels, and the decrease in locomotor activity induced by forced walking. Taking into consideration these findings with our previous reports, it is suggested that physical fatigue leads to an increase in dopamine synthesis in the brain through a calcium/calmodulin-dependent system, thereby inducing behavioral changes, and that F-III inhibits this pathway and may alleviate overwork-induced physical fatigue.

Animals↗
PubMed2000

Long-term follow-up of vitamin B(6)-responsive West syndrome.

We performed a clinical and electroencephalographic follow-up study on 25 patients with West syndrome that was responsive to vitamin B(6) (eight cryptogenic patients and 17 symptomatic patients) who were older than 3 years at the last follow-up. All cryptogenic patients and 13 symptomatic patients were seizure free at the last follow-up. All cryptogenic patients and seven symptomatic patients had intelligent quotient or developmental quotient scores of 75 or higher. The recurrence of clinical seizures was always associated with increases in epileptic discharges. We could successfully discontinue pyridoxal phosphate administration in four cryptogenic and four symptomatic patients who were 1 year, 8 months to 24 years old.

Administration, Oral↗
PubMed2000

Structure and function of phosphatidylinositol-3,4 kinase.

Activation of phosphatidylinositol (PI)-kinase is involved in the regulation of a wide array of cellular activities. The enzyme exists as a dimer, consisting of a catalytic and a regulatory subunit. Five isoforms of the regulatory subunit have been identified and classified into three groups comprising respectively 85-kDa, 55-kDa, and 50-kDa proteins. Structural differences in the N-terminal regions of the different group members contribute to defining their binding specificity, their subcellular distributions, and their capacity to activate the 110-kDa catalytic subunit. Two widely distributed isoforms of the catalytic subunit have been identified-p110alpha and p110beta. Despite the fact that they bind to the p85alpha regulatory subunit similarly, p110alpha and p110beta appear to have separate functions within cells and to be activated by different stimuli. Moreover, although p85/p110 PI-kinase almost exclusively phosphorylates the D-3 position of the inositol ring in phosphoinositides when purified PI is used as a substrate in vitro, it appears to phosphorylate the D-4 position with similar or higher efficiency in vivo. Thus, it is highly probable that p85/p110 PI-kinase transmits signals to downstream targets via both D-3- and D-4-phosphorylated phosphoinositides.

Animals↗
PubMed2000

Effect of the FAA1 gene disruption of sake yeast on the accumulation of ethyl caproate in sake mash.

Fatty acid activation gene (FAA1) in sake yeast Kyokai no. 701 (K701) was disrupted to investigate the accumulation of ethyl caproate in sake mash. Ethyl caproate, recognized as an important apple-like flavor in sake, is generated by fatty acid synthesis in yeast cells. The disruptant for the FAA1 gene (K701deltafaa1) exhibited a reduced growth rate in a medium containing cerulenin and myristic acid or oleic acid compared with that of the parental strain (K701). In a sake brewing test in which the rice used was polished to 60% of its original size, the fermentation ability of K701deltafaa1 was inferior to that of K701 but the production of ethyl caproate by K701deltafaa1 was 1.6-fold higher than that by K701. These results suggest that the FAA1 gene in sake yeast plays an important role in sake brewing and the accumulation of ethyl caproate.

Journal Article↗
PubMed2000

Long-lasting binding of IT-066 to human histamine H2 receptor.

Based on animal models, IT-066, a histamine H2-receptor antagonist, is reported to possess potent and long-lasting antagonisms on histamine H2 receptor (H2R) -mediated effects. However, no reports have been published concerning its interaction with the human H2R. The aim of this study is to characterize its interaction with human H2R. Chinese hamster ovary cell lines stably expressing human H2Rs were obtained. The effects of IT-066, famotidine, and ranitidine on tiotidine binding and histamine-stimulated cAMP production were analyzed. IT-066 inhibited [3H]tiotidine binding and histamine-stimulated cAMP production more potently than famotidine or ranitidine. In addition, preincubation with 10(-5) M IT-066, but not with 10(-5) M famotidine or 10(-4) M ranitidine, had marked inhibitory effects long after extensive washing. Paraformaldehyde fixation of the cells blunted inhibition of [3H]tiotidine binding induced by preincubation with IT-066, but not that by preincubation with famotidine or ranitidine. IT-066 has potent and long-lasting antagonisms on human H2R. At least one of the IT-066 binding sites is not shared by famotidine, ranitidine, or tiotidine and is affected by paraformaldehyde fixation.

Animals↗
PubMed2000

Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy.

The effects of bone marrow transplantation (BMT) in X-linked childhood adrenoleukodystrophy (ALD) are described in four Japanese patients. Two older patients, 10-year-old boys with IQ 60 and difficulty in school, had favourable results. IQ levels and MRI findings were generally maintained after BMT. One patient showed improvement of gait disturbance. They have both attended ordinary schools after BMT, although a learning disorder persists. On the other hand, two other younger patients with a rapid course and indeterminate IQ at BMT showed deterioration of neurological functions. Indication for BMT seems to be a maintained IQ level, preferably higher than 80, since it seems to be difficult to normalize IQ level after BMT. Younger patients have higher risk of developing a rapidly progressive form of the disease. Identification of presymptomatic boys, and serial and careful follow-up by neuropsychological and neuroradiological studies, are essential prerequisites to successful BMT in X-ALD.

Adrenoleukodystrophy↗