Biomedical subjects

Hitoshi Ikeda

Publications and source records attributed to Hitoshi Ikeda.

67 records · Page 4Linked to original sources

PubMed2002

Detecting functional asymmetries through the dipole moment of magnetoencephalography.

To assess the accuracy of magnetoencephalography (MEG) as a tool for quantitative detection of neuronal activity, the dipole moment was estimated at N20m of somatosensory evoked fields (SEFs) produced by median nerve stimulation. Neurologically stable patients were examined twice within 2 weeks. Since the estimated moment values of the two examinations should be essentially the same, we assessed the margin of error for our measurement system. The results showed that a change of more than 5.2 nAm is statistically significant (p=0.05; n=91). The patients were classified as without or with functional asymmetries by measuring the conventional cerebral blood flow (CBF) with single photon emission CT (SPECT), and the dipole moment difference between hemispheres was measured. Hemispheric moment differences were statistically larger for the group with CBF laterality, indicating consistency between conventional CBF results and the moment measurements as a group. Moreover, MEG was able to detect more functional asymmetries than CBF study. The dipole moment provided a reliable quantitative index of cortical response to somatosensory stimulus, and the moment measurement thus holds promise as a clinical tool for direct quantification of cortical response.

Adult↗

PubMed2002

Novel 5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers with antidiabetic activities.

Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an omega-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA(y) mice and Wistar fatty rats. A large number of the 2,4-thia(oxa)zolidinediones showed potent glucose- and lipid-lowering activities. The antidiabetic activities of the 2,4-oxazolidinediones were superior to those of the 2,4-thiazolidinediones. Among the compounds, both enantiomers of 5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (64), one of the most interesting compounds in terms of activity, were synthesized by using an asymmetric O-acetylation of the corresponding alpha-hydroxyvalerate (26) with immobilized lipase, followed by cyclization of the oxazolidinedione ring. (R)-(+)-64 showed more potent glucose-lowering activity (effective dose (ED)25 = 0.561 mg/kg/d) than (S)-(-)-64 (ED25 > 1.5 mg/kg/d) or pioglitazone (ED25 = 6 mg/kg/d) in KKA(y) mice. It also exhibited a 10-fold more potent antidiabetic activity (ED25 = 0.05 mg/kg/d) than pioglitazone (ED25 = 0.5 mg/kg/d) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (EC(50) = 8.87 nM).

Animals↗

PubMed2002

Stabilization of RNA strands in protein synthesis by type I procollagen C-proteinase enhancer protein, a potential RNA-binding protein, in hepatic stellate cells.

Type I procollagen C-proteinase enhancer (PCPE) exists in hepatic stellate cells (HSCs) which can produce collagen. The deduced amino acid sequence of PCPE contains motifs specific for RNA-binding proteins. The effect of PCPE on the syntheses of collagen and noncollagenous protein was studied using an HSC clone derived from cirrhotic rat liver. When the cells were cultured in the presence of an antisense oligonucleotide (AS) against PCPE mRNA, the synthesis of noncollagenous protein as well as collagen was reduced compared to the cells cultured with addition of a nonsense oligonucleotide (NS). The extent of the reduction was similar in both syntheses. The total RNA content of the AS-treated cells and NS-treated cells did not differ. In the presence of actinomycin D, however, such total RNA content was decreased more rapidly in the AS-treated cells than in the NS-treated cells. PCPE may be involved in stabilization of RNA strands in noncollagenous protein synthesis as well as collagen synthesis.

Adipocytes↗

PubMed2002

Clonotypic analysis of T cells accumulating at arthritic lesions in HTLV-I env-pX transgenic rats.

Human T cell leukemia virus type I (HTLV-I) env-pX transgenic rats (env-pX rats) develop chronic destructive arthritis resembling rheumatoid arthritis in humans. Immunological characteristics were compared with those of collagen-induced arthritis (CIA). Rheumatoid factor was present in some env-pX rats regardless of the development of arthritis, but not in nontransgenic rats with CIA. All rats with CIA produced anti-type II collagen (IIC) antibody, but never so in env-pX rats with naturally occurring arthritis. Although expansions of oligoclonal T cells were evident in the affected joints, no particular clone was shown to infiltrate into the arthritic lesions in env-pX rats. In contrast to CIA, in which clonal expansions of IIC-specific T cells are implicated, locally expanded T cell clones against various antigens of the joints may play pathogenetic roles in the arthritis seen in env-pX rats. However, complementarity-determining region 3 of the TCR Vbeta gene of T cells accumulating at the affected joints in env-pX rats contained the GGA amino acid sequence, which was reported to be a conserved motif in HTLV-I env-pX transgenic mice with arthritis. These findings suggest that common antigen(s) might be recognized by T cells accumulating at sites of arthritis in both transgenic rats and mice.

Amino Acid Motifs↗

PubMed2002

The role of the thymus in development of necrotizing arteritis in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type-I.

Necrotizing arteritis mimicking polyarteritis nodosa occurred in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I. To investigate the pathogenesis of necrotizing arteritis in these rats (env-pX rats), adoptive transfers of spleen cells and bone marrow cells were done from env-pX rats before they developed arteritis to nontransgenic rats. Necrotizing arteritis occurred in lethally irradiated nontransgenic rats reconstituted by env-pX spleen cells, thus indicating that the env-pX transgene in affected vessels may not be essential for the development of arteritis. In contrast, arteritis was not induced in nontransgenic recipients by adoptive transfers of env-pX bone marrow cells, which suggested that T cells derived from the env-pX thymus may play a role in the development of arteritis. To clarify if the process of differentiation of T cells in the env-pX thymus is crucial to develop necrotizing arteritis, reciprocal exchange of thymus frameworks was done between env-pX and nontransgenic rats. Necrotizing arteritis occurred in nontransgenic rats with an env-pX thymus framework, whereas development of arteritis was suppressed in env-pX rats in which the thymus framework was replaced with a nontransgenic one. This collective evidence shows that the thymus is directly associated with the development of necrotizing arteritis in env-pX rats.

Animals↗

PubMed2002

A novel animal model of thymic tumour: development of epithelial thymoma in transgenic rats carrying human T lymphocyte virus type I pX gene.

The pX region encodes a major product of human T lymphocyte virus type I (HTLV-I) that has been implicated previously in tumour formation. To investigate the pathogenesis of pX gene in lymphoid tissues, we established a series of novel transgenic rats carrying the pX gene under the control of a rat lymphocyte-specific protein tyrosine kinase (p56lck) proximal promoter. The transgene was constructed with the -269 to +26 region of a rat p56lck proximal promoter and the pX cDNA, and was microinjected into fertilized ova of Fischer 344/jcl female rats. Six transgenic lines from 114 pups were established. Integration and expression of the transgene were detected by polymerase chain reaction (PCR) and Southern hybridization or by reverse transcriptase-PCR, northern hybridization, and immunostaining. Thymic tumours with lethal expansion occurred in 4 of 6 transgenic lines. The tumour consisted of spindle shaped cells. Immunohistochemical and ultra-structural analysis characterized the tumour cells to as epithelial cell type, and in the tumour arose in the medulla. Therefore, the tumour is classified into predominantly epithelial and spindle cell of medullary thymoma (type A of the new World Health Organization classification), as based on the human classification. Tumor occurrence increased in proportion to levels of the pX transcription in the thymus, for each line, and sex distinction was evident regarding rates related to tumour expansion. The transgenic rat model described here is suitable as a model for analysing tumorigenesis in epithelial thymoma occurring in humans.

Animals↗

PubMed2002

Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats.

1. The effects of combined treatment with pioglitazone.HCl and metformin on diabetes and obesity were investigated in Wistar fatty rats, which are hyperglycaemic and hypertriglyceridaemic and have higher plasma levels of total ketone bodies than lean rats. 2. Plasma glucose was significantly decreased when pioglitazone.HCl or metformin was administered alone and combined treatment accentuated this decrease. The administration of pioglitazone.HCl, but not metformin, also decreased plasma levels of triglyceride and total ketone bodies. 3. The glycogen content of skeletal muscle was not increased by pioglitazone.HCl or metformin alone, but was increased by combined treatment (P=0.003, ANOVA). 4. Pioglitazone.HCl produced increased food intake and bodyweight in hyperphagic Wistar fatty rats; however, concurrent administration of metformin significantly ameliorated these pioglitazone.HCl-induced increases. 5. These results indicate that combined treatment with pioglitazone.HCl and metformin induces a marked hypoglycaemic effect accompanied by a reduction in plasma levels of total ketone bodies and prevention of excessive bodyweight gain in Wistar fatty rats. These favourable effects suggest that the combination would be beneficial in treating patients with type 2 diabetes.

Adipose Tissue↗

PubMed2002

p53 May positively regulate hepatocyte proliferation in rats.

p53, known as a tumor suppressor gene, is a transcription factor that regulates various cellular functions. Recently, several growth factor gene promoters, including that of transforming growth factor alpha (TGF-alpha), were shown to be direct targets of p53-mediated transcription. Hepatic p53 mRNA is up-regulated during liver regeneration in rats. The aim of this study is to examine the role of p53 in hepatocyte proliferation. p53 protein levels were examined in rat hepatocytes cultured in the medium containing hepatocyte growth factor (HGF). p53 levels began to increase after 6 hours of incubation, reached a maximum at 18 hours, and decreased thereafter. DNA synthesis increased at 12 hours and peaked at 30 hours. When hepatocytes were incubated with p53 antisense oligonucleotide in addition to HGF, increases of p53 and TGF-alpha levels were suppressed, and DNA synthesis was reduced. The increases of TGF-alpha levels and DNA synthesis were also suppressed by a chemical inhibitor of p53, pifithrin-alpha. In rats after two-thirds partial hepatectomy, hepatic p53 increased and reached maximal levels around 16 hours when hepatic HGF levels have been shown to reach a maximum followed by an increase in hepatic TGF-alpha levels or hepatocyte proliferation. In contrast, sham-operated rats showed minor elevations of hepatic p53 levels. In conclusion, p53 production is stimulated by HGF and may contribute to the proliferation of rat hepatocytes. Considering previous findings indicating the importance of endogenous TGF-alpha for the proliferation of hepatocytes stimulated by HGF, TGF-alpha might play a role in HGF-p53 mediated hepatocyte proliferation.

Animals↗

PubMed2002

Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents.

A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitrites reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKAy mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED25=0.0839 mg x kg(-1) x d(-1)), being 72 times more active than pioglitazone hydrochloride (ED25=6.0 mg x kg(-1) x d(-1)). This compound also showed strong glucose lowering (ED25=0.0873 mg x kg(-1) x d(-1)) and lipid lowering effects (ED25=0.0277 mg x kg(-1) x d(-1)) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (PPARgamma) (EC50 = 6.75 nM).

Animals↗

PubMed2002

[Discovery and development of a new insulin sensitizing agent, pioglitazone].

Insulin resistance is a characteristic feature of type II diabetes as well as obesity. This insulin resistant state at the peripheral tissue level causes impaired glucose utilization, leading to hyperglycemia. Studies of antidiabetic agents by Takeda originated more than three decades ago when KK mice were introduced, followed by the development of a highly insulin-resistant animal model, KKAy mice. The first 2,4-thiazolidinedione derivative AL-321, which exhibited hypoglycemic effects in KKAy mice, was discovered by modification of the hypolipidemic agent AL-294 as a lead compound. Extensive structure-activity relationship studies on the analogues of AL-321 led to the selection of ciglitazone (ADD-3878) as a candidate for clinical evaluation. Ciglitazone, a prototypical compound in the series, was shown to normalize hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in various insulin-resistant animal models without altering normoglycemia in nondiabetic animal models. However, it appeared that a more potent compound was needed for further clinical evaluation of this class of compound. Further study of this series of compounds led to the finding of pioglitazone (AD-4833) as a promising clinical candidate. Pioglitazone clearly ameliorates the abnormal glucose and lipid metabolism in diabetic patients and was marketed in the USA in August 1999 for the treatment of type II diabetes. Pioglitazone is now marketed in more than 40 countries world wide. Historical aspects of our studies on pioglitazone and its biological activities are described.

Animals↗

PubMed2002

A case of lung cancer with hypercalcemia which was incidentally complicated with primary hyperparathyroidism due to parathyroid adenoma.

In lung cancer patients, hypercalcemia is a fairly common metabolic problem associated with malignancy. However, the occurrence of hypercalcemia in lung cancer patients means an ominous prognostic sign. As hypercalcemia often causes early death, quick diagnosis and treatment for hypercalcemia are required. A 69-year-old woman was admitted to our hospital with anorexia caused by hypercalcemia. On admission, serum level of PTH was elevated and PTHrP was normal. From the results of CT findings and transbronchial lung biopsy, the cause of the hypercalcemia was determined as lung cancer incidentally complicated with primary hyperparathyroidism. First, serum calcium level was returned to normal through hydration with saline and bisphosphonates. Next, left hemithyroidectomy for primary hyperparathyroidism was performed. Histologically, the tumor was diagnosed as parathyroid adenoma. Fifteen days later, left lower lobectomy for primary lung cancer was performed under a video-assisted thoracoscopic approach. Histologically, the tumor was diagnosed as a moderately differentiated adenocarcinoma. Four years and three months after the operation, the patient is alive and well with no sign of recurrence. When a lung cancer patient is complicated with hypercalcemia, we need to consider that primary hyperparathyroidism is a possible cause of the hypercalcemia.

Adenocarcinoma↗

PubMedDate not supplied

Beckwith-Wiedemann syndrome-associated hepatoblastoma: wnt signal activation occurs later in tumorigenesis in patients with 11p15.5 uniparental disomy.

Beckwith-Wiedemann syndrome (BWS) patients with chromosome 11p15.5 uniparental isodisomy (UPD) have an increased risk for developing embryonal tumors. UPD in these patients involves maternal loss of heterozygosity (LOH) and paternal duplication, which leads to tissue overgrowth and tumor development. Although 11p15.5 UPD predisposes to tumorigenesis, the events leading to tumorigenesis in UPD patients remains unknown. We have examined two hepatoblastomas in the BWS patients with UPD to determine the sequence of genetic events. Constitutional 11p15.5 LOH was detected in the blood or nonneoplastic liver of the BWS patients with hepatoblastoma. Mutation of beta-catenin gene (CTNNB1) was found in one hepatoblastoma. Although mutations in CTNNB1 were not found in the second hepatoblastoma, nuclear accumulation of beta-catenin was detected. However, mutation of CTNNB1 or nuclear accumulation of beta-catenin was not detected in the tissue with hepatomegaly which contains UPD cells. These data indicate that Wnt signal activation can be involved as a later event in BWS-associated hepatoblastoma involving 11p15.5 UPD.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer.

BACKGROUND: Gastric adenocarcinoma producing alpha-fetoprotein (AFP) has a very poor prognosis. In search of new therapeutic strategies against AFP-producing gastric cancer, we examined the efficacy of suicide gene therapy, which has been effective on AFP-producing hepatoma. MATERIALS AND METHODS: The herpes simplex virus thymidine kinase (HSVtk) gene was transduced into an AFP-producing gastric adenocarcinoma cell line, FU97, using adenovirus vectors carrying the constructed AFP enhancer/promoter element, followed by ganciclovir (GCV) administration. RESULTS: Expression of the transgene was evident in FU97 but not in an AFP-nonproducing gastric adenocarcinoma cell line, MKN28, which meant that AFP enhancer/promoter-specific transcriptional targeting was achieved by the vectors. The viability of FU97 but not of MKN28 significantly decreased after the suicide gene therapy in vitro. CONCLUSION: Therapeutic application of the AFP enhancer/promoter-specific transfer of the HSVtk gene followed by GCV administration against AFP-producing gastric cancer deserves attention and further research.

Adenocarcinoma↗