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Biomedical subjects

Y Hashimoto

Publications and source records attributed to Y Hashimoto.

At least 451 records · Page 25Linked to original sources
PubMed1998

A rat model of chemical-induced polycystic kidney disease with multistage tumors.

Diphenylthiazole (DPT) induces polycystic kidney disease in the rat which serves as a model of human acquired cystic disease of the kidney. However, DPT administration alone does not produce neoplastic changes in renal cysts. We examined the effect of N-nitrosomorpholine (NNM), a carcinogen, in rats bearing DPT-induced renal cysts. Forty Sprague-Dawley rats were divided into four groups: DPT/NNM, DPT, NNM, and nontreated groups. DPT was administered throughout the experimental period, and NNM was given from weeks 4 to 7 after the start of the experiment. The rats were sampled from weeks 39 to 48, and histopathological examinations of the excised kidneys were performed. Multiple cystic changes were observed in all the DPT-treated rats in both DPT and DPT/NNM groups which were absent in almost all other rats. Solid adenomatous lesions were observed in the NNM-treated rats: in 7 of 9 and in 3 of 10 rats in the DPT/NNM and NNM groups, respectively. Cystic adenomatous lesions were found in 4 of 9 rats in the DPT/NNM group exclusively and not in the other groups. Combined DPT and NNM administration to rats produced an animal model showing neoplastic changes in renal cysts resembling microscopically renal cancer lesions in human acquired cystic disease of the kidney (on hematoxylin and eosin staining).

Animals↗
PubMed1998

The 20-kilodalton (kDa) human growth hormone (hGH) differs from the 22-kDa hGH in the complex formation with cell surface hGH receptor and hGH-binding protein circulating in human plasma.

In spite of recent advance in understanding of the stoichiometry of 22-kDa human GH (22K-hGH) with cell surface hGH receptor (hGHR) and hGH-binding protein (hGH-BP) circulating in human plasma, that of 20-kDa hGH (20K-hGH) is poorly understood. To clarify this, mouse pro-B Ba/F3 cells stably expressing the full-length hGHR (Ba/F3-hGHR) and both recombinant and native hGH-BP were used in this study. Cell proliferation assay revealed that the two hGH isoforms increased Ba/F3-hGHR cells to the same extent in a dose-dependent manner at 0.1 pM-10 nM. However, the self-inhibition observed in 20K-hGH at 5 microM was significantly less than that in 22K-hGH. Furthermore, addition of 1 and 10 nM recombinant hGH-BP caused a slight inhibition in 20K-hGH, but a drastic inhibition in 22K-hGH. Gel filtration chromatography of mixtures of 20K-hGH with recombinant hGH-BP clearly demonstrated that 20K-hGH formed a 1:2 (hGH:hGH-BP) complex efficiently but no detectable 1:1 complex in any conditions. Supporting data were also obtained with native hGH-BP. Computer-aided homology modeling of 20K-hGH has provided speculative data that the conformational change caused by deletion of 15 residues may occur only in the loop between helix 1 and helix 2, resulting in the reduction of its site 1 affinity. In conclusion, 20K-hGH possesses a unique property for forming a 1:2 complex to the same extent as 22K-hGH but has difficulty in forming a 1:1 complex, which might be attributed to the conformational change restricted to its site 1 region.

Animals↗
PubMed1998

Potent retinoid synergists with a diphenylamine skeleton.

4-[N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)amino]benzoic acid (5) exhibited weak retinoidal and retinoid synergistic activities in HL-60 cell differentiation assay. N-Alkylation of 5 caused decrease or loss of differentiation-inducing activity, but enhanced the synergistic activity with a synthetic retinoid Am80 (2), as reflected in the potent synergistic EC50 (SEC50) values of DA023 (11, 1.6 x 10(-10) M) and DA113 (14, 1.4 x 10(-10) M) in the presence of 1.0 x 10(-10) M Am80 (2).

Cell Differentiation↗
PubMed1998

Novel thiazolidinedione derivatives with retinoid synergistic activity.

Several arylmethylidene thiazolidinediones were synthesized and their retinoidal activities were examined. TZ181 (7a), having a benzanilide skeleton, exhibited differentiation-inducing activity in HL-60 cell assay, while TZ191 (7b), the N-methylated analog of TZ181 (7a), TZ245 (9) and TZ335 (10) acted as retinoid synergists like the RXR-selective ligand, LGD1069 (5).

Cell Differentiation↗
PubMed1998

Hepatic extraction of tacrolimus in rats with experimental liver diseases.

Tacrolimus, an immunosuppressive agent, is metabolized mainly in the liver and has shown large intra- and interindividual pharmacokinetic variability. We investigated the effect of liver dysfunctions on the pharmacokinetics of tacrolimus in rats with experimental liver diseases. Experimental hepatic failure was induced by CCl4-treatment or bile duct ligation. Tacrolimus (1 or 0.3 mg/kg) was administered intravenously or intraportally to the rats (n = 5-6 per group), and blood samples were collected over a 240-min period. The tacrolimus concentrations in the blood were then measured by a high-performance liquid chromatography-enzyme immunoassay. In the normal rats, the hepatic extraction ratio of tacrolimus (EH) was dose-independent, ranging from 0.556-0.598 at 0.3 and 1.0 mg/kg doses. The EH were dose-dependent in the CCl4-treated rats and in the bile duct-ligated rats: the EH at 1.0 mg/kg dose were 0.158-0.170 and those at 0.3 mg/kg dose were 0.329-0.394. The intermediate EH of tacrolimus suggested that the clearance of tacrolimus depends not only on hepatic intrinsic clearance but also on hepatic blood flow. The present pharmacokinetic study also suggested that the decrease of EH and the dose-dependence of EH contribute to the elevation of blood tacrolimus concentrations and to the large variability in the pharmacokinetics of tacrolimus after oral administration in hepatic dysfunctions.

Animals↗
PubMed1998

Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: influence of substituents at the phthaloyl moiety on the activity and stereoselectivity.

The synthesis and tumor necrosis factor (TNF)-alpha production enhancing activity of substituted 3'-methylthalidomides on human leukemia cell line HL-60 stimulated with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) are described. Though the introduction of an electron-donating amino group at the phthaloyl moiety of alpha-methylthalidomides enhanced the activity, substituted alpha-methylthalidomides showed decreased stereoselectivity as compared to that of non-substituted alpha-methylthalidomide. The data indicates that the TNF-alpha production enhancing activity of thalidomide derivatives depends on both the electronic-state of substituents at the fused benzene ring and the stereochemistry of the glutarimide moiety.

HL-60 Cells↗
PubMed1998

A novel angiotensin II-receptor antagonist, 606A, induces regression of cardiac hypertrophy, augments endothelium-dependent relaxation and improves renal function in stroke-prone spontaneously hypertensive rats.

It is well-known that cardiac hypertrophy and arterial and renal dysfunction are serious complications of hypertension. Therefore, we investigated the chronic effects of 606A (2-propyl-3-[2'(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-5-acetyl-4,5,6,7- tetrahydro imidazo [4,5-c]pyridine-4-carboxylic acid disodium salt), a novel AT1-receptor antagonist, on these complications of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) using Wistar Kyoto rats (WKY) as the control. After 8 weeks treatment from 16 weeks of age with 606A by a subcutaneously implanted osmotic pump, cardiac function, cardiac weight, acetylcholine-induced endothelium-dependent relaxation in the isolated aorta and renal function were estimated. Furthermore, wall thickness of the left ventricle was studied morphologically. We found that 606A (0.3 mg, 1 mg and 3 mg/head/day) dose-dependently lowered blood pressure without any effects on heart rate in SHRSP. Long-term treatments with 606A significantly reduced cardiac weight, left ventricular wall thickness and left ventricular end diastolic pressure, whereas it did not affect cardiac contractility. Endothelium-dependent relaxation of the aorta was recovered, and total protein excretion as well as total protein excretion/creatinine excretion ratio was reduced to the level of WKY by the treatment. These results suggest that 606A not only has a hypotensive effect but also protects cardiac, renal and vascular tissues from complications of hypertension. Thus, 606A could be an useful drug for treatment of hypertension.

Acetylcholine↗
PubMed1998

Discrimination of productive and non-productive cough by sound analysis.

There are two types of coughs, productive and non-productive; the former is caused by excess airway secretions. The analysis of cough may provide important clues not only to aid diagnosis, but also for the selection of drugs for treatment. In this study, cough sounds recorded in a free acoustic field from patients with productive cough and non-productive cough due to chronic airway diseases were compared with those of voluntary cough of healthy subjects and were analyzed by sound spectrogram and time-expanded waveform. All cough sounds could be separated into two or three phases. The implementation of the novel technique to record cough sounds in the free acoustic field and to analyze the sounds of the high frequency range enable recognition of the characteristics of the cough sounds in phase 2 of the cough.

Acoustics↗
PubMed1998

Axoplasmic transport and its signal transduction mechanism.

Neuron requires a continual supply of materials synthesized in the cell body, for example a wide range of soluble proteins, membranous components, and various organelles. The transported materials are needed to replace constituents that turn over in the membrane and organelles of the fiber and also are needed to bring substances participating in energy metabolism. Other transported components are neurotransmitters or transmitter-related components supplied to the nerve terminals for the release and subsequent excitation of postsynaptic cells. Moreover, neurotropic substances and modulators are released from the nerve terminals to affect the functional state of the neuron. Conversely, some materials are conveyed back to the cell body. These include organelles, lysosomes, nerve growth factor, and selected small molecules such as adenosine, Ca2+, and some neurotransmitters. Axoplasmic transport is thought to be fundamental for a variety of neuronal cell functions. Thus it may be considered that axoplasmic transport relates to the dynamic physiological activity of neurons; in other words, axoplasmic transport is supposed to express the physiological activity of neurons. In turn, as in the case for many other physiological functions, axoplasmic transport is possibly controlled by neuronal, hormonal, and immunological systems. Since axoplasmic transport supplies neuron materials toward the synapses and back to the cell body, a feedback system of regulatory mechanisms of a variety of neuronal functions might be operated through axoplasmic transport pathways. Although axoplasmic transport is the important neuronal function, its regulation is poorly understood. In this review, we focus on the dynamics of organelle transport and its regulatory mechanisms mediated by neurotransmitters.

Animals↗
PubMed1998

[A juxtaglomerular cell tumor. Analysis of immunohistochemistry, electron microscopy and in situ hybridization].

We present a case of juxtaglomerular cell tumor measuring 8 mm in diameter in the right kidney. The hypertension was cured and plasma renin activity returned to normal level following tumor resection with partial nephrectomy. We studied histopathologic, electron microscopic, and immunohistochemical findings of the tumor. The majority of tumor cells stores renin granules in cytoplasm. In situ hybridization confirmed us that the most tumor cells produce renin. We use the digoxigenin labeled 0.6-kb length RNA probe of human renal renin, the specificity was analyzed by competition assay (1:50).

Adenocarcinoma↗
PubMed1998

Isolation and structure of an antimitotic cyclic peptide, ustiloxin F: chemical interrelation with a homologous peptide, ustiloxin B.

Ustiloxin F, a microtubule inhibitor, was isolated as a minor metabolite of Ustilaginoidea virens. The structure was determined from the spectral data and by chemical interrelation to ustiloxin B through reductive removal of the sulfoxide-containing side chain of ustiloxin B to give ustiloxin F. Ustiloxin F inhibited microtubule assembly with an IC50 value of 10.3 microM.

Anti-Bacterial Agents↗
PubMed1998

Synthesis and anti-tubulin activity of ustiloxin D derivatives.

Ustiloxin D, produced by the rice plant pathogen Ustilaginoidea virens, exhibits potent anti-tubulin activity. In order to elucidate the effects of functional groups in ustiloxin D on its activity, several derivatives were synthesized and their anti-tubulin activities were estimated. The N,N-dimethylamino derivative and the 14-O-methyl derivative were inactive (IC50 > 50 microM). 20-Hydroxymethylated ustiloxin D showed decreased inhibitory activity compared with ustiloxin D.

Animals↗
PubMed1998

Effect of rearing at non-permissive temperature on silkworm larvae infected with temperature-sensitive lef-8 mutant of bombyx mori nucleopolyhedrovirus.

A temperature-sensitive (ts) mutant of bombyx mori nucleopolyhedrovirus (BmNPV), ts-S1, contains a mutation in a putative RNA polymerase gene, which is involved in late viral gene expression. When 4th-instar silkworm larvae were infected with 1.0 x 10(5) TCID50 of ts-S1 per larva and reared at 33 degrees C, the titre of budded virus (BV) and number of occlusion bodies (OBs) in the haemolymph of the infected larvae were very low in the early stage but markedly increased in the late stage of infection. In contrast, a rapid increase in both BV titre and OB number was detected in the haemolymph of infected larvae reared at 25 degrees C. LD50 values of ts-S1 and wild type BmNPV (wtBmNPV) for 4th-instar larvae were 2.41 and 0.96 TCID50 per larva at 25 degrees C, and > 1.0 x 10(6) and 1.70 TCID50 per larva at 33 degrees C, respectively. These results indicate that the virulence of ts-S1 for the larvae reared at 33 degrees C was markedly reduced. To examine further the reduction of ts-S1 virulence at the non-permissive temperature of 33 degrees C, silkworm larvae were infected with ts-S1 at the multiplicity of 1.0 x 10(2) - 1.0 x 10(6) TCID50 per larva, reared for various time at 33 degrees C and then shifted to 25 degrees C. Longer rearing periods at 33 degrees C resulted in better survival rates indicating that the reduction of virulence of ts-S1 was proportional to cumulative rearing time at 33 degrees C. When large virus inocula were used, a growth alteration of larvae was preferentially induced. However, when small virus inocula were used, the appearance of abortive infection due to the non-permissive temperature became more evident.

Animals↗
PubMed1998

[A case of Marshall syndrome with secondary glaucoma due to spontaneous rupture of the lens capsule].

An eight-year-old boy developed acute glaucoma in his left eye. He was diagnosed as having Marshall syndrome because of bilateral cataract, high myopia, saddle nose, hypertelorism, and lack of arthropathy. When seen immediately after the glaucomatous attack, the affected eye showed ruptured anterior and posterior lens capsules and displacement of the lens nucleus into the anterior chamber and vitreous cavity. Lens extraction and vitrectomy induced normalization of intraocular pressure and visual acuity. There are forty cases reported in the world literature and only one cases in Japan. To the best of our knowledge, this is the first case treated successfully by vitreous surgery.

Acute Disease↗
PubMed1998

Novel biological response modifiers derived from thalidomide.

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha, a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.

Androgen Antagonists↗