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Biomedical subjects

N Sakai

Publications and source records attributed to N Sakai.

At least 397 records · Page 22Linked to original sources
PubMed1995

Age-related changes in the static and dynamic mechanical properties of mouse lungs.

To investigate the effects of aging on pulmonary mechanical properties in mice, we devised a new experimental apparatus to measure the respiratory impedance of excised lungs in mice and examined age-related changes in both static and dynamic properties. In an accelerated senescence-resistant strain of mice, SAMR1 (Takeda, T., Y. Fukuchi, Y. Uejima, K. Teramoto, T. Oka and H. Orino, J. Am. Geriatr. Soc. 39: 911-919, 1991), ranging from 3 to 24 months of age, static compliance (Cst) as well as total lung capacity increased significantly with age, whereas specific compliance and the K value, as determined by exponential analysis, showed no significant change. In the dynamic study, dynamic compliance (Cdyn) increased significantly with age, whereas the frequency dependence of Cdyn (Cdyn/Cst) did not vary with age. From these results we concluded that lung elasticity, normalized to lung volume, remained constant with age and that the effects of aging on pulmonary mechanics might be solely derived from increases in lung volume in the SAMR1 strain of mice.

Age Factors↗
PubMed1995

Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice.

The effect of thioperamide, a histamine H3 receptor antagonist, on learning and memory was studied in the senescence-accelerated mice-prone strain (SAM-P/8) and normal-rate aging strain (SAM-R/1). In a passive avoidance test, SAM-P/8 mice of 12 months showed significant impairment of learning and memory compared with SAM-R/1 mice of the same age. Thioperamide significantly improved the response latency in SAM-P/8 mice when injected intraperitoneally at a dose of 15 mg/kg. The histidine decarboxylase (HDC) activity in the forebrain was significantly lower in SAM-P/8 mice than in SAM-R/1 mice. Thioperamide administration significantly potentiated HDC activity in the forebrain of SAM-P/8 mice as well as improving learning and memory. These results suggest that central histaminergic neurons may be involved in learning and memory impairment of SAM-P/8 mice, although other possibilities are not ruled out.

Aging↗
PubMed1995

Conditioned taste aversion in rats with excitotoxic brain lesions.

Conditioned taste aversion (CTA) is well known to be a robust and long-lasting learning after a single conditioned stimulus (CS) (taste)--unconditioned stimulus (US) (malaise) pairing. The neural mechanisms of this taste aversion learning still remain to be resolved. To elucidate the basic brain mechanisms of the taste aversion learning, we examined the effects of lesions of various sites of the rat brain on the acquisition and retention of CTAs. Confined brain lesions were made by injections of a small amount of excitotoxic drug, ibotenic acid. CTAs were established to saccharin (CS) by pairing its ingestion with an i.p. injection of LiCl (US). Rats lacking the parabrachial nucleus (PBN) almost completely failed to acquire CTAs. The second most effective lesion was in the medial thalamus including the parvocellular part of the ventral posteromedial nucleus of the thalamus (VPMpc) and the midline part, followed by the damage of the lateral nuclear group of the amygdala including the basolateral amygdaloid nucleus. Lesions of the gustatory cortex (GC) and hippocampus induced moderate effects, but lesions in the other subnuclei of the amygdala, such as the medial and central amygdaloid nuclei, entorhinal cortex, lateral hypothalamic area, and ventromedial hypothalamic nucleus induced slight or no effects. On the other hand, paired lesions among the amygdala, medial thalamus and GC caused severe impairment of CTAs; in particular, lesions of amygdala and VPMpc completely disrupted acquisition of CTAs. These results suggest that the PBN, medial thalamus and the lateral nuclear group of the amygdala play an essential role in the formation of taste aversion learning.

Animals↗
PubMed1995

Effect of RU 486 on the atrophogenic and antiinflammatory effects of glucocorticoids in skin.

Clobetasol-17-propionate (CP), a synthetic glucocorticoid (GC), reduced skin thickness in rats. Both the subcutaneous injection and topical applications of RU 486 counteracted CP-induced reduction in skin thickness. Topical application of the CP cream completely inhibited the ear edema produced by croton oil. A less potent GC, hydrocortisone-17-butyrate, also inhibited ear edema. This antiinflammatory effect was not abolished by the subcutaneous injection or topical application of RU 486. These observations suggest that GC-induced skin atrophy is mediated by glucocorticoid receptors (GRs), while the inhibition of croton oil-induced inflammation by GC is primarily related to the direct effects of GC, which are not mediated by GRs. Our findings suggest that RU 486 inhibits the atrophogenic effect of GCs without interfering with their antiinflammatory effect. Dissociation of antiinflammatory and atrophogenic activity of GC seems favorable in treating inflammatory skin diseases lacking epidermal proliferation.

Animals↗
PubMed1995

Parallel induction of nitric oxide and tetrahydrobiopterin synthesis by cytokines in rat glial cells.

Activation of monocyte-derived macrophages with cytokines leads to the induction of nitric oxide synthase. Much less is known about the effects of cytokines on microglia, resident brain macrophages, or on astrocytes. In this study, we compared the induction by lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha of nitric oxide production and synthesis of tetrahydrobiopterin, the required cofactor for nitric oxide synthase, in microglia and peritoneal macrophages. Activation of microglia induced parallel increases in nitric oxide and intracellular tetrahydrobiopterin levels, although induction of the latter appears to be somewhat more sensitive to diverse stimulators. As with macrophages, inducible nitric oxide production in microglia was blocked by inhibitors of tetrahydrobiopterin biosynthesis. Interleukin-2, an important component of the neuroimmunomodulatory system, was only a weak activator of microglia by itself but potently synergized with interferon-gamma to stimulate production of both nitric oxide and tetrahydrobiopterin. Astrocytes were also activated by lipopolysaccharide and combinations of cytokines but showed a somewhat different pattern of responses than microglia. Biopterin synthesis was increased to higher levels in astrocytes than in microglia, but maximal induction of nitric oxide production required higher concentrations of cytokines than microglia and the response was much lower. These results suggest that tetrahydrobiopterin synthesis in glial cells is a potential target for therapeutic intervention in acute CNS infections whose pathology may be mediated by overproduction of nitric oxide.

Animals↗
PubMed1995

Molecular defects in Krabbe disease.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous systems due to an enzymatic defect of the galactocerebrosidase. In this study, molecular defects in Krabbe disease were investigated in 11 patients (seven Japanese and four non-Japanese) using cultured skin fibroblasts. A Japanese late infantile patient had a missense mutation of Pro at codon 302 to Ala and a non-Japanese patient had a missense mutation of Val at codon 550 to Gly. The reduced enzymatic activities expressed from the cDNAs with these missense mutations and from the previously reported nonsense mutation (E369X, Glu at codon 369 to stop codon) were confirmed. Genomic DNA analyses revealed that the P302A and E369X mutations were heterozygous and the V550G mutation was homozygous in these patients. A 12 base deletion with a 3 base insertion was found in three unrelated Japanese infantile patients, but not in 30 controls. The mutation was homozygous in two patients and heterozygous in one patient. We could not find any confirmed mutation in the coding region in the other six patients. These findings suggest that mutations in infantile and late infantile patients are relatively heterogeneous.

Amino Acid Sequence↗
PubMed1995

Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency.

We have reported that the disorder of lipoprotein metabolism in hyperalphalipoproteinaemic patients with a deficiency of cholesteryl ester transfer protein (CETP) is characterized by the polydisperse low density lipoprotein (LDL) particles and the accumulation of cholesteryl ester (CE) in high density lipoprotein (HDL) particles, forming cholesterol-induced HDL (HDLc)-like particles. In the present study we have investigated the interaction of these abnormal LDL with LDL receptors of normal human fibroblasts. Since the ultracentrifugally separated LDL fraction (1.019 < d < 1.063 g mL-1) from the CETP-deficient patients contained HDLc-like particles, these particles were removed by anti-apolipoprotein (apo) A-I immunoaffinity column chromatography. The lipoproteins eluted in the unbound fraction of this column did not contain apo A-I, so this fraction was considered to be authentic LDL. The authentic LDL of the patients were deficient in CE and rich in triglycerides and apo B. The authentic LDL itself showed polydispersity, ranging in size from 23 nm to 30 nm. The affinity of these abnormal LDL particles for LDL receptors was analysed by a competitive assay in which cold LDL from the patients or control compete with 125I-labelled LDL for fibroblast LDL receptors. The concentration of LDL particles at which 50% of 125I-labelled normal LDL was replaced was two to three times higher for the patients than for the normal control. Therefore, the affinity of patient LDL was thought to be reduced compared to that of control LDL. These results demonstrate that CETP may play an important role in making LDL particles homogeneous and rich in CE.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Effect of T-kinin on microvascular permeability and its modulation by peptidases in rat airways.

T-kinin (Ile-Ser-bradykinin), the product of T-kininogen, has been found in rat plasma during systemic inflammation, but the effect of this kinin on airway inflammatory response is unknown. We examined the effect of T-kinin on vascular permeability in airways of anesthetized rats in vivo by using photometric measurement of the extravasated Evans blue. Intravenous injection of T-kinin (0.1-10 mumol/kg) increased dye extravasation in a dose-dependent manner, with 134% for trachea and 117% for bronchi by 1 mumol/kg. Pretreatment with bradykinin B2-receptor antagonist Hoe-140 (100 nmol/kg), but not the B1-receptor antagonist des-Arg9-Leu8-bradykinin (5 mg/kg), abolished plasma extravasation evoked by T-kinin (1 mumol/kg). NK1 tachykinin-receptor antagonist CP-99994 (4 mg/kg) did not affect T-kinin-induced vascular leakage. Pretreatment with captopril (2.5 mg/kg), angiotensin-converting enzyme inhibitor, potentiated T-kinin (100 nmol/kg)-induced plasma extravasation, whereas phosphoramidon (2.5 mg/kg), a neutral endopeptidase inhibitor, had no effect. We conclude that T-kinin produces airway vascular extravasation via stimulation of B2 receptors. The effect is modulated by endogenous angiotensin-converting enzyme and is not mediated via activation of sensory nerve.

Amino Acid Sequence↗
PubMed1995

Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase.

Hyperalphalipoproteinemia (HALP) has been regarded as a beneficial state accompanied by a longevity syndrome. However, we reported the cases of markedly hyperalphalipoproteinemic subjects with juvenile corneal opacification. The patients had reduced postheparin hepatic triglyceride lipase (HTGL) activities, and one of them has recently been identified to be homozygous for a missense mutation in exon 15 (D442: G) in the cholesteryl ester transfer protein (CETP) gene. In the current study, to elucidate the clinical significance of and atherogenicity in marked HALP, we determined the incidence of atherosclerotic cardiovascular disease (ACD) in patients with marked HALP and characterized the lipoprotein abnormalities in those who had ACD, focusing especially on CETP and HTGL. The subjects were 201 patients (111 males and 90 females) with marked HALP ( > or = 2.58 mmol/L [100 mg/dL]), 67% of whom were demonstrated to have the CETP gene mutations in the intron 14 splice donor site or in exon 15. Their mean age was 54 +/- 15 years. Plasma levels of total cholesterol, HDL cholesterol, and triglyceride in all subjects were 6.28 +/- 1.78, 3.15 +/- 0.90, and 1.08 +/- 0.53 mmol/L, respectively. Ten of the male patients (9.0%) and two of the female patients (2.2%) had apparent ACD such as myocardial infarction, angina pectoris, and peripheral vascular diseases. Ten patients with HALP who had ACD were identified to be heterozygotes for CETP deficiency. To further clarify the characteristics of marked HALP in patients with ACD, we compared the plasma lipids, lipoproteins, CETP, and HTGL activities between heterozygotes for CETP deficiency who were with and without ACD.

Adult↗
PubMed1995

Effect of erythromycin on endotoxin-induced microvascular leakage in the rat trachea and lungs.

To determine whether the macrolide antibiotic erythromycin prevents microvascular leakage produced by lipopolysaccharide (LPS), we studied tracheae and lungs of pathogen-free rats. Tracheal vascular permeability and neutrophil recruitment were assessed by the percent area occupied by Monastral blue-labeled blood vessels and by myeloperoxidase-containing granulocytes, respectively, in tracheal whole mounts. Pulmonary microvascular leakage was evaluated by lung wet-to-dry (W/D) weight ratio. Inhalation of Escherichia coli LPS (5 mg/kg) caused time-dependent increases in tracheal vascular permeability, neutrophil influx, and lung W/D ratio. These responses were inhibited by pretreatment with oral erythromycin, but not by ampicillin or cefaclor, in a dose-dependent manner: erythromycin at 10 mg/kg daily for 1 wk reduced the area density of Monastral blue-labeled vessels from 6.7 +/- 1.2 to 1.4 +/- 0.3% (p < 0.01), the number of neutrophils (from 365 +/- 51 to 149 +/- 30 cells/mm2, p < 0.01), and lung W/D weight ratio (from 6.76 +/- 0.30 to 5.39 +/- 0.21, p < 0.01). This inhibitory effect of erythromycin was abolished by depletion of circulating neutrophils with cyclophosphamide. These results suggest that LPS causes acute lung injury, microvascular leakage, and neutrophil recruitment in the trachea, and that erythromycin protects against these changes, probably by acting on neutrophils.

Ampicillin↗
PubMed1995

Activation of phosphoinositide-specific phospholipase C by transferrin in porcine cerebral arterial smooth muscle cells.

The effect of transferrin on phosphoinositide metabolism was investigated in smooth muscle cells isolated from the porcine basilar artery. Ferric iron-bound transferrin induced a rapid increase in the level of inositol phosphates, the metabolic products of phosphoinositides through the phospholipase C pathway. Neither transferrin free of ferric iron nor ferric iron alone caused the activation of phospholipase C. This study suggests that ferric iron-bound transferrin is capable of eliciting receptor-mediated signal transduction in porcine cerebral arterial smooth muscle cells, which could result in the contraction of smooth muscle cells. Transferrin may be involved with the cerebral arterial narrowing in pathological conditions such as subarachnoid hemorrhage.

Animals↗
PubMed1995

Cytosolic free calcium elevation in vascular smooth muscle cells induced by cerebrospinal fluid from patients with subarachnoid hemorrhage--biochemical nature of the calcium-mobilizing factor.

The present study was undertaken to characterize the biochemical nature of the factor in cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage (SAH) that induces a transient elevation of cytosolic free calcium in cultured vascular smooth muscle cells. Cell-free CSF collected from patients on days 7-10 after SAH was treated in three different ways: heating, ultrafiltration, and salting out with ammonium sulfate. The effects of the resultant solutions on the level of cytosolic free calcium in cultured vascular smooth muscle cells were then examined. Heated CSF and ultrafiltrated solution containing substances with molecular weights of less than 10,000 caused no significant elevation of cytosolic free calcium. Proteins precipitated by 50-75% saturated ammonium sulfate caused an increase in the level of cytosolic free calcium and also produced a rapid accumulation of inositol 1,4,5-trisphosphate in vascular smooth muscle cells. The results indicate that the factor responsible for the increase in cytosolic free calcium in cultured vascular smooth muscle cells is a protein with a molecular weight of more than 10,000, and the factor stimulates receptor-mediated phosphoinositide breakdown.

Calcium↗
PubMed1995

A novel bioactive delta lactone FD-211. Taxonomy, isolation and characterization.

During our screening program for natural product drugs effective against multidrug-resistant mammalian cells, we have discovered a new delta lactone FD-211 from the fermantation broth of Myceliophthora lutea TF-0409. FD-211 had a broad spectrum activity against cultured tumor cell lines, including adriamycin-resistant HL-60 cells.

Animals↗
PubMed1995

Bassiatin, a new platelet aggregation inhibitor produced by Beauveria bassiana K-717.

A new platelet aggregation inhibitor, bassiatin, was isolated from the cultured broth of Beauveria bassiana which had been isolated from a soil sample collected in Yunnan province, China. The structure of bassiatin was determined to be (3S, 6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-1, 4-perhydrooxazine-2,5-dione by NMR analysis, X-ray crystallographic analysis and chemical synthesis. Bassiatin inhibited ADP-induced aggregation of rabbit platelets with the IC50 being 1.9 x 10(-4) M.

Animals↗
PubMed1995

[Results of mutation analyses of von Hippel-Lindau disease gene in Japanese patients: comparison with results in United States and United Kingdom].

Recently the gene responsible for the von Hippel-Lindau (VHL) disease was identified as a tumor suppressor gene. Our ongoing studies on the mutation of the VHL gene in Japanese 28 VHL families with single strand conformational analyses of DNA and Southern blot analyses revealed 6 cases of insertion or deletion, 1 cases of splice site mutation and 9 cases of missense mutation, and 3 possible intragenic deletions. Our analytical findings are essentially similar to those observed in the western countries. The VHL families associated with pheochromocytoma had the same mutational hot spot as those in the western countries. Molecular analyses of the VHL gene in the Japanese VHL disease substantially improved the understanding of this disease and its inheritance character.

Blotting, Southern↗
PubMed1995

Retinoblastoma gene mutation in primary human renal cell carcinoma.

We searched for possible mutations in the E2F-binding region of retinoblastoma gene in primary human renal cell carcinomas, using polymerase chain reaction and single-strand conformational polymorphism analysis of RNA. Retinoblastoma gene mutation was detected in 1 of 21 cases (5%). DNA sequencing of the polymerase chain reaction product verified that this case had a 6-base deletion at the beginning of exon 8. Our findings suggest that mutation of the retinoblastoma gene is involved in only a subgroup of sporadic human renal cell carcinomas.

Base Sequence↗