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Biomedical subjects

S Nagase

Publications and source records attributed to S Nagase.

At least 109 records · Page 6Linked to original sources
PubMed1992

Toxicity to rats of methanol-fueled engine exhaust inhaled continuously for 28 days.

Fischer 344 rats were exposed to three concentrations of exhaust generated by an M85 methanol-fueled engine (methanol with 15% gasoline) without catalyst for 8 h/d, 7 d/wk for 7, 14, 21, or 28 d. Concentration- and time-dependent yellowing of the fur was prominent in all treated groups. Concentration-dependent increases in the erythrocyte count, hematocrit, hemoglobin concentration, formaldehyde in plasma, and carboxyhemoglobin in the erythrocytes, and decrease in serum alkaline phosphatase activity were seen after all exposure periods. Histopathologically, lesions were found in the nasal cavity and lungs after 7 d of exposure. Squamous metaplasia of the respiratory epithelium of level 1 (level of the posterior edge of the upper incisor teeth) lining of the nasoturbinate and/or maxilloturbinate and infiltration of neutrophils into the submucosa, and decreases of Clara cells in the terminal bronchiolus and of cilia in the bronchiolar epithelium, were observed in the high-concentration group (carbon monoxide, 94 ppm; formaldehyde, 6.9 ppm; methanol, 17.9 ppm; nitrogen oxides, 52.7 ppm; nitrogen dioxide, 10.6 ppm). The histopathological extents of several lesions increased slightly with the exposure time. Slight squamous metaplasia and hyperplasia of the respiratory epithelium at level 1 were also observed in the medium-concentration group (one in three of the high-concentration group). No histopathological changes were found in the olfactory epithelium of the nasal cavity. In the low-concentration group (one in nine of the high-concentration group), no marked histopathological changes in these organs were observed. These results may suggest that the lesions observed in the nasal cavity of rats exposed to methanol-fueled engine exhaust were mainly caused by formaldehyde, although other components in the exhaust also may have affected nasal cavity and/or lungs to less extent.

Alkaline Phosphatase↗
PubMed1992

High susceptibility of analbuminemic rats to neurogenic tumor induction by transplacental administration of N-ethyl-N-nitrosourea.

The susceptibilities of Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR) to N-ethyl-N-nitrosourea (ENU) were compared. In Experiment I, the rats were given daily subcutaneous injections of 10 mg/kg of ENU for a week from 4 weeks of age. In Experiment II, mother rats were given a single subcutaneous injection of 60 mg/kg of ENU on day 17 of pregnancy and tumor development in their offspring was examined. In Experiment I, the incidence of neurogenic tumors was slightly, but not significantly, higher in NAR than in control rats. In Experiment II, the incidence of total tumors including neurogenic tumors was significantly higher in NAR (40/43, 93.0%) than in SDR (13/61, 21.3%). NAR showed particularly high susceptibility to induction of neurogenic tumors (34/43, 79.1%) and renal tumors (15/43, 34.9%). In an attempt to elucidate the underlying mechanisms of the increased susceptibility of NAR to ENU, O6-ethylguanine, a major premutagenic ethylated DNA adduct, was quantitated in fetal brain DNA of NAR and SDR after a pulse exposure to 60 mg/kg ENU. No significant difference in the initial formation or subsequent repair of O6-ethylguanine was observed in the two strains, indicating that abnormality at some later stage(s) of chemical carcinogenesis may lead to the increased susceptibility of NAR to induction of neurogenic tumors.

Animals↗
PubMed1992

Biosynthesis of methylguanidine in the hepatic microsomal fraction.

We have investigated various synthetic mechanisms for the production of methylguanidine, a potent uremic toxin, and reported a role for active oxygen in its biosynthesis from creatinine in studies using isolated hepatocytes. In this study, we turn our attention to the hepatic microsomes. Liver homogenates were made from rats, and various organelles were obtained by centrifugation and incubated with creatinine. The results show that methylguanidine synthesis occurs only in the microsomal fraction in the presence of nicotinamide adenine dinucleotide phosphate, reduced form. The microsomal activity is inhibited by the addition of methimazole, metyrapone, superoxide dismutase, catalase or dimethylsulfoxide. These results suggest that methylguanidine is synthesized from creatinine by microsomes, and at least 2 enzymes are involved, an FAD-containing monooxygenase and a P-450-dependent oxidase based on the inhibitory effect of methimazole and metyrapone, respectively. Moreover, the inhibition by various scavengers of active oxygen suggests that active oxygen plays a role in the intermediate steps of the enzymatic reaction.

Animals↗
PubMed1992

Hematological and clinico-biochemical characteristics of leukemia in Fischer 344 rats.

Seventy-one male and 52 female F 344 rats with leukemia used as controls in the 30-month inhalation studies were characterized by hematological and clinico-biochemical findings. Hematological findings revealed that the leukocyte count, mean corpuscular volume, and mean corpuscular hemoglobin increased in both sexes of leukemic rats showing profound anemia, while the platelet count, erythrocyte count, hematocrit, and hemoglobin concentration decreased. In these rats, the serum levels of low density lipoprotein, free cholesterol, total bilirubin, blood urea nitrogen, and triglyceride and the activities of glutamic oxalacetic transaminase, glutamic pyruvic transaminase, creatine phosphokinase, alkaline phosphatase, and lactate dehydrogenase increased markedly and the level of high density lipoprotein, the oxygen partial pressure, and the cholinesterase activity decreased. Clinical signs such as decrease in redness of the eyes, decrease in body weight, abdominal distension, staining of the public region, and debility were seen in most leukemic animals. These clinical signs and hematological and clinico-biochemical findings may be helpful in diagnosis of leukemia in long-term experiments.

Animals↗
PubMed1992

Albuminuria is not an aggravating factor in experimental focal glomerulosclerosis and hyalinosis.

It is widely known that the severity of glomerular sclerosis is proportional to the degree and chronicity of proteinuria and that the degenerative changes of glomerular epithelial cells that are associated with overflow albuminuria can be experimentally induced by the injection of large quantities of heterologous albumin. Such evidence suggests that autologous albuminuria per se may have a harmful effect on the kidneys. To examine the cause and effect relationship between renal lesions and albuminuria, we produced Adriamycin-induced experimental focal glomerular sclerosis in Nagase analbuminemic (NA) rats and control Sprague-Dawley (SD) rats and observed both the renal functional and histologic changes for 20 weeks. At week 4 after injection of Adriamycin glomerular epithelial lesions including foot process fusion were similarly revealed by an electron microscopic study in both groups in spite of the presence of a large difference in the amount of proteinuria (SD rats: 491 +/- 84 mg/day, NA rats: 43 +/- 30 mg/day) and albuminuria (SD rats: 383 +/- 73 mg/day, NA rats: 2 +/- 1 mg/day). At week 20, a light microscopic study showed the same degree of glomerular sclerosis and hyalinosis and tubulointerstitial changes associated with a decrease in inulin clearance in both groups. The increased glomerular accumulation of immunoglobulin M or complement 3 and glomerular trapping of aggregated human immunoglobulin G were also similar between the SD and NA groups. In summary, renal destruction of Adriamycin-nephropathy was not dependent on the degree of albuminuria. These results suggest that albuminuria is not an aggravating factor in focal glomerulosclerosis.

Albumins↗
PubMed1991

Marked increases of two kinds of two-exon-skipped albumin mRNAs with aging and their further increase by treatment with 3'-methyl-4-dimethylaminoazobenzene in Nagase analbuminemic rats.

Nagase analbuminemic rats (NARs) have a 7-base-pair deletion at the 5' splice site of the HI intron of the albumin gene. The level of immunohistochemically albumin-positive hepatocytes is about 1 per 10(5) cells in neonatal NARs, increases with age, and further increases with chronic oral treatment with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). The mechanisms involved in the increase in albumin-positive hepatocytes during aging of NARs and their treatment with 3'-MeDAB were analyzed. NARs were found to have four species of albumin mRNA: intact mRNA and those lacking the regions corresponding to exon H, exon G-H, and exon H-I. In 4-week-old NARs, the level of intact albumin mRNA was about 1/4000 of that in normal rats and mRNA lacking the exon H sequence was the major species. In aged and 3'-MeDAB-treated aged NARs, all four species of mRNA increased and the relative proportion of mRNAs lacking two exon sequences to mRNAs lacking one exon sequence was greatly increased, suggesting that aging is associated with changes of the splicing pattern and that 3'-MeDAB treatment enhanced these changes. In aged NARs and 3'-MeDAB-treated aged NARs, there was an increase in the amount of aberrant 60-kDa albumin. The 60-kDa protein could be a translation product of mRNAs lacking two exons, the amount of which increases in aged NARs and 3'-MeDAB-treated NARs.

Aging↗
PubMed1991

A case of insulin allergy: the crystalline human insulin may mask its antigenicity.

We report an unusual case of insulin allergy. A 48-year-old man with non-insulin-dependent diabetes mellitus receiving biosynthetic isophane human insulin (Humulin N) developed itchy wheal-and-flare reactions at the sites of injection. When Humulin N was changed to a semi-synthetic crystalline human insulin zinc (Novolin U), the allergic reactions completely disappeared. Evaluation of his serum showed a high level of insulin-specific IgE. Skin testing with all commercially available insulins showed immediate local reactions to all agents tested except for Novolin U. In addition, decrystallized Novolin U prepared by lowering the pH with acetic acid also induced a positive reaction. These observations suggest that the crystallized structure of human insulin may mask its antigenicity for allergic reactions.

Diabetes Mellitus, Type 2↗
PubMed1991

Lack of bladder carcinogenicity of dietary sodium saccharin in analbuminaemic rats, which are highly susceptible to N-nitroso-n-butyl-(4-hydroxybutyl)amine.

A previous 1-wk study measuring the agglutinability of bladder epithelial cells by concanavalin A had suggested a high susceptibility of analbuminaemic rats to bladder carcinogenesis by sodium saccharin (Honma et al., Cancer Letters 1983, 19, 7). A long-term study was conducted to confirm the results of this short-term assay. Sodium saccharin was administered at 5% in the diet to groups of 35 male analbuminaemic rats and 36 male rats of the Sprague-Dawley strain. No bladder carcinomas nor precancerous lesions were observed in any of the rats exposed to sodium saccharin. The discrepancy between the results of the agglutination assay and the long-term experiment might be attributable to a sharp increase in urine volume in analbuminaemic rats during the first week of treatment. The resultant distension of the bladder wall might make the epithelial cells more susceptible to concanavalin A agglutination. The results indicated no demonstrable bladder carcinogenicity of sodium saccharin in analbuminaemic rats and excluded the possibility that these particular mutant rats could be useful animals for shorter-duration screening for bladder carcinogens.

Administration, Oral↗
PubMed1991

Induction of intestinal adenocarcinomas by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Nagase analbuminemic rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine in cooked foods, was examined for carcinogenic potential using Nagase analbuminemic rats (NARs), which are sensitive to various carcinogens. The concentration of PhIP in the diet was 0.04% at the beginning of the experiment, this being subsequently gradually reduced to 0.01% to avoid severe body weight loss. Ten of 13 treated NARs developed a total of 36 intestinal tumors within the 311-day experimental period. Among these, 22 were adenocarcinomas and 2 were adenomas of the small intestine, 4 were adenocarcinomas of the cecum and 8 were adenocarcinomas of the large intestine. The results suggest that PhIP could represent a significant risk to human populations exposed to foods containing heterocyclic amines.

Adenocarcinoma↗
PubMed1991

Effect of starvation and refeeding on the circadian rhythms of hematological and clinico-biochemical values, and water intake of rats.

We investigated the effect of starvation for 24 hr and subsequent refeeding for 12 hr on the circadian rhythms of 39 hematological and clinico-biochemical parameters, and water intake of F344 rats. The rats scarcely drank any water during the starvation period, but subsequently their intake of water were normal, even in the light period. During starvation, 12 parameters such as serum levels of alkaline phosphatase activity and PaCO2 decreased with time-related and time-related increases of 8 parameters such as the erythrocyte count and cholinesterase activity. During refeeding for 12 hr, almost all these biochemical parameters were normalized, but none of the hematological values except the leukocyte count returned to normal levels. Starvation and refeeding had little affect on the circadian rhythms of others.

Alkaline Phosphatase↗
PubMed1990

Dynamic aspects of thrombus formation in mutant analbuminemic rats.

To elucidate the mechanism for thrombus formation in hypoalbuminemic and hyperlipidemic subjects, the experimental thrombus formation was analyzed in Nagase analbuminemic rats (NAR). The mutant rat reveals similar biochemical findings to those of NS, such as hyperlipidemia. When thrombus was induced in a small branch of the mesenteric artery by inserting a glass micropipette, thrombus formation was observed within 4 min in NAR and Sprague-Dawley rat (SDR). In SDR, the thrombus gradually grew up in size and detached from the inserted glass micropipette within 4 min after its formation. In contrast, the thrombus formed in NAR did not dissociate from the micropipette until 10-13 min after its formation. The maximum size of the thrombus formed in NAR was about 4 times larger than that in SDR. In the presence of fibrin, the plasma samples from NAR inhibited the activity of tissue-plasminogen activator (t-PA) 1.7 times more potently than did SDR plasma. Plasma gamma 2-plasmin inhibitor activity was significantly higher than that in SDR. Albumin significantly enhanced the t-PA-catalyzed activation of plasminogen, suggesting that the serum albumin might contribute, at least in part, to the plasma fibrinolytic activity. Thus, the higher thrombogenic potential in NAR than in SDR might be due to the reduced thrombolytic activity in NAR.

Animals↗
PubMed1990

Disposition of phenytoin in analbuminemic rats.

The disposition characteristics of phenytoin were investigated in analbuminemic rats to study the effect of plasma protein binding on phenytoin disposition. Blood and plasma phenytoin concentration determinations, measurement of plasma protein phenytoin binding, and whole-body autoradiography were performed after intravenous bolus injection of 10 mg kg-1 of phenytoin. When plasma phenytoin was assayed, total body phenytoin clearance (CL) was faster and its apparent volume of distribution (Vd) greater in the analbuminemic rats in comparison to the controls. The plasma protein binding of phenytoin was significantly lower in the analbuminemic rats, suggesting the disposition characteristics of phenytoin were altered in the presence of low plasma albumin concentrations due to reduced plasma phenytoin protein binding. On the other hand, when blood phenytoin levels were analyzed, no difference in CL and a less pronounced difference in Vd were noted between the two groups of rats. The red blood cell-to-plasma phenytoin concentration ratios were greater in analbuminemic rats, suggesting that the distribution of phenytoin into red blood cells was greater in the mutant rats.

Animals↗
PubMed1990

Identification of a protein increasing in serum of Nagase analbuminemic rats bearing intestinal tumors as an isotype of T-kininogen.

Increase in an unidentified protein was observed in serum of Nagase analbuminemic rats (NAR) bearing intestinal tumors induced by azoxymethane. This protein seemed to be a polymer of a protein of 73 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and so was tentatively named 73K-protein. The serum concentration of 73K-protein in NAR bearing intestinal tumors was 11.9 +/- 2.2 mg/ml (mean +/- SD, n = 5), whereas that in control NAR was 2.0 +/- 0.2 mg/ml. Increase of the serum 73K-protein level was also observed in Sprague-Dawley rats bearing intestinal tumors, skin tumors, subcutaneous sarcomas, or mammary tumors and in ACI rats bearing urinary bladder tumors. On double immunodiffusion analysis, the 73K-protein was not detected in mouse, guinea pig, pig, horse, or human serum. A cDNA clone bearing the sequence encoding 73K-protein was isolated from a cDNA library constructed from rat liver mRNA. The nucleotide sequence of the 73K-protein showed 98.8% and 96.9% homologies with the sequences of the 3'-proximal domains of the cDNAs for TI- and TII-kininogen, respectively. Therefore, the 73K-protein was concluded to be an isotype of T-kininogen.

Amino Acid Sequence↗
PubMed1990

Genotypic differentiation of intrahepatically transplanted hyperplastic nodule cells of analbuminemic and normal rat origin by polymerase chain reaction.

DNA fragments encompassing the region of the seven-base-pair deletion in the albumin gene, which is a characteristic abnormality of Nagase's analbuminemic rat (NAR), were amplified by polymerase chain reaction, and we could differentiate the genotypes of normal rat, homozygous NAR and heterozygous NAR electrophoretically. This genotyping method was applied to the differentiation of hyperplastic nodules on immunostained tissue sections in the intrahepatic transplantation model. When the hyperplastic nodule cells of normal rat were transplanted to the livers of homozygous NAR, the donor cells were effectively differentiated from the host cells by the genotype.

Albumins↗
PubMed1990

[An evaluation method for hematological and clinico-biochemical values in aged F 344 rats on chronic toxicity tests such as long-term inhalation studies on the effects of diesel exhaust].

To determine the chronic toxicity of diesel exhaust, 2,150 F 344 rats were made to inhale various dilutions of exhaust under specific pathogen-free conditions for 16 hours a day, 6 days a week, for 30 months. Ten experimental groups, each with 120 male and 95 female 5 week-old rats, were set up and 14 males and 9 females were usually sacrificed for measurement of the 51 hematological and clinico-biochemical parameters at 7, 13, 19, and 25 months of age, respectively. These parameters were also examined in all surviving rats after 30 months of exhaust inhalation. In this experiment, no remarkable change in any of the parameters was observed in the periodic examinations. Therefore, tendencies of change in parameters were examined by comparing histograms for control and experimental groups. For the reference histograms, we used the values obtained from 144 males and 116 females aged 13-31 months. The first histogram was based on data from 1,352 rats, and the range from the minimum to the maximum value was divided into eight parts. When almost all the values were centered on a peak in the first histogram, this peak was divided into a further eight parts in the second histogram. Histogram evaluation clarified the differences between the control and experimental groups better than general statistical methods such as Student's t-test.

Administration, Inhalation↗
PubMed1990

[Urinary excretion rate of methylguanidine as a new maker of active oxygen in vivo: demonstration in hyperbaric oxygen therapy].

Methylguanidine (MG) which is known as a uremic toxin, is synthesized from creatinine (Cre). We have clarified that active oxygen plays an important role on MG synthesis in vitro and in rat hepatocytes. On the other hand, hyperoxia is very injurious in various tissues, and it has been reported that active oxygen produced in hyperoxia plays an important role on the tissue injury. This study was performed to investigate the effect of hyperoxia on MG synthesis in vivo. The subjects in this study were patients who were treated by hyperbaric oxygen therapy (HBO). Serum Cre, MG, and urinary Cre, MG before and after HBO were measured in these subjects. The subjects were classified into four groups. Group I-III were undergone HBO with condition of 100% O2, 2 atmosphere absolute (ATA), 1 hour, (I: Ccr less than 10 ml/min, II: 10 less than or equal to Ccr less than 50 ml/min, III: Ccr greater than or equal to 50 ml/min) and group IV (Ccr greater than or equal to 50 ml/min) with 100%O2, 3ATA, 1 hour. Urinary excretion rate of MG (urine MG/urine Cre) significantly increased after HBO therapy in every group. Urine MG/urine Cre/serum Cre ratio which was used as a index of MG synthesis rate also increased. In this study, it is clarified that MG excretion rate increases in hyperoxic condition. These results suggest that active oxygen plays an important role on MG synthesis in vivo, and that the urine MG/urine Cre/serum Cre ratio can be a useful maker of the active oxygen products in vivo.

Adult↗