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Biomedical subjects

I Inoue

Publications and source records attributed to I Inoue.

At least 109 records · Page 6Linked to original sources
PubMed1995

A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system.

Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues. In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in Km (from 1.1 to 0.09 microM) and a 5-fold decrease in kcat (from 1.0 to 0.22 s-1); as a result, catalytic efficiency (kcat/Km) is increased by a factor of 2 (1.1 versus 2.4 microM-1 s-1). In the reaction of angiotensin-converting enzyme on angiotensin decapeptides, the substitution has no effect on Km (38.0 versus 30.0 microM), but increases kcat and catalytic efficiency > 2-fold (kcat = 15.0 versus 37.0 s-1; kcat/Km = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.

Angiotensinogen↗
PubMed1995

Inhibitory effects of selenium, vitamin A and butylated hydroxytoluene on in vitro growth of human tongue cancer cells.

The effects of vitamin A, selenium and butylated hydroxytoluene (BHT) on the growth of a human tongue cancer cell line were examined in monolayer cell cultures. A colony-forming assay showed a 50% reduction in the survival rate of the cell line at a concentration of 2.6 micrograms/ml selenium, 60 micrograms/ml vitamin A and/or 38 micrograms/ml BHT. Relatively low concentrations of selenium markedly inhibited glucose consumption. Flow cytometric analysis with both fluorescein-isothiocyanate-labelled bromodeoxyuridine monoclonal antibody and propidium iodide demonstrated an increase in S-phase fractions 1 day after the addition of selenium, increased G0/G1 phase fractions in the presence of vitamin A and increased G2-M phase fractions when BHT was added. These results suggest that these compounds inhibit DNA synthesis of in vitro human tongue cancer cells by different mechanisms.

Butylated Hydroxytoluene↗
PubMed1995

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats.

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Animals↗
PubMed1995

[An elder case of accidental hypothermia].

A 87-year-old woman with accidental hypothermia was admitted to our hospital. On admission, she showed consciousness disturbance (JSC III-200) the decorticate rigidity and shock. Her body temperature was too low to been measured and her ECG revealed a J wave. She received the external rewarming and warm fluid replacement. Her consciousness level recovered to JSC II-20 after 2.5 hours of treatment, to JCSI-1 after 7.5 hours. Her body temperature reached 34.5 degrees C 9.5 hours later, and the J wave on ECG disappeared. She was discharged without complications on the 6th hospital day. it was suggested that early diagnosis and the proper therapy improves the mortality of accidental hypothermia.

Accidents, Home↗
PubMed1994

On the relationship between the metabolic and thermodynamic stabilities of T4 lysozymes. Measurements in Escherichia coli.

Escherichia coli cells were transformed with plasmids encoding 12 site-specific variants of T4 lysozyme, and pulse-chase protocols were used to measure the metabolic stability of each protein. The resulting half-lives ranged from 1 h to more than 50 h. Although the metabolic half-lives of T4 lysozymes correlated roughly with their thermal stabilities, three mutant enzymes were clear exceptions. A reasonably temperature-resistant variant, G156D, exhibited a half-life of 1 h. By contrast, two temperature-sensitive variants, T157I and I3G, were as metabolically stable as wild-type T4 lysozyme. Degradation of two short lived variants, L91P and G156P, required ATP both in vivo and in vitro. Degradation of variant and wild-type enzymes was unimpaired in cells lacking the Lon protease, Clp A or Clp P. However, degradation of L91P and G156D was inhibited in Clp B-cells. Decreased proteolysis of L91P was accompanied by its accumulation in inclusion bodies, indicating that Clp B prevents accumulation of aggregated protein either by preventing aggregation of misfolded polypeptides or solubilizing aggregates.

Adenosine Triphosphate↗
PubMed1994

On the relationship between the metabolic and thermodynamic stabilities of T4 lysozymes. Measurements in eukaryotic cells.

We have measured the metabolic stabilities of wild-type and 17 temperature-sensitive mutants of T4 lysozyme in HeLa cells, in Xenopus egg extract, and in reticulocyte lysate. [35S]Methionine-labeled T4 lysozymes were expressed in Escherichia coli, purified, injected into HeLa cells, and their degradation rates were determined. Wild-type T4 lysozyme has a half-life of 4 h; the half-lives of 16 lysozyme variants ranged from 2 to 10 h. Surprisingly, the most temperature-sensitive enzyme in the set, R96H, was significantly more stable (half-life = 10 h). Different T4 lysozyme variants yield conflicting answers to the proposed relationship between thermal and metabolic stabilities. For mutations at Thr157 there is no correlation between melting temperature and half-life. By contrast, T4 lysozymes mutated at various positions show a definite correlation between the two parameters. Treatment of injected HeLa cells with the lysosomotropic agents chloroquine or ammonium chloride did not alter the stability of T4 lysozyme. However, the enzyme's half-life increased 10-fold in HeLa cells depleted of ATP. Although T4 lysozyme is degraded rapidly within HeLa cells, the molecule is stable in reticulocyte lysate and Xenopus egg extract. Presumably, there is a specific proteolytic event(s) in HeLa cells which is not manifest in the in vitro extracts.

Animals↗
PubMed1994

Cellular catabolism of normal very low density lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is induced by the C-terminal domain of lipoprotein lipase.

Lipoprotein lipase (LPL) binds to the low density lipoprotein receptor-related protein (LRP)/alpha 2-macroglobulin receptor and induces catabolism of normal human very low density lipoproteins (VLDL) via LRP in vitro. Recent studies showed that the C-terminal domain of LPL can bind LRP in solid phase assays and inhibit cellular catabolism of two LRP ligands, activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein (Williams, S.E., Inoue, I., Tran, H., Fry, G. L., Pladet, M.W., Iverius, P.-H., Lalouel, J.-M., Chappell, D.A., and Strickland, D.K. (1994) J. Biol. Chem. 269, 8653-8658). The current study investigated the potential for this region of LPL to promote cellular catabolism of VLDL via LRP. A fragment comprising the C-terminal domain of LPL (designated LPLC) was expressed in bacteria and found to promote cellular binding, uptake, and degradation of normal human VLDL in a dose-dependent manner. These effects were present whether LPLC was added simultaneously with 125I-VLDL or was prebound to cell surfaces prior to the assay. Mutations involving Lys407, Trp393, Trp394, or deletion of the C-terminal 14 residues reduced the effects of LPLC. Three LRP-binding proteins, the receptor-associated protein, lactoferrin, and a polyclonal antibody against LRP, competed for 125I-VLDL degradation induced by LPLC. Heparin or heparinase treatment of cells prevented LPLC-induced 125I-VLDL catabolism. Thus, cell-surface proteoglycans play an important role in this pathway. Interestingly, either LPLC or LPL when added in excess could block LPL-induced 125I-VLDL degradation presumably by interacting directly with LRP. However, unlabeled VLDL could not prevent catabolism of 125I-labeled LPLC or LPL. These data show that cellular fates for VLDL versus LPLC or LPL are divergent. This is probably due to independent catabolism of the latter via cell-surface proteoglycans. In summary, these in vitro studies indicate that a fragment of LPL corresponding to the C-terminal domain mimics the native enzyme with respect to induction of VLDL catabolism via LRP. Because LPLC lacks the catalytic site of native LPL, these studies establish that lipase activity is not required for LRP-mediated lipoprotein catabolism.

Binding, Competitive↗
PubMed1994

The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

Amino Acid Sequence↗
PubMed1994

Regulation of a non-selective cation channel of cultured porcine coronary artery smooth muscle cells by tyrosine kinase.

A non-selective cation channel was found in primary cultured porcine coronary artery smooth muscle cells. In patch-clamp studies in the cell-attached mode, this channel was activated by bath application of genistein, a specific inhibitor of tyrosine kinase, but not by daidzein, which is similar in structure to genistein but has no inhibitory effect on tyrosine kinase. This channel discriminated poorly between Na+ and K+ (permeability ratio PNa/PK = 1.03), and also transported Ca2+. The single-channel conductance measured with a pipette solution containing 150 mM Na+ was 139 +/- 24 pS (mean +/- SD, n = 5), and that for the inward current measured with 100 mM Ca2+ solution was 25 +/- 9 pS (n = 3). This non-selective cation channel was also activated by staurosporine, a non-specific protein kinase inhibitor, but not by H-7, an inhibitor of protein serine/threonine kinase. These results suggest that the activity of the non-selective cation channel is negatively regulated by tyrosine kinase activity, and thus a decrease of the enzyme activity in porcine coronary artery smooth muscle cells may result in membrane depolarization and Ca2+ entry.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Improvement of glucose tolerance by bezafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance.

Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease.

Bezafibrate↗
PubMed1994

Histopathology of the lungs of rabbits experimentally infected with Dirofilaria immitis.

The lungs of rabbits experimentally infected with Dirofilaria immitis were examined histopathologically, to compare the changes with those seen in human pulmonary dirofilariasis. Eight rabbits were infected subcutaneously with two to eight immature worms to induce pulmonary dirofilariasis. Obstructive changes, similar to those reported in human pulmonary dirofilariasis, were observed in the blood vessels surrounding the worms. A form of arteritis, similar to occlusive arteritis, and periarteritis were also observed in the lungs of the rabbits. These results suggest that experimentally induced dirofilariasis in the rabbit is a useful animal model for human pulmonary dirofilariasis.

Animals↗
PubMed1994

Fetal bladder outlet obstruction diagnosed at 13-weeks' gestation.

An ultrasonographic examination revealed increased fetal bladder size as well as fetal bilateral hydronephrosis at 13-weeks' gestation. Diagnosis of the fetal urethral obstruction was made. Repeated ultrasonography was undertaken from the 13th to through 16th weeks of gestation. Percutaneous puncture with aspiration and laboratory analysis of fetal urine was performed at 15-weeks' gestation. The fetal renal function seemed not to be damaged by use of these antenatal procedures. Following induced abortion at 16-weeks' gestation, an autopsy showed that the fetal urethral obstruction was caused by a posterior valve, with no histological evidence of fetal renal dysplasia.

Adult↗
PubMed1994

Molecular screening of the lipoprotein lipase gene in hypertriglyceridemic members of familial noninsulin-dependent diabetes mellitus families.

Hypertriglyceridemia is common among individuals with noninsulin-dependent diabetes mellitus (NIDDM), and heterozygous lipoprotein lipase (LPL) mutations may result in the syndrome of familial hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. To test the hypothesis that heterozygous LPL mutations predispose to the hypertriglyceridemia and low HDL cholesterol levels observed among members of familial NIDDM families, we examined 36 members and 3 unrelated spouses selected from members of 20 pedigrees for triglyceride levels exceeding the age- and sex-specific 95th percentile. Eighteen pedigree members and 2 spouses were diabetic. LPL exons 1-9 were screened by single strand conformation polymorphism analysis. Six different variants were detected in exons 2, 3, 4, 8, and 9, including 4 (exons 3, 4, and 8) silent nucleotide substitutions. A common nonsense mutation (exon 9; Ser-->Ter) was present in 2 pedigrees, and a missense mutation (exon 2; Asp-->Asn) was also present in members of 2 pedigrees. Analysis of members of these families suggested an association of the exon 2 variant with hypertriglyceridemia, although this trend was no longer significant when individuals with diabetes were excluded from the analysis. The variant enzyme was not present among 83 random control individuals, and when expressed in COS-1 cells, it was similar to the wild type with respect to specific activity, heparin binding, and heat stability. Our data suggest that coding region mutations of the LPL gene cannot account for the elevated triglyceride and low HDL levels noted in diabetic individuals and their relatives in most NIDDM pedigrees, but the exon 2 Asn variant may contribute to the hypertriglyceridemia in some families.

Adult↗
PubMed1994

Japanese family with Creutzfeldt-Jakob disease with codon 200 point mutation of the prion protein gene.

We report the first Japanese case of familial Creutzfeldt-Jakob disease (CJD) with the heterozygous point mutation at codon 200 of the prion protein gene. This suggests that the mutation is not race-specific. The clinical and pathologic features of this case are not different from those of sporadic CJD without point mutations. Some healthy members of the family also carry the same mutation in the autosomal dominant inheritance expression.

Adolescent↗
PubMed1994

Role of adenosine in dialysis-induced hypotension.

First, this investigation showed that plasma levels of inosine, hypoxanthine, and xanthine, which are metabolites of adenosine, rose sharply when blood pressure dropped suddenly along with symptoms during a hemodialysis session (sudden hypotension), but not when it decreased gradually with eventual symptoms (gradual hypotension). Because adenosine has an action to dilate vessels, this result indicates the possibility that the increased release of adenosine would be a cause of sudden hypotension. Second, it was found that the frequency of sudden hypotension decreases with the administration of caffeine, which is an adenosine-receptor antagonist, whereas the frequency of gradual hypotension did not change. This result supports the above-mentioned hypothesis that adenosine may well be a mediator of sudden hypotension, but not of gradual hypotension. Third, our investigation demonstrated no significant differences in plasma norepinephrine level, in plasma renin activity, or in mean blood pressure between the hemodialysis session in which caffeine was administered and the session in which a placebo was given. These findings suggest that the effect of caffeine administration to prevent sudden hypotension is not mediated by the stimulation of the sympathetic nervous system or activation of the renin-angiotensin system, but by the adenosine-receptor antagonism.

Adenosine↗
PubMed1994

[Permanent pacemaker therapy in a community with many elderly people].

To clarify the utility of permanent pacemakers in a society composed largely of elderly people, clinical characteristics, pacemaker characteristics, outcome, and quality of life in a total of 116 patients in a community with many (19.6%) elderly people were evaluated after permanent pacemaker implantation. Patients above age 65 accounted for 88.8%, while those above 80 years accounted for 24.1%. Syncope was the most common observation before pacemaker implantation and emergency care was needed in 35% of patients. Sick sinus syndrome and complete AV block were seen in a majority, while atrial fibrillation with bradycardia was seen in a minority of patients. Although the physiological pacing and ventricular pacing mode (VVI) were used in about 50% each, recently the physiological pacing mode has markedly increased. During the mean follow-up of 26.1 +/- 16.2 months, only four patients died. NYHA 3 symptom improved to NYHA 1 after pacemaker implantation and 72.5% patients of all cases returned to their jobs. We conclude that the permanent pacemaker is effective in improving symptoms and reducing the death rate in elderly patients.

Aged↗
PubMed1994

[Cytofluorometric DNA analysis in different histological patterns of thyroid papillary carcinoma].

Some papillary carcinomas of thyroid glands contain not only typical papillary structures but also various histological features in the same tumor. To investigate how areas with variable histological features differ in proliferative activity and how these differences influence the biological behavior of the whole tumor, we measured DNA contents by cytofluorometry in six papillary carcinomas with different histological features in the same tumor. DNA ploidy patterns were determined and the percentage of S plus G2M phase cells (S + G2M fraction) was calculated only in diploid tumors to assess the proliferative activity. The following conclusions were drawn. 1) It was demonstrated that there were differences in proliferative activity among areas with variable histological features in 4 of six tumors. 2) In the tumors which invaded adjacent tissues, the proliferative activity of the invasive area tended to be higher than that of the original area of the tumor. Therefore, the possibility exists that more precise evaluation of the biological behavior of the tumor can be obtained by measuring DNA contents of the tumor cells in invasive areas. 3) There was the gap in S + G2M fractions among some tumors with the same histological differentiation. Accordingly, DNA analysis of tumors would be of value in estimating proliferative activity.

Aged↗