PubMed Health⌕ Search

Biomedical subjects

R Sakai

Publications and source records attributed to R Sakai.

At least 19 recordsLinked to original sources
PubMed1992

Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo.

Ecteinascidins (Ets), isolated from the Caribbean tunicate Ecteinascidia turbinata, protect mice in vivo against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma xenografts. Crystal structures of two tris(tetrahydroisoquinoline) Ets were investigated with single crystals of the 21-O-methyl-N12-formyl derivative of Et 729 and the natural N12-oxide of Et 743. Representatives of an additional class of Ets, Et 722 and Et 736, isolated from the same organism, were assigned tetrahydro-beta-carboline-substituted bis(tetrahydroisoquinoline) structures by NMR and fast atom bombardment MS spectra.

Animals↗
PubMed1992

The measurement of activin/EDF in mouse serum: evidence for extragonadal production.

Many studies have shown that activin/EDF mediates local physiological events at various sites. In this study, the authors confirmed the presence of activin in mouse serum by high performance liquid chromatography (HPLC) monitored by a specific bioassay. The retention time of the active fraction in HPLC was identical to that of authentic activin A, and the activity was neutralized by follistatin. That the serum activin levels in ovariectomized and aged mice were decreased suggests that the serum activin was generated partly by ovary (35%), but also by extragonadal organs. Activin and inhibin are structurally closely related, and both are involved in many physiological processes including control of follicle stimulating hormone secretion by the pituitary. The regulation of serum activin, however, appeared to differ from that of inhibin.

Activins↗
PubMed1992

Effects of alkyl substitutions of xanthine skeleton on bronchodilation.

Structure-activity relationships in a series of 1,3,7-trialkyl-xanthine were studied with guinea pigs. Relaxant actions in the tracheal muscle were increased with alkyl chain length at the 1- and 3-positions of the xanthine skeleton, but decreased by alkylation at the 7-position. Positive chronotropic actions in the right atrium were potentiated with 3-alkyl chain length but tended to decrease with 1-alkylation and diminish by 7-substitution. Consequently, while the 1- and 3-substitutions were equally important for the tracheal smooth muscle relaxation, the substitution at the 1-position was more important than the 3-substitution for bronchoselectivity. The 7-alkylation may be significant to cancel heart stimulation. There were good correlations between the smooth muscle relaxant action and the cyclic AMP-PDE inhibitory activity in 3-substituents and the affinity for adenosine (A1) receptors in 1-, 3-, and 7-substituents. This suggests that not only the cyclic AMP-PDE inhibitory activity but also the adenosine antagonistic activity is important in the bronchodilatory effects of alkylxanthines. Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Molecular cloning of bovine actin-like protein, actin2.

Actins are major cytoskeletal components and highly conserved in evolution. In mammals, there are six actin isoforms, a pair of which shows at least 93% identity in the amino acid sequence. We have cloned cDNA for a bovine protein that is distantly related to members of the mammalian actin isotypes. The predicted amino acid sequence (418 residues long, calculated molecular mass 47369) shows that this protein, which we have named actin2, exhibits 36% identity to mammalian actins and 60% identity to the yeast actin-like protein, act2. We have concluded that actin2 defines a new class of mammalian actin-like proteins. It was also revealed that actin2 messenger RNA is expressed in a broad range of tissues.

Actins↗
PubMed1992

Frequent mutations in the p53 gene in human myeloid leukemia cell lines.

The p53 gene is currently considered to function as a tumor-suppressor gene in various human malignancies. In hematologic malignancies, alterations in the p53 gene have been shown in some human leukemias and lymphomas. Although mutations in the p53 gene are infrequent in acute myelogenous leukemia (AML) patients, we show in this report that alterations in the p53 gene are frequent in myeloid leukemia cell lines. We studied alterations of the p53 gene in nine human myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and direct sequencing. Expression of the p53 gene was not detected at all by RT-PCR in two of the nine cell lines. In these two cell lines, Southern blot analysis showed gross rearrangements and deletions in both of the p53 alleles. Six of the nine cell lines were found to express only mutant p53 mRNA by RT-PCR/SSCP analysis and direct sequencing, and wild-type p53 mRNA was not detected. Two of the mutant p53 mRNAs were shown to be products of abnormal splicing events induced by intronic point mutations. Taken together, eight of nine human myeloid leukemia cell lines expressed no or an undetectable amount of wild-type p53 mRNA. Three of the eight cell lines were growth factor-dependent. Our results suggest that inactivation of the p53 gene may be a common feature in myeloid leukemia cell lines and may play an important role in the establishment of these cell lines.

Base Sequence↗
PubMed1992

Evidence for the participation of endogenous activin A/erythroid differentiation factor in the regulation of erythropoiesis.

Activin A/erythroid differentiation factor (EDF) is a human protein that induces differentiation of a murine erythroleukemia cell (the Friend cell). In this study, we demonstrate that endogenous activin A/EDF activity is present in murine bone marrow and spleen. In addition, this activity is secreted by bone marrow and spleen cells in primary culture. Administration of follistatin (a specific binding protein for activin A/EDF) to mice results in a decrease of erythroid progenitors in the bone marrow and spleen. These findings support the concept that activin A/EDF and follistatin have opposing actions in the regulation of erythropoiesis.

Activins↗
PubMed1992

The existence of activin A/erythroid differentiation factor and its inhibitor in human serum: comparison of normal and chronic renal failure sera.

Activin A/EDF, initially found as a differentiation inducer of murine Friend erythroleukemia, also has a stimulatory effect on erythropoiesis in vitro and in vivo. Here we proved activin A/EDF activity in human serum. The activin A/EDF level in 18 normal human serum samples was measured by a specific bioassay and was found to be 8.3 +/- 4.6 ng/ml, indicating that there exists sufficient activity to affect erythropoiesis in normal serum. In contrast, activin A/EDF activity was reduced in the chronic renal failure patients and 23/26 serum samples examined showed levels below 1.2 ng/ml. Further analysis using HPLC revealed that chronic renal failure serum actually contained as much activin A/EDF as normal serum, and that the difference between normal and patient serum existed in the content of a specific inhibitor of activin A/EDF. This observation suggests the possibility that the inhibitor is participating in the regulation of activin A/EDF activity in vivo in chronic renal failure patients and also the possibility of activin A/EDF could be utilized in the therapy of the anemia of such patients.

Activins↗
PubMed1992

Bronchodilatory activity and pharmacokinetics of new xanthines in guinea-pigs.

1. The in vitro biological activities and the effect of protein binding on the relaxant effects in vivo of N-3-alkylxanthine and N-3-alkyl-N-1-methylxanthine derivative were investigated in guinea-pigs. 2. A significantly positive correlation was observed among the in vitro muscle relaxant activity, the cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitory activity and the protein-binding potency of xanthine derivatives. However, there was a weak relationship between these activities and affinity for adenosine receptors. 3. When theophylline, enprofylline and 1-methyl-3-propylxanthine (MPX) were injected intravenously in guinea-pigs, their ED50 values were 6.1, 3.3 and 1.0 mg/kg, respectively. Plasma concentrations of these drugs obtained following the intravenous injection of the ED50 approximated the theoretically effective concentration (EC50) predicted from both the relaxant effects in vitro and the protein binding parameters. A good linear correlation was observed between bodyweight in four species (rats, guinea-pigs, rabbits and humans) and certain pharmacokinetic parameters of enprofylline and theophylline. 4. The present study indicates that differences in the relaxant effects of these drugs in vitro and in vivo can be explained in part by protein binding, and that the protein binding of these xanthine bronchodilators is an important determinant for their pharmacological activity. Guinea-pigs provide a useful model for studying pharmacodynamic-pharmacokinetic relationships of new bronchodilators.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Selective bronchodilators from 1-(5'-oxohexyl)xanthines.

A series of twenty one 1-(5'-oxohexyl)xanthines substituted with alkyl chains at the N3 and N7 positions of the xanthine nucleus were prepared and their relaxant activity in guinea-pig isolated tracheal muscle and positive chronotropic activity in isolated right atrium of guinea-pig were compared. The tracheal relaxant activities were markedly increased with alkyl chain length at the N3 position, but decreased by the N7 alkylation. The positive chronotropic activities in the right atrium were increased by introduction of an n-propyl group at the N3 position but decreased by substitution of longer alkyl chains, and the action on the heart was diminished by N7 substitution. The activities of compounds on cAMP-phosphodiesterase (PDE) and binding of [3H]8-cyclopentyl-1,3-dipropylxanthine were measured in the homogenate of tracheal muscle and the membrane preparation of cerebral cortex, respectively. No relationship among tracheal muscle relaxant activity, cAMP-PDE inhibitory activity and adenosine antagonism of these xanthines was observed, and other action mechanisms should be considered for their relaxant activities. This study indicated that N3 alkylation is important for the selectivity for tracheal muscle, while the introduction of long alkyl chains such as n-butyl and n-pentyl groups at the N3 and N7 positions diminished the potency for the right atrium in guinea-pigs. 3-n-Pentyl- and 7-methyl-3-n-pentyl-1-(5'-oxohexyl)xanthines showed much higher bronchoselectivity than oxpentifylline and theophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Effects of reduction of contractile work on mechanical function in post-hypoxic guinea pig papillary muscles and on myocardial energy metabolism in post-ischemic rat hearts.

This study was designed to investigate effects of quiescence by cessation of electrical stimulation during the first stage of reoxygenation on recovery of mechanical function from hypoxia-induced contractile dysfunction in papillary muscles and effects of the absence of cardiac output on myocardial energetic metabolism of post-ischemic hearts. (1) Regular contractions and postextrasystolic contraction were evoked. After 120 min hypoxia, muscles were reoxygenated. In muscles of quiescence during the first 30 min reoxygenation, the recovery of regular contractions was better than that in muscles in which programmed stimulation was continued. However, the quiescence had no effect on the recovery of post-extrasystolic contractions from hypoxia-induced contractile dysfunction. (2) Isolated hearts were perfused either according to Langendorff technique or as working heart preparations. After 40 min ischemia, hearts were reperfused for 25 min. Although there was no difference in energy charge of myocardium between 2 modes of reperfusion, % incidence of sustained ventricular fibrillation in muscles in which non-working mode was maintained for the first step of reperfusion was lower than that in which working mode was continued. We presume that the reduction of contractile work during the initial step of reperfusion is of value for cardio-protection.

Animals↗
PubMed1992

Effects of hypoxia and reoxygenation on steady-state and potentiated contractions in papillary muscle of guinea pigs.

We studied the effects of hypoxia and reoxygenation on steady-state contractions and potentiated contractions of papillary muscles of guinea pigs. Isometric tension was measured while 120 min periods of hypoxia and reoxygenation were repeated twice. Reoxygenation after the first period of hypoxia induced a gradual recovery in steady-state contractions and a rapid recovery in potentiated contractions from the first hypoxia-induced contractile depression. After the second period of hypoxia, steady-state and potentiated contractions decreased progressively. During the second period of reoxygenation, the recovery of steady-state and potentiated contractions was very poor and the marked elevation of diastolic tension did not decrease. There were no good correlations between hypoxic depression just before reoxygenation and the recovery of both potentiated contraction and steady-state contraction at 120 min of reoxygenation. The recovery from the hypoxia-induced depression was poor in the preparations with marked elevation in diastolic tension. From these findings, we conclude that hypoxia-induced depression is progressively worsened by an additional episode of hypoxia and that diastolic tension is one of the determinants of the low contractile level achieved by steady-state and potentiated contractions in the severely hypoxic state. The degree of hypoxia-induced depression does not determine redevelopment of force with reoxygenation.

Animals↗
PubMed1992

[A case of unusually muscle localization of 99mTc-hydroxy methylene diphosphonate scintigraphy in a patient with acute rhabdomyolysis].

A 85-year-old man was admitted with a history of right upper arm pain following trauma. Laboratory studies included an initial CPK level of 5,385 IU/liter. Other laboratory values were GOT, 114 IU/L; LDH, 701 IU/L; myoglobin, 1,100 ng/ml; aldolase, 13.8 IU/L. The patient was presumed to have have rhabdomyolysis. A 99mTc-hydroxy methylene diphosphonate (99mTc-HMDP) scan revealed an increased uptake in the right shoulder area. 99mTc-HMDP scan is a sensitive indicator of local skeletal muscle injury in rhabdomyolysis.

Acute Disease↗
PubMed1992

[Electrophysiologic effects of flecainide on guinea pig atrium].

We investigated the effects of flecainide on guinea pig atrial muscle. Using Langendorff's method, the whole heart of a guinea pig was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Then, with right atrial extrastimulus and high frequency pacing method, the following values were measured before and after administration of flecainide (10(-7)-10(-5) M). A) Effective refractory period (ERP); the longest coupling interval which failed to produce right atrial activity at premature stimulus. B) Interatrial conduction time (ACT); After right atrial stimuli by trains at PCL 200 ms for 5 min the interval from the stimulation to the first deflection of the left atrial activity. C) Atrial fibrillation threshold (AFT); the minimal amount of current required to induce atrial fibrillation lasting for more than 30 sec by 50 Hz high frequency stimulation. Flecainide lengthened ERP (> or = 3 x 10(-5) M) and ACT (> or = 10(-7) M). Flecainide (10(-5) M) significantly increased AFT which correlated well with ERP (r = 0.81, p < 0.002) and ACT (r = 0.84, p < 0.002). In conclusion these effects of flecainide on guinea pig atrium might explain in part the clinical effectiveness of the drug on paroxysmal atrial fibrillation.

Animals↗
PubMed1992

[Iron deficiency anemia and hypoproteinemia induced by fresh cow's milk].

We reported two patients who developed severe iron deficiency anemia and hypoproteinemia which were induced by excessive drinking cow's milk. Case 1, a 23-month-old girl, had started drinking 800-1,000ml of cow's milk everyday since the age of 9 months. She developed generalized edema at the age of 23 months and visited Saga Medical School for Treatment. Case 2, a 14-month-old girl began to drink cow's milk at the age of 6 months. She drank 1,500ml cow's milk every day at the age of 14 months. She was, referred to our hospital by her physician because of severe anemia. Hypoproteinemia and severe iron deficiency anemia in both of these patients were improved by oral iron intake and prohibiting of cow's milk. Although many children at their age usually drink more than 500ml cow's milk every day, manifestations of symptoms such as iron deficiency anemia and hypoproteinemia do not occur frequently. Thus some investigations suggest that genetic defects as well as other factors related to this disease may be important factors.

Anemia, Hypochromic↗
PubMed1992

[Electrophysiologic study of cibenzoline in patients with paroxysmal atrial fibrillation with special reference to atrial fibrillation threshold].

Electrophysiologic effects of cibenzoline were studied in 7 patients (6 males and one female) aged from 40 to 69 years (mean +/- SD; 52 +/- 10) with paroxysmal atrial fibrillation which was documented by 12 leads ECG or by 24 hours Holter monitoring. No organic heart diseases were found except in one patient with dilated cardiomyopathy and sick sinus syndrome (SSS). Cibenzoline (200mg) given orally increased P wave duration, PR interval and QRS duration significantly. The duration of P wave was gradually increased as the pacing frequency was increased. Neither sinus cycle length, nor sinus node recovery time (SRT), nor Wenkebach cycle length, nor atrial effective refractory period, nor QT interval was changed by the drug. One patient with SSS showed increase in SRT from 2,303 msec to 5,150 msec. The minimum current which was required to induce atrial fibrillation by rapid atrial stimulation (50 Hz, 1 sec) lasting more than 30 sec was defined as atrial fibrillation threshold (AFT). The AFT was 4.0 +/- 2.2 mA at the baseline state in 7 patients. After the oral administration of cibenzoline, 5 patients showed increase in AFT, while 1 patient showed decrease and another patient showed no change in AFT. Statistically, AFT was significantly increased to 7.3 +/- 3.4 mA in 7 patients. The results suggest that cibenzoline might be effective to prevent paroxysmal atrial fibrillation in patients without organic heart diseases.

Administration, Oral↗
PubMed1991

Mutations of the p53 gene in lymphoid leukemia.

p53 is currently considered to be a tumor suppressor gene product, and its alterations are suggested to be involved in several human malignancies. Here we show evidence of the possible involvement of p53 gene mutations in lymphoid leukemias studied by reverse transcriptase-polymerase chain reaction, single strand conformation polymorphism analysis, and nucleotide sequencing. Fourteen patients with various leukemias were examined and two with acute lymphoblastic leukemia and one with Waldenström's macroglobulinemia were identified to have mutations in the coding region of the p53 gene. These mutations included point mutation, triplet deletion, and single nucleotide insertion. Furthermore, expression of the wild-type p53 mRNA was not detected in the samples from these three patients. In one of them, chromosome 17p was deleted, suggesting the absence of the nonmutated p53 gene, whereas in the other two patients, chromosome 17p seemed to be intact by cytogenetic analysis. Our results suggest that alterations of the p53 gene may have a role in the genesis of some leukemias.

Base Sequence↗