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M Shinomiya

Publications and source records attributed to M Shinomiya.

At least 37 records · Page 2Linked to original sources
PubMed1995

Structural, physical, and biological characteristics of RNA.DNA binding agent N8-actinomycin D.

The crystal structure of the self-complementary DNA octamer d(GAAGCTTC)2 complexed with N8-actinomycin D (N8AMD) has been determined at 3.0 A resolution (space group: P3(1)21; unit cell: a = 62.30, b = 62.30, c = 42.97 A; R = 0.173 for 1845 reflections). The DNA structure was severely distorted by the N8AMD bound intercalatively into the middle dinucleotide, 5'-GC-3'. The two cyclic depsipeptides, which differ from each other in overall conformation, lie in the minor groove. The complex is further stabilized by forming base--peptide and chromophore--backbone hydrogen bonds. The complexes are stacked together to form a pseudocontinuous helix running through the crystals. The structure of d(GAAGCTTC)2-actinomycin D (AMD) crystallized in the space group C2 [Kamitori S., & Takusagawa, F. (1992) J. Mol. Biol. 225, 445-456] was re-refined in order to compare it directly to the N8AMD complex structure. The asymmetrical binding mode of AMD has been confirmed on the basis of the two complex structures. The crystal structures of the N8AMD and AMD complexes bound to the same d(GAAGCTTC)2 differed by a root-mean-square deviation on all atom positions of 1.77 A, but most of the structural differences can be attributed to molecular packing in two different crystal forms, and not to structural differences induced by the interaction with the intercalating agents. However, the DNA binding and biological characteristics of N8AMD and AMD are quite different from each other. The DNA association constant of N8AMD is 33-fold less than that of AMD in an aqueous solution. N8AMD required a concentration > 10.0 microM to inhibit RNA synthesis activity in HeLa cells by 50%, whereas AMD reached to the same inhibitory level at only 35 nM. The structure of the DNA-N8AMD complex suggested that substitution of the N-methyl-L-valine residue in the cyclic depsipeptide with a N-methyl-D-valine residue might increase the hydrophobic interaction with the minor groove of the DNA. Thus the DNA association constant and RNA synthesis inhibitory activities of 5,5'-N-methyl-D-valine AMD (D-MeVal-AMD) have also been determined. The DNA association constant of D-MeVal-AMD is more than 2-fold greater than that of AMD, and the RNA synthesis inhibitory activity is about 20-fold greater.

Base Sequence↗
PubMed1995

Novel DNA photocleaving agents with high DNA sequence specificity related to the antibiotic bleomycin A2.

We have designed and synthesized a series of novel DNA photocleaving agents which break DNA with high sequence specificity. These compounds contain the non-diffusible photoactive p-nitrobenzoyl group covalently linked via a dimethylene (or tetramethylene) spacer to thiazole analogues of the DNA binding portion of the antibiotic bleomycin A2. By using a variety of 5' or 3' 32P-end labeled restriction fragments from plasmid pBR322 as substrate, we have shown that photoactive bithiazole compounds bind DNA at the consensus sequence 5'-AAAT-3' and induce DNA cleavage 3' of the site. Analysis of cleavage sites on the complementary DNA strand and inhibition of DNA breakage by distamycin A indicates these bithiazole derivatives bind and attack the minor groove of DNA. A photoactive unithiazole compound was less specific inducing DNA breakage at the degenerate site 5'-(A/T)(AA/TT)TPu(A/T)-3'. DNA sequence recognition of these derivatives appears to be determined by the thiazole moiety rather than the p-nitrobenzoyl group: use of a tetramethylene group in place of a dimethylene spacer shifted the position of DNA breakage by one base pair. Moreover, much less specific DNA photocleavage was observed for a compound in which p-nitrobenzoyl was linked to the intercalator acridine via a sequence-neutral hexamethylene spacer. The 5'-AAAT-3' specificity of photoactive bithiazole derivatives contrasts with that of bleomycin A2 which cleaves DNA most frequently at 5'-GPy-3' sequences. These results suggest that the cleavage specificity exhibited by bleomycin is not simply determined by its bithiazole/sulphonium terminus, and the contributions from other features, e.g. its metal-chelating domain, must be considered. The novel thiazole-based DNA cleavage agents described here should prove useful as reagents for probing DNA structure and for elucidating the molecular basis of DNA recognition by bleomycin and other ligands.

Base Sequence↗
PubMed1995

Treatment of obesity by personality classification-oriented program.

It is apparent that personality is related to the pathogenesis of obesity, and that understanding the personality of the patient may be a key to successful treatment of the disease. Using the Rorschach test and interviews by a psychiatrist, the types of personality were classified into four groups according to the healthiness of personalities. The judgment of healthiness was based mainly on the scores obtained from the Rorschach test. This classification revealed that the occurrence of mental and physical symptoms during therapy with a very low calorie diet (VLCD) and subsequent rebound of bodyweight were more frequently observed in patients with relatively less healthy personalities. We used this classification to adapt our program to treat obese patients. In this program, severe diet restrictions were applied to patients with relatively healthy personalities. These restrictions were applied with modifications to patients with less healthy personality, because severe restrictions would be possibly very stressful for them and would bring about an undesirable reaction. For strengthening the patients' motivation for therapy, the significance of body weight reduction was explained in different ways to patients with different types of personality. The target of bodyweight reduction, reward for patients with successful weight reduction, and the duration of therapy were set up differently for patients with different personalities types. The results showed that bodyweight rebound one or two years after treatment was reduced with the personality-oriented therapy program compared to that observed with the previous conventional therapies. Also, the incidence of psychological problems was remarkably decreased.

Adult↗
PubMed1994

C-type natriuretic peptide inhibits intimal thickening of rabbit carotid artery after balloon catheter injury.

C-type natriuretic peptide (CNP) stimulated cGMP production in rabbit cultured vascular smooth muscle cells, and thymidine uptake was inhibited by CNP. We tested whether CNP inhibits the development of intimal lesions induced by balloon catheter injury in rabbit common carotid artery. CNP (1 microgram/kg/min) infusion through the left jugular vein by DIB balloon catheter pump was started at 30 min before injury and continued until sacrifice. The median of the mean ratio of intima to media in each rabbit after 14 days was 29.5% [14.5-57.8] for control group and 12.0% [2.5-29.8] for CNP group (p < 0.01). Maximum ratio was also significantly low in CNP group. These results suggest that CNP may act as local regulator which suppresses intimal thickening.

Animals↗
PubMed1994

Enhancement of CDDP cytotoxicity by caffeine is characterized by apoptotic cell death.

The ability of caffeine, an agent that suppresses cell replication by inhibiting deoxyribonucleic acids (DNA) repair, to modulate the cytotoxicity of cis-diamminedichloroplatinum (CDDP) was investigated in murine lymphoma cell line EL-4. EL-4 cells were precultured with or without 20 micrograms/ml CDDP for 1 h and then cultured in the presence of 5 mM caffeine up to 48 h after reseeding. In CDDP-pretreated cells, suppression of cell growth and decrease in cell viability from 24 h were observed. Cell cycle arrest in G2 + M phase and a concomitant increase in both rhodamine 123 (R123) uptake and cell size (forward scatter) were observed in these cells. Treatment with caffeine alone suppressed growth rate, R123 uptake, cell size, and frequency of S phase fraction in the cell cycle. Combination of the two agents, CDDP+caffeine, strongly suppressed not only cell viability but also R123 uptake and cell size, compared with CDDP pretreatment alone. DNA histogram analysis by flow cytometry revealed that cultivation with caffeine hastened G2 + M arrest in CDDP-pretreated cells by reduction in the time of passing through S phase. DNA fragmentation was observed following incubation of CDDP-pretreated cells with caffeine for 16 h when marked accumulation in G2 + M phase was observed. The intensity of these ladder fragments increased in a time-related manner. These results demonstrate that enhancement of cytotoxic activity against CDDP-treated cells by caffeine is characterized by an acceleration of DNA degradation in G2 + M phase, namely apoptotic cell death. The fact that induction of DNA fragmentation during G2 + M phase by caffeine modulates the cytotoxicity of CDDP may give rise to a new combination regime of chemotherapy against malignant tumor cells.

Animals↗
PubMed1994

Enhanced arterial intimal thickening after balloon catheter injury in diabetic animals accompanied by PDGF beta-receptor overexpression of aortic media.

Cultured aortic smooth muscle cells (SMC) of diabetic rats and rabbits, which overexpress platelet-derived growth factor (PDGF) beta-receptor compared with controls, have a unique phenotype. In this study we report on the PDGF beta-receptor overexpression in aortas of diabetic animals and the increased intimal thickening of carotid arteries in diabetic rabbits after balloon catheter injury compared with that in controls. In diabetic aortas with no treatments of balloon catheter injury, intimal thickening was not observed in spite of the overexpression of PDGF beta-receptor, indicating that the growth property of medial SMC in diabetic aortas was changed before the intimal thickening could take place. PDGF is known to be the main contributor to the intimal thickening induced by balloon catheter injury, which is one of several forms of arterial injuries. Intimal thickening after balloon catheter injury in diabetic rabbits increased compared with that in controls. These results imply that PDGF beta-receptor overexpression of SMC in medial layers plays an important role in intimal thickening in the formation of advanced diabetic macroangiopathy.

Animals↗
PubMed1993

Granulocyte colony-stimulating factor enhances the extracellular emission of reactive oxygen from neutrophils stimulated with formylmethionylleucylphenylalanine.

Pretreatment of neutrophils with granulocyte colony-stimulating factor (G-CSF) enhanced luminol-dependent chemiluminescence emission by the stimulation of formylmethionylleucylphenylalanine (FMLP), opsonized zymosan, and zymosan. The intensity of the priming effects was in the following order: FMLP > zymosan > opsonized zymosan. However, the priming effect of G-CSF was not detected by the stimulation of phorbol myristate acetate. The reaction curve with the stimulation of FMLP showed a bimodal shape, and the elevation of the first peak by the priming effect was further prominent in comparison with the elevation of the second peak. This indicates that G-CSF mainly enhances the extracellular release of oxygen radicals in response to the stimulation with FMLP. This is the first report investigating intra- and extracellular events in chemiluminescence reaction of neutrophils primed with G-CSF.

Cytochalasin B↗
PubMed1993

Positive correlation between probucol in low density lipoprotein and LDL-lowering.

The relationship between the content of probucol in plasma and lipid lowering was studied after administration of probucol. The study group consisted of 44 patients with Type II hyperlipidaemia (mean age 56 y). Total cholesterol level was decreased from 293 to 232 mg.dl-1 by the administration of probucol. The plasma probucol concentration was 2.03 mg.dl-1 after 4 weeks of administration of 500 mg b.d. Although there was no relationship between the change in total cholesterol and the plasma probucol, a linear relation was observed between the decrease in LDL-cholesterol concentration and the probucol concentration in LDL. Neither the VLDL nor the HDL-probucol content were related to the magnitude of the decrease in lipoprotein cholesterol. The present study has demonstrated that an increase in the probucol content in LDL was associated with a decrease in plasma LDL-cholesterol.

Adult↗
PubMed1993

Abdominal wall fat index, estimated by ultrasonography, for assessment of the ratio of visceral fat to subcutaneous fat in the abdomen.

PURPOSE: To establish a new index of regional fat distribution using ultrasonography for assessment of the ratio of the visceral fat area (V) to the subcutaneous fat area (S) (V/S ratio). SUBJECTS AND METHODS: The subjects examined were 62 patients (23 males and 39 females); 51 patients had hyperlipidemia and 11 patients had glucose intolerance. The mean body mass indices ranged from 20.3 to 42.9. The mean age of the patients was 44 +/- 13 years. The thicknesses of the preperitoneal fat layer (P) and subcutaneous fat layer (S) in the abdomen were measured by ultrasonography and the P/S ratio was calculated. The V/S ratio was obtained with radiographic computed tomography. RESULTS: Of the various P/S ratios examined, the ratio of the maximum thickness of preperitoneal fat to the minimum thickness of subcutaneous fat was most closely correlated with the V/S ratio (r = 0.746, p < 0.0001). This ratio was termed the abdominal wall fat index (AFI). AFI was positively correlated with serum triglyceride levels and negatively correlated with high-density lipoprotein cholesterol (r = -0.312, p < 0.05), whereas the V/S ratio was correlated with triglyceride levels. AFI was positively correlated with basal insulin levels in both men and women. CONCLUSION: These results suggest that AFI measured by ultrasonography may be a new indicator of visceral fat deposition, and may reflect metabolic disorders such as lipid metabolism and glucose metabolism disorders.

Abdominal Muscles↗
PubMed1993

Therapeutic effect of granulocyte colony-stimulating factor and cephem antibiotics against experimental infections in neutropenic mice induced by cyclophosphamide.

Effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) against severe infections in cyclophosphamide (CY)-induced neutropenic mice were investigated by its single use or by its combination with cephem antibiotics. Treatment with rhG-CSF increased the number of peripheral blood leucocytes and strikingly shortened the duration of the neutropenic state. Most of the regained population in the peripheral blood leucocytes were neutrophils. Functions of neutrophils, such as phagocytic activity, superoxide release, and expression of Mac-1 molecules, were remarkably enhanced by administration of rhG-CSF. When rhG-CSF was administered to CY-induced neutropenic mice before infection, protective effects against various kinds of bacteria were remarkable. On the other hand, such remarkable effects were not observed when rhG-CSF was administered after infections. However, even in the case of post-infectious treatment, a combination therapy of rhG-CSF with cephem antibiotics, particularly with Cefodizime (CDZM), showed a significant improvement in the survival rate and a decrease in the number of viable bacteria in the liver. These results suggest that a combination therapy of rhG-CSF with cephem antibiotics, especially with CDZM, is an efficient regime against severe infections in patients with neutropenia induced by a heavy anti-tumour chemotherapy.

Animals↗
PubMed1993

Characteristic features of long-living patients with familial hypercholesterolemia in Japan.

OBJECTIVE: To assess characteristics of long-living familial hypercholesterolemics (FHs) in comparison with younger patients. DESIGN: Cross-sectional study. SETTING: Lipid clinics of a university hospital and 14 related medical institutions. PATIENTS: A total of 335 heterozygous FHs including 17 patients over 70 years old. The average ages of the aged (> or = 70 years old) and the younger groups were 73.5 +/- 3.7 and 46.5 +/- 15.0 years, respectively. MEASUREMENTS: Medical history, serum lipids and apolipoproteins, and radiographic measurement of Achilles tendon xanthomas. MAIN RESULTS: Age distribution of FHs suggests shorter life of FHs compared with the general population. The age distribution of FH females was shifted to older age compared with that of FH males (P < 0.01). No significant differences were found between the levels of serum lipids and apolipoproteins in the aged and the younger groups. The thickness of the Achilles tendon was positively correlated with the product of excess total serum cholesterol and age in the patients (P < 0.01). Progression of Achilles tendon thickening was less in females than in males. A few cases of longevity could not be explained by any of the anti-atherogenic factors including female gender, a relatively low concentration of serum total cholesterol, a high concentration of HLD-cholesterol, a non-smoking habit, and a familial predisposition for longevity. CONCLUSIONS: The female gender was found to be one of the most important factors for long survival of FHs. The different progression of Achilles tendon thickening in females and males may be related to the slower development of atherosclerosis and higher survival rate of the female patients.

Achilles Tendon↗
PubMed1993

The 'midband' lipoprotein is a coronary risk factor in Japanese patients with familial hypercholesterolaemia.

The relationship between coronary stenosis and 'midband' lipoprotein, which was observed between low density lipoproteins and very low density lipoproteins by 3% polyacrylamide gel electrophoresis, was studied in patients with heterozygous familial hypercholesterolaemia (FH). The subjects were 46 patients with FH, who were evaluated by coronary angiography. The groups with and without coronary artery disease (CAD) were compared. Age, sex ratio, total cholesterol, triglyceride, HDL-cholesterol and lipoprotein(a) levels were matched in these two groups. In addition, Achilles tendon thickness and the incidence of risk factors such as diabetes mellitus, hypertension and smoking between these two groups were matched. Under these conditions, the frequency of midband was higher in the patients with CAD (20/26) than that in patients without (4/20). The results suggest that the presence of a midband among Japanese is an independent risk factor for coronary stenosis even in cases of FH who have severe hypercholesterolaemia.

Adult↗
PubMed1992

Structures of new DNA photocleaving agents: 3,6-bis(dimethylamino)-10- [6-(4-nitrobenzoyloxy)hexyl]acridinium chloride (I) and 9-([6-(4- nitrobenzoyloxy)-hexyl]amino)acridinium chloride monohydrate (II).

(I) C30H35N4O4+.Cl-, Mr = 551.07, triclinic, P1, a = 10.512 (2), b = 11.203 (2), c = 14.469 (2) A, alpha = 111.49 (1), beta = 105.74 (1), gamma = 95.82 (1) degrees, V = 1487.4 (4) A3, Z = 2, Dm = 1.23 (by flotation), Dx = 1.231 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 14.68 cm-1, F(000) = 584, T = 296 K, R = 0.109 for 3100 unique reflections with I greater than 3 sigma(I). (II) C26H26N3O4+.Cl-.H2O, Mr = 497.98, triclinic, P1, a = 9.4810 (8), b = 14.495 (2), c = 9.255 (1) A, alpha = 95.48 (1), beta = 98.17 (1), gamma = 101.78 (1) degrees, V = 1222.3 (5) A3, Z = 2, Dm = 1.35 (by flotation), Dx = 1.353 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 17.34 cm-1, F(000) = 524, T = 296 K, R = 0.052 for 3589 unique reflections with I greater than 3 sigma(I). The diffraction work confirmed the molecular structures of the newly synthesized DNA photocleaving compounds, in which the p-nitrophenyl group is nearly coplanar with the acridine moiety in (I), whereas the two planar groups form a dihedral angle of 98.7 degrees in (II). The flexibility of the methylene chain and the substantial stacking ability of the aromatic groups observed may be essential for binding to DNA and reaction with the deoxyribose H atoms.

Aminoacridines↗
PubMed1992

Inhibition of intimal thickening of the carotid artery of rabbits and of outgrowth of explants of aorta by probucol.

The effect of administration of probucol in preventing intimal thickening of rabbit carotid artery after balloon catheter injury and the mechanism of action of the drug were studied. Groups of 6 male New Zealand-White rabbits were given normal diet (Group I), high cholesterol diet (Group II) or high cholesterol diet plus probucol (Group III) for 4 weeks. Balloon catheter injury was made in week 2 and animals were killed in week 4. No significant differences in the total cholesterol levels in Groups II and III were found in week 4. The medians of areas of the intimal layer in cross-sections of the carotid arteries of Groups I, II and III were 0.237, 0.475 and 0.309 mm2, respectively. Thus high-cholesterol diet increased the thickness of the intimal layer and probucol reduced its effect. There were no significant differences in the areas of the medial layers in these 3 groups. For the examination of the mechanism of the effect of probucol, rabbits were given chow containing 0.5% cholesterol with and without 0.5% probucol (7 rabbits each) and then the numbers of explants from their aortas showing outgrowth were compared. The plasma total cholesterol levels of these two groups were the same. The probucol concentrations in the plasma and aorta of the former group were 18.6 +/- 13.2 micrograms/ml and 7.3 +/- 5.4 micrograms/g wet tissue, respectively. The number of explants showing outgrowth on day 14 was suppressed by 34% in the probucol-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Reproductive and developmental toxicity study of suplatast tosilate (IPD-1151T) (2)--Teratological study in rats by oral administration].

A teratological study of suplatast tosilate (IPD-1151T), a new anti-allergic agent which has a suppressive action on IgE antibody formation, was conducted with pregnant Wistar rats. Dosage levels of IPD-1151T 0, 300, 900 and 2700 mg/kg/day were administered to dams orally by gavage on days 7 through 17 of gestation. Two-thirds of dams per group was caesarean-sectioned on day 20 of gestation and their fetuses were removed for examination of external, visceral and skeletal anomalies. The remaining one-third was allowed to deliver naturally. F1 neonates were examined developmental, functional and behavioral parameters and reproductive abilities. The results were as follows: 1. Toxicities on F0 dams in the 2700 mg/kg/day group were salivation, piloerection, and decreases in body weight and food consumption. Seven animals (19.4%) showed severe toxicity and were dead. Toxicity in the 900 mg/kg/day group was a slight decrease in food consumption. The dosage level of 300 mg/kg/day was non-toxic. 2. Toxicities on F1 fetuses in the 2700 mg/kg/day group were a decrease in body weight and an increase in visceral anomalies (main one was ventricular septal defect that might be related to developmental retardation). No toxicities were seen in the 300 and 900 mg/kg/day. 3. In F1 neonates, suppressions of body weight were observed clearly in the male and female 2700 mg/kg/day and slightly in the male 900 mg/kg/day groups. But no changes in parameters of development, function, behavior or reproductive ability were seen in any dosed groups. It was suggested that no effective dose levels of IPD-1151T were 300 mg/kg/day for F0 dams and F1 neonates, and 900 mg/kg/day for F1 fetuses.

Abnormalities, Drug-Induced↗