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Biomedical subjects

H Nagashima

Publications and source records attributed to H Nagashima.

At least 127 records · Page 7Linked to original sources
PubMed1994

Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl-CoA synthase inhibitors: 2-oxetanones with a side chain mimicking the extended structure of 1233A.

Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2- naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level.

Animals↗
PubMed1994

Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitors: 2-oxetanones with a side chain mimicking the folded structure of 1233A.

To mimic the folded side chain conformation of 1233A (1), which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitor, 1233A analogs with aromatic rings in the side chain were synthesized. The 2-oxetanone moiety was kept intact. Among 1233A and its synthetic analogs, trans-3-hydroxymethyl-4-[2-(7-methoxycarbonyl-1-naphthyl)ethyl]-2-oxe tanone (23) showed the highest HMG-CoA synthase inhibitory activity in vitro. The structure-activity relationship at the side chain is discussed.

Animals↗
PubMed1993

Blotting membrane micropreparation in capillary electrophoresis to evaluate enzyme purity and activity.

A micropreparation system for proteins and peptides analyzed by capillary electrophoresis that uses a blotting membrane and an improved micro-test-plate was developed. The system is useful for enzyme diagnosis and purification. In the system, enzyme is collected in a concentrated spot on these membranes, and the activities are measured enzymatically to evaluate the resolution of the system.

Capillary Action↗
PubMed1993

Aberrant tissue specific expression of the transgene in transgenic mice that carry the hepatitis B virus genome defective in the X gene.

The control mechanisms for the transgene expression in mice that carry the hepatitis B virus genome defective in the polymerase and X genes were analyzed. Ten lines of transgenic mouse were established, and in seven lines the surface and e antigens were detected in the serum. In transgenic mice from five lines examined, the transgene was markedly expressed in a broad spectrum of tissues including the kidney, heart, brain, muscle and intestine, but only poorly in the liver. In the kidney and heart the 3.5 kb and 2.1 kb mRNAs were expressed, whereas only the 0.8 kb and 4.0 kb mRNAs were detected in the testis and brain, respectively, suggesting that each of the mRNAs was transcribed through a different control mechanism. The surface, e and core antigens accumulated in the kidney and heart. DNA was hypomethylated at a region closely downstream of the enhancer in the liver, kidney and heart, and a DNase I hypersensitive site was detected upstream of the enhancer in these tissues. In the testis, however, the whole transgene was hypomethylated and the DNase I hypersensitive site was closer to the enhancer. These differences may be relevant to the preferential expression of the 0.8 kb mRNA in the testis, but cannot explain the inefficiency of transgene expression in the liver. Our observations suggest that the X protein is required for efficient expression of the viral gene in the liver but not in other tissues.

Animals↗
PubMed1993

Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme A synthase inhibitor, 1233A, in mice.

We have studied the in vivo inhibition of hepatic sterol biosynthesis by 1233A, a specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase. Administration of the compound orally to mice resulted in a dose-dependent inhibition of [14C]acetate incorporation into sterols in liver, but did not exert any significant effect on [14C]mevalonate incorporation. The results indicate that the in vivo inhibition of sterol synthesis occurs only at pre-mevalonate enzymatic steps in the sterol biosynthetic pathway, thus being compatible with the presumed site of inhibition, HMG-CoA synthase. Moreover, owing to irreversible inactivation of the enzyme by 1233A, it was possible to detect in vivo effect on the enzyme by assays of its activity in cell-free extracts from livers; the drug-treatment also resulted in a similarly dose-dependent inhibition of HMG-CoA synthase activity. In contrast, acetoacetyl-CoA thiolase and HMG-CoA reductase, the enzymes also responsible for mevalonate synthesis in the pathway, did not show any significant change in activity. These results clearly demonstrate that the inhibition of hepatic sterol synthesis caused by 1233A is indeed due to selective inhibition of HMG-CoA synthase in the tissues.

Animals↗
PubMed1993

Comparative studies in molecular stability of immunoglobulin G from different species.

1. Molecular stability of immunoglobulin G (IgG) from chicken and four mammalian species (cow, goat, pig and rabbit) was compared from immunochemical and biochemical view-points. 2. IgG from cow, goat and pig showed similar stability against denaturation caused by heat, acid and denaturant treatments, while rabbit IgG was shown to be more resistant to all of the treatments than other mammalian IgGs, suggesting that rabbit IgG has a highly stable molecular structure. 3. The heat- and acid-stability of chicken IgG measured by immunochemical methods were similar to those of cow, goat and pig IgG. Conformational stability of chicken IgG measured by fluorometric and enzymatic methods, however, was lower than the mammalian IgGs, suggesting that chicken IgG has a more flexible and unstable molecular structure.

Animals↗
PubMed1993

Investigation of postmortem functional changes in human cerebral arteries.

This study demonstrated the time-dependent changes in postmortem responses of isolated human middle cerebral artery strips to vasodilators. The relaxation induced by prostaglandin (PG) I2 or nitroglycerin remained stable for 24 h postmortem. In arterial strips precontracted with PGF2 alpha, substance P and bradykinin both elicited relaxation that was almost completely abolished by removal of the endothelium. The endothelium-dependent response to both peptides was significantly degraded in strips obtained > 12 h postmortem. These results indicate a selective functional or anatomical vulnerability of the vascular endothelium compared with that of the vasodilator mechanisms of the smooth muscle in the postmortem period. However, cerebral arteries isolated from human cadavers within 12 h postmortem should be adequate for studies of both smooth muscle and endothelial reactivity to vasodilators.

Adult↗
PubMed1993

Effects of long-term continuous respiratory resistive loading on rat diaphragm function and structure.

The effects of long-term (24- to 28-wk) continuous respiratory resistive loading on diaphragm mass, contractility, fatigue, and fiber types were studied in male rats. Increased respiratory resistance was produced by extratracheal banding, and results were compared with sham-operated pair-fed controls. At the time the animals were killed, banded tracheal segment internal diameter was reduced by 57% of control values. Diaphragm surface area and muscle mass (normalized for body mass) increased by 19% of control values. Isometric diaphragm contractility and fatigue resistance indexes were measured using an in vitro diaphragm costal strip preparation at 37 degrees C. Twitch and tetanic stimulations were evoked using direct stimulation. Compared with controls, baseline tensions (normalized for diaphragm cross-sectional area) were significantly decreased at low frequencies. Fatigue resistance (endurance) indexes were significantly increased at all frequencies. These findings were consistent with observed increases in number and cross-sectional area of type I (low-tension high-endurance) fibers. We conclude that the diaphragm adapts to chronic long-term resistive loads by sacrificing peak tensions for an increase in endurance capacity.

Airway Resistance↗
PubMed1993

Incidence and prognosis of dysvascular amputations in Okayama Prefecture (Japan).

This survey analysed the clinical characteristics of subjects who first underwent major amputation of lower limbs necessitated by dysvascular disease during the 5 year period from 1984 to 1988. All were residents of Okayama Prefecture, Japan, and have been issued with a Physically Disabled Person's Certificate. In total, 114 dysvascular amputees, representing 58.2% of all lower limb amputations performed in the resident population during the study period, were surveyed. The underlying diagnosis was arteriosclerotic obstruction in 64.9% of the subjects, diabetic gangrene in 22.8%, acute embolism in 7.0% and Buerger's disease in 5.3%. The yearly incidence of new dysvascular amputees per 100,000 people was estimated to be 1.2 among the general population and 5.7 among those aged over 65 years. At three years after primary amputation, the survival rate was 52.3% in arteriosclerotic obstruction, and 66.7% in diabetic gangrene. Secondary amputation was performed in 17.0% of the entire group. The concurrent incidence of hemiplegic stroke was 19.8%. Among 36 amputees due to arteriosclerotic obstruction, who survived 3 years postoperatively, 10 (27.8%) were fitted with prosthetic limbs.

Adult↗
PubMed1993

Longitudinal study of in vivo bone mineral changes in rats using dual X-ray absorptiometry--effect of ovariectomy and prednisolone.

Longitudinal bone mineral measurement was performed by dual X-ray absorptiometry (DXA) in fifty 14-week-old Wistar rats divided into the following five groups: ovariectomized (OVX); sham-ovariectomized (SHAM); ovariectomized with release of proximal tail muscles (OVX + MR); prednisolone-administered (PDN); and saline-administered (control). Bone mineral density (BMD) was measured at the skull, distal femur, proximal tibia, and caudal vertebrae at 4, 8, 12, 16, 20, and 24 weeks after surgery or onset of administration. This in vivo DXA technique accurately showed correlation with the ash weight (r = 0.912-0.971), with a precision error of 1.01-2.05%. In the OVX group, the percent changes in distal femoral BMD and proximal tibial BMD were -7.6% and -5.3% at four weeks, followed by a gradual increase toward the initial value by 12 weeks. On the other hand, both OVX and SHAM rats gained BMD of the skull and caudal vertebrae. OVX+MR rats also gained BMD of the caudal vertebrae. Release of proximal tail muscles only had no significant effect on bone mineral of the caudal vertebrae. Prednisolone had no significant effect on bone mineral at any site.

Absorptiometry, Photon↗
PubMed1992

Freezability of porcine blastocysts at different peri-hatching stages.

The freezability of porcine peri-hatching stage blastocysts was investigated by the cryopreservation of embryos at -196 degrees C with 1.5 M glycerol and by thawing, followed by in vitro culture. Of 66 expanded blastocysts frozen, 34 (51.5%) developed in vitro after thawing, while only 2 (6.7%, P<0.05) of 30 earlier stage blastocysts survived freezing. After freezing of 85 hatched blastocysts with an embryonic diameter of 150 to 300 mum, 59 (69.4%) surviving embryos were obtained, whereas none of the 78 advanced staged hatched blastocysts (>300 mum) survived the cryopreservation. High post-thaw survival (32 39 , 82..1%) was obtained with in vitro-hatched blastocysts precultured in Whittingham's M-16 medium containing 12mg/ml bovine serum albumin (BSA). In contrast, none of the 14 in vitro-hatched blastocysts precultured in the M-16 medium supplemented with 15% fetal calf serum (FCS) survived freezing. Similarly 51 of 56 hatced blastocysts (diameter = 150 to 300 mum) precultured in the M-16 medium supplemented with BSA survived cryopreservation, compared with 3 of 26 embryos precultured in the medium supplemented with FCS (P<0.001). Because both groups of the embryos precultured with BSA or FCS possessed normal ability to develop after transfer (developmental rate = 61.1 and 93.3%), the improved freezability of the embryos precultured with BSA may relate to a favorable change of embryonic cell membranes during the culture period. It was concluded that in vitro-hatched blastocysts precultured in medium containing BSA and in vivo-hatched blastocysts at the appropriate stage of development could both tolerate deep freezing to -196 degrees C; however, a differece in the freezability of embryos between breeds of pig was suggested from a further experiment performed with German Landrace embryos.

Journal Article↗
PubMed1992

Molecular stability of chicken and rabbit immunoglobulin G.

Molecular stability of chicken egg yolk immunoglobulin G (IgY) and that of rabbit IgG were compared by measuring antibody activities and conformational changes. Stability of rabbit IgG to acid denaturation was much higher than that of IgY. Conformation of the IgY molecule was readily changed in acidic conditions, resulting in a rapid loss of antibody activity. Much less stable natures of IgY to heat-treatment and guanidine-HCl denaturation than rabbit IgG were also observed. Differences in the structure between the two immunoglobulins that might participate in their different stability were inferred from their amino acid sequence data. Importance of the intramolecular disulfide linkage in the rabbit light chain and some other structural differences were suggested.

Animals↗
PubMed1992

Giant thrombosed vertebral artery aneurysm managed with extracranial-intracranial bypass surgery and aneurysmectomy. Case report.

A case is presented of a left giant thrombosed vertebral artery aneurysm in a 46-year-old man. The giant thrombosed aneurysm was successfully resected with trapping of the affected artery after right external carotid artery-posterior cerebral artery bypass surgery using a radial arterial graft. The clinical course is reported, and the details of the operative approach and techniques are discussed.

Humans↗
PubMed1992

Synthesis of 1233A analogs and their inhibitory activity against hydroxymethylglutaryl coenzyme A synthase.

Simple and efficient syntheses of 1233A analogs were developed and the inhibitory activity of the analogs against hydroxymethylglutaryl coenzyme A (HMG-CoA) synthase was determined. Study of the structure-activity relationships revealed that not only the geometry in beta-lactone moiety but also the length of the carbon side chain is important for inhibitory activity against HMG-CoA synthase.

Animals↗
PubMed1992

[Neuromuscular blocking effect of ORG9426, a new non-depolarizing muscle relaxant, and its recovery with various antagonists in vitro].

We evaluated the neuromuscular blocking effect of ORG9426, a new non-depolarizing muscle relaxant, and its recovery by means of washout or by antagonists in vitro, using phrenic nerve-hemidiaphragm preparations of rats. IC50 and IC90 of ORG9426 in single twitch were 10.62 +/- 0.58 microM and 15.75 +/- 0.95 microM; and those in train of four ratio were 9.04 +/- 0.38 microM and 11.87 +/- 0.42 microM, respectively. The potency of ORG9426 in vitro was compared with those of other non-depolarizing muscle relaxants. The order of potency among the non-depolarizing muscle relaxants was the following: d-tubocurarine greater than pipecuronium greater than pancuronium greater than vecuronium greater than ORG9426. There was no difference between ORG9426 and vecuronium in the recovery from block with washout, neostigmine, 4-aminopyridine, 3, 4-diaminopyridine, and edrophonium. In conclusion, the potency of ORG9426 is relatively low, and it can be easily antagonized by anti-cholinesterases and aminopyridines.

Aminopyridines↗
PubMed1992

[The acute and chronic effects of bunazosin on exercise capacity estimated by the anaerobic threshold in patients with chronic congestive heart failure].

To study the effect of bunazosin on exercise capacity in patients with congestive heart failure (NYHA II-III), anaerobic thresholds (AT, VO2, ml/min/kg) were measured before (control) and after initial 1 = 2mg administration of bunazosin (acute phase; N = 14) and after two weeks of bunazosin therapy (3mg/day, 1mg t. i. d., chronic phase; N = 6). AT were determined by Wasserman's V-slope method during ergometer exercise test with a ramp loading (10 watt/min). AT increased significantly from control during both acute (14.2 +/- 2.7 to 16.9 +/- 3.6 ml/min/kg p < 0.005) and chronic (13.6 +/- 2.5 to 16.7 +/- 1.0 p < 0.05) phase. Additionally, work (watt) attained at AT increased significantly from control during both acute (33.6 +/- 19.2 to 52.6 +/- 30.2 p < 0.005) and chronic (35.8 +/- 25 to 49.3 +/- 15 p < 0.05) phase. Pressure-rate-products (PRP, x 10(2) mmHg/min) at AT increased significantly from control during the acute phase (119 +/- 35 to 240 +/- 50 p < 0.005) alone. In the chronic phase, PRP decreased significantly at the work level equal to AT during control (from 207 +/- 41 to 187 +/- 39 p < 0.05). These data suggest that bunazosin has favorable acute and chronic effects on exercise capacity in patients with congestive heart failure.

Adult↗
PubMed1992

[The effect of ionized calcium concentration on muscle contraction and on the effect of non-depolarizing neuromuscular blocking agent].

The influence of serum ionized calcium (Ca2+) on the muscle contraction and on the effect of non-depolarizing neuromuscular blocking agent, d-tubocurarine (dTc), was investigated. The isolated phrenic nerve-diaphragma preparation of the rat was stimulated directly and indirectly at 0, 0.4, 0.7, 1.4, 2.5 mM of total calcium concentration (Ca2+: 0, 0.39, 0.52, 1.12, 2.32 mM, respectively). With indirect stimulation, no contraction was observed from 0 to 0.4 mM of calcium, but the twitch tension returned to 100 percent of control at over 0.7 mM of calcium. However, with direct stimulation, the twitch tension was obtained up to 100 percent of control independent of Ca2+ concentration. The ED50 of dTc was correlated well with the serum Ca2+. These findings suggest that the decrease of serum Ca2+ concentration interferes with the muscle contraction and potentiates the effect of dTc. We speculate that the site of its action may be primarily prejunctional.

Animals↗