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Biomedical subjects

S Nagao

Publications and source records attributed to S Nagao.

At least 91 records · Page 5Linked to original sources
PubMed1999

Increased phosphorylation of DNA topoisomerase II in etoposide resistant mutants of human glioma cell line.

The efficacy of the epipodophyllotoxins VP-16 and VM-26 is limited by the occurrence of drug resistance in the tumor cell population. Cellular insensitivity to drugs that stabilize the cleavable complex is frequently expressed as multidrug resistance (MDR). In some cell lines, overexpression of MDR-1/P-glycoprotein or the multidrug resistance associated protein (MRP) has been demonstrated and implicated as the mechanism of resistance. Typically, these cells have reduced drug accumulation, secondary to increased drug efflux. In other cell lines, an atypical MDR phenotype has been identified, with the predominant mechanism of resistance shown to be qualitative and/or quantitative changes in the levels and activity of topoisomerase II. For VP-16, increased expression of MDR-1 or MRP and alterations in topoisomerase II have been shown to confer tolerance. To further understand resistance to VP-16, T98G-VP(1000) was initially isolated as a single clone from parental cell, T98G, by exposure to VP-16. Subsequently, a population of cells from this subline was exposed to three-fold higher drug concentration allowing stable sublines to be established at higher extracellular drug concentration. Characterization of the resistant sublines demonstrates the adaptation that occurs with advancing drug concentrations during in vitro selections. Reduced topoisomerase II mRNA and protein levels were observed in the initial isolate. This reduction was accompanied by a decrease in topoisomerase II activity and cellular growth rate and was associated with 47-fold resistance to topoisomerase II poisons. With advancing resistance, MRP expression increased, with increased VP-16 efflux and reduced accumulation. This adaptation allowed for partial restoration of topoisomerase II activity secondary to increased expression and hyperphosphorylation, with a resultant increase in growth rate. In this cell line, hyperphosphorylation coincided with increased casein kinase II mRNA protein levels, without increased PKC protein levels, suggesting a role for this kinase in the acquired hyperphosphorylation. In this cell line, hyperphosphorylation mediated the increased activity despite a fall in topoisomerase II protein levels secondary to an acquired 615 bp deletion in one topoisomerase II allele, which resulted in reduced protein levels. In this subline, high levels of resistance were attained as a result of synergism between the reduced topoisomerase II levels and MRP overexpression. These studies demonstrate how cellular adaptation to increasing drug pressure occurs and how more than one mechanism can contribute to the resistant phenotype when increasing selecting pressure is applied. Reduced expression of topoisomerase II is sufficient to confer substantial resistance early in the selection process, with synergy from additional mechanisms helping to confer high levels of resistance.

ATP-Binding Cassette Transporters↗
PubMed1999

Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease.

The Han:SPRD strain is an SD-background strain known to be a model of polycystic kidney disease (PKD) expressed through an autosomal dominant gene (Cy). However, different genotypes of this strain cannot be identified in the neonatal period. First, to establish an accurate method of determining the genotypes (Cy/Cy, Cy/+, +/+) which cause different disease progressions, we used polymorphic markers on rat chromosome 5. PCR products of tissue DNA templated with D5Rat9 showed distinct patterns on electrophoresis indicating three genotypes. Second, to determine whether the same locus plays a major role in expressing PKD, we performed linkage analyses in a [BN x (BN x Han:SPRD)F1] backcross. Cy/Cy and Cy/+ also caused PKD in a BN background. In this backcross, we discovered that D5Rat11 is located closer to the Cy locus than D5Mgh10, which is regarded as one of the closest loci. We conclude that D5Rat9 and D5Rat11 are useful markers for determining the presence of the Cy allele, which is regarded as the gene responsible for PKD.

Alleles↗
PubMed1999

Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase gene.

Although xenotransplantation of retrovirus-producing cells into a tumor has been shown to be effective for the treatment of cancer, injections of recombinant retroviruses are much more feasible for clinical applications. We established a clone producing retroviruses carrying the herpes simplex virus thymidine kinase (HSVtk) gene with titers of up to 4 x 10(7) colony-forming units/ml, and examined the effectiveness of in vivo gene therapy against cancer. Syngeneic mice were inoculated subcutaneously with murine hepatocellular carcinoma (HCC) cells, BNL1ME A.7R.1, and the treatment was initiated after tumors were established. When mice were given an intratumoral injection of HSVtk-carrying retroviruses or their producing cells followed by ganciclovir (GCV) treatment, significantly prolonged survival periods were observed. When mice were treated with repeated intratumoral injections of HSVtk-carrying retrovirus-producing cells, significant antitumor responses and some cures were induced by GCV treatment. Furthermore, repeated intratumoral injections of HSVtk-carrying retroviruses and GCV treatment resulted in complete regression of established HCC tumors in all animals used in the experiment. Mice that completely eradicated tumors exhibited protective immunity against wild-type HCC tumors. These results suggest that repeated injections of HSVtk-carrying retroviruses followed by GCV treatment is a potent modality for the treatment of solid tumors.

Animals↗
PubMed1999

Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver.

Although adenovirus is an attractive vehicle for transferring therapeutic genes in vivo, animal studies have indicated that the clinical usefulness of adenoviruses may be limited by their immunogenicity. Although immunosuppressive strategies around the time of initial exposure of adenoviruses have been shown to prevent the formation of neutralizing antibodies and permit the successful readministration of adenoviruses in animals, the practicality of the approaches remains questionable. Because the majority of prospective gene therapy patients have already been infected with wild-type adenoviruses, initial treatment with adenoviruses in humans may correspond to readministration of adenoviruses into animals. It is shown here that although intraportal infusion of adenoviruses carrying a reporter lacZ gene resulted in transient high levels of transgene expression in the rat liver, intraportal readministration of adenoviruses failed to induce detectable levels of transgene expression. Conversely, when animals were treated transiently with cyclophosphamide before the intraportal readministration of adenoviruses, development of neutralizing antibodies and antigen-specific T cell proliferation in response to adenoviral readministration was significantly suppressed and successful re-expression of the transgene was achievable. These results may have important implications for efficacy considerations when adenoviral vectors are employed in clinical settings.

Adenoviridae↗
PubMed1999

Treatment of brain edema with a nonpeptide arginine vasopressin V1 receptor antagonist OPC-21268 in rats.

OBJECTIVE: Recent experimental evidence suggests that centrally released arginine vasopressin plays a significant role in brain capillary water permeability as well as in pathogenesis of vasogenic brain edema. The purpose of this study was to examine the effects of orally administered OPC-21268, a nonpeptide arginine vasopressin V1 receptor antagonist, on cold-induced brain edema in rats. METHODS: Cold brain injury was induced for 1 minute in 140 rats. Treatment with OPC-21268, at dosages of 100 mg (n = 20), 200 mg (n = 20), and 300 mg/kg (n = 15), or with saline (n = 17) was started 1 hour after the induction of cold injury and was continued every 8 hours for 24 hours. Two percent Evans blue in saline (1 ml/kg) was administered intravenously before cold injury in another group of rats, 15 of which were saline-treated and 55 of which were OPC-21268-treated at the above dosages. After 24 hours, brain tissue water and electrolytes, brain tissue swelling, blood-brain barrier permeability to Evans blue, and plasma electrolytes and osmolality were determined. RESULTS: Compared with the saline-treated group, OPC-21268 treatment at the dosages of 200 and 300 mg/kg significantly reduced brain water content in both hemispheres (P<0.01). Swelling of the traumatized hemispheres was also significantly reduced at 200 and 300 mg/kg dosages (P<0.05). Brain tissue sodium content was significantly reduced at the dosage of 300 mg/kg (P<0.05). Blood-brain barrier permeability to Evans blue was significantly decreased in a dose-dependent manner compared with the saline-treated group (P<0.01). No significant changes were observed in other parameters. CONCLUSION: Our results indicate that OPC-21268 predominantly exerts a protective effect in areas where the maximum amount of blood-brain barrier breakdown occurs, and it is effective in the treatment of cold-induced vasogenic brain edema.

Administration, Oral↗
PubMed1999

Renal carbonic anhydrase activity in DBA/2FG-pcy/pcy mice with inherited polycystic kidney disease.

DBA/2FG-pcy/pcy (D2-pcy) mice are a hereditary murine model of slowly progressive polycystic kidney disease (PKD) and characterized by the persistent excretion of acidic urine, in association with polyuria, after weaning. In this study, the activity of carbonic anhydrase (CA) and it histological distribution in the kidney of D2-pcy mice were investigated by immunohistochemistry. Significantly higher CA activity was detected in the cytosolic, but not membrane, fraction of kidney homogenates in 5-week-old D2-pcy mice than in age-matched, control DBA/2 (D2) mice, and a more rapid rate of urine acidification was noted in 11-week-old mice when acetazolamide, an inhibitor of the enzyme, was administered orally. By immunohistochemistry for the major renal CA isoenzyme (CA II), epithelial cells in the distal straight tubules and the cortical collecting ducts were stained intensely, whereas those of the proximal convoluted tubules had only weak and diffuse staining. The glomeruli, the proximal straight tubules and the ascending thin limb of Henle's loop were almost free from staining. In the cells lining cysts and/or dilated tubules, CA II activity was well preserved, although the staining intensity was considerably reduced in fully-flattened, lining cells of cysts, but no difference was found between D2-pcy and D2 mice in any segmental localization of renal CA II activity. From these results it seems that D2-pcy mice in the early stages of the cystic disease continue to secrete excess protons through the CA-mediated reaction that is stimulated for regulation of acid-base balance in the distal portion of the nephron and the collecting duct in kidney. It also suggests that monitoring urine pH may be useful in predicting the effects of early interventions on the progression of slowly developing renal cysts.

Acetazolamide↗
PubMed1999

Inhibition of topoisomerase II alpha subunit de novo synthesis by specific antisense oligonucleotides suppresses human glioma T98G cell growth.

Deoxyribonucleic acid (DNA) topoisomerases are enzymes which resolve topological problems in eukaryotic DNA, and may be involved in cell proliferation. The involvement of topoisomerase II in cell proliferation was examined in the human glioma cell line T98G. The growth rate of T98G cells was suppressed by treatment with topoisomerase II antisense oligonucleotides dose-dependently, with significant suppression at concentrations greater than of 0.1 mM. The growth rate of T98G treated with control oligonucleotide was suppressed at concentrations greater than 3.0 mM. The activity of topoisomerase II in T98G cells treated with 0.5 mM topoisomerase II antisense oligonucleotide was one fourth of that in cells treated with control oligonucleotide. When topoisomerase II translation was suppressed, the activity of topoisomerase I was increased. These results suggest that de novo synthesis of the topoisomerase II protein is required to maintain a normal growth rate in cultured T98G cells. These topoisomerases may be functionally related, and might provide compensatory mechanisms in the case of compromised function.

Antigens, Neoplasm↗
PubMed1999

Influence of rewarming conditions after hypothermia in gerbils with transient forebrain ischemia.

OBJECT: Recently, several studies have demonstrated that hypothermia has a beneficial effect on clinical outcome; however, it is difficult to determine the appropriate rewarming conditions in clinical use. The purpose of the present study was to examine the influence of rewarming conditions in gerbils with transient forebrain ischemia. METHODS: Ischemia was induced in the gerbils by a 5-minute bilateral common carotid artery occlusion, after which the animals were immediately subjected to moderate or deep hypothermia. After moderate hypothermia (30.5 degrees C for 4 hours) the animals were rewarmed over standard, fast, or slow time periods. After deep hypothermia (24 degrees C for 2 hours) the animals were rewarmed in a standard, fast, slow, or stepwise manner. Cerebral blood flow (CBF), extracellular glutamate, and lactate were monitored. Hippocampal CA I cell damage was assessed 7 days after induction of ischemia. In animals treated with moderate hypothermia, the rewarming rate had no influence on the number of surviving neurons. However, fast rewarming from deep hypothermia (to 37 degrees C for 30 minutes) failed to provide the neuroprotective effect of hypothermia. Furthermore, this group showed a poor recovery of CBF (p < 0.01) and, consequently, an increase in extracellular glutamate (p < 0.01) and lactate (p < 0.01) in the hippocampus. CONCLUSIONS: The results of this study indicate a transient uncoupling of CBF and cerebral metabolism during fast rewarming from deep hypothermia, whereas slow and stepwise rewarming periods were found to be useful for protection against uncoupling of CBF and cerebral metabolism during rewarming.

Animals↗
PubMed1999

In vivo gene transfer of a suicide gene under the transcriptional control of the carcinoembryonic antigen promoter results in bone marrow transduction but can avoid bone marrow suppression.

We constructed the CEA419/CD retrovirus vector carrying the cytosine deaminase (CD) gene directed by the carcinoembryonic antigen (CEA) promoter. pCD2 retrovirus vector carrying the CD gene directed by the retrovirus long terminal repeat promoter was also used. When mice bearing intraperitoneally disseminated colorectal carcinomas (CRCs) were infused intraperitoneally with pCD2 or CEA419/CD retrovirus-producing cells, a CD fragment was detected in CRCs and bone marrow cells. It was shown that the CD gene was expressed both in CRCs and in the bone marrow of animals infused with pCD2 retrovirus-producing cells, while the CD gene was expressed solely in CRCs of animals infused with CEA419/CD retrovirus-producing cells. These results indicate that the use of a tumor-selective promoter may warrant the safety of in vivo gene therapy using suicide genes.

Adenocarcinoma↗
PubMed1998

Suppression of hyperemia after brain ischemia by L-threo-3,4-dihydroxyphenylserine.

Although several studies have shown that L-threo3,4-dihydroxyphenylserine (DOPS) may provide a neuroprotective effect against ischemic brain damage, its protective mechanism is not fully understood. Glutamate release and hippocampal blood flow in ischemia with administration of DOPS were investigated to elucidate the neuroprotective mechanism of DOPS. Pre- (but not post-) ischemic administration of DOPS rescued 73% of hippocampal CA1 neurons (p < 0.001, compared with ischemia only) 1 week after transient global ischemia in gerbils. While glutamate release induced by ischemia was not affected, the increase of hippocampal blood flow during reperfusion was significantly suppressed by DOPS. These results demonstrate that DOPS may prevent reperfusion injury by suppression of hyperemia after ischemia, resulting in neuroprotection.

Animals↗
PubMed1998

Dynamic characteristics and adaptability of mouse vestibulo-ocular and optokinetic response eye movements and the role of the flocculo-olivary system revealed by chemical lesions.

The dynamic characteristics of reflex eye movements were measured in two strains of chronically prepared mice by using an infrared television camera system. The horizontal vestibulo-ocular reflex (HVOR) and horizontal optokinetic response (HOKR) were induced by sinusoidal oscillations of a turntable, in darkness, by 10 degrees (peak to peak) at 0.11-0.50 Hz and of a checked-pattern screen, in light, by 5-20 degreesat 0.11-0.17 Hz, respectively. The gains and phases of the HVOR and HOKR of the C57BL/6 mice were nearly equivalent to those of rabbits and rats, whereas the 129/Sv mice exhibited very low gains in the HVOR and moderate phase lags in the HOKR, suggesting an inherent sensory-motor anomaly. Adaptability of the HOKR was examined in C57BL/6 mice by sustained screen oscillation. When the screen was oscillated by 10 degrees at 0.17 Hz, which induced sufficient retinal slips, the gain of the HOKR increased by 0.08 in 1 h on average, whereas the stimuli that induced relatively small or no retinal slips affected the gain very little. Lesions of the flocculi induced by local applications of 0. 1% ibotenic acid and lesions of the inferior olivary nuclei induced by i.p. injection of 3-acetylpyridine in C57BL/6 mice little affected the dynamic characteristics of the HVOR and HOKR, but abolished the adaptation of the HOKR. These results indicate that the olivo-floccular system plays an essential role in the adaptive control of the ocular reflex in mice, as suggested in other animal species. The data presented provide the basis for analyzing the reflex eye movements of genetically engineered mice.

Animals↗
PubMed1998

Central pressor effect of parathyroid hormone-related protein in conscious rats.

Although the parathyroid hormone-related protein gene is widely expressed in the central nervous system, the role of this protein in blood pressure is unknown. This article examines whether parathyroid hormone-related protein is involved in the central regulation of blood pressure. An intraventricularly injected solution of parathyroid hormone-related protein elicited a dose-dependent increase of mean arterial pressure accompanied by a decrease of heart rate in conscious Sprague-Dawley rats. An anti-parathyroid hormone-related protein monoclonal antibody, given in an intraventricularly injected solution, blocked the pressor effect of parathyroid hormone-related protein. Furthermore, this pressor effect of parathyroid hormone-related protein was also abolished after pretreatment by intravenous administration of either hexamethonium bromide or doxazosin mesylate. These results suggest that central parathyroid hormone-related protein is implicated in the regulation of blood pressure, and that this effect may be mediated through sympathetic activation.

Analysis of Variance↗
PubMed1998

Significance of multimodal cerebral monitoring under moderate therapeutic hypothermia for severe head injury.

The therapeutic significance of moderate hypothermia and cerebral monitorings was assessed in the 10 patients with severe head injury. Cooling was begun as soon as possible after admission, using water blankets under general anesthesia. Jugular venous or tympanic temperature of patients was maintained at 32 degrees C for 3 to 5 days, then rewarming at the rate of 1 degree C a day was started. The intracranial pressure was controllable less than 20 mmHg under hypothermia. Moderate hypothermia reduced the jugular venous lactate (33.5%) as well as the cerebral blood flow velocity at M1 portion of middle cerebral artery (CBFV-M1) measured by transcranial Doppler (7.2%), while increase of the jugular venous oxygen saturation (SjO2) (17.9%) was observed in a majority of the patients. Our results demonstrated that moderate therapeutic hypothermia significantly reduced cerebral circulation and metabolism. Measurement of SjO2 and CBFV-M1 seems to be useful for estimation of cerebral circulation and metabolism in therapeutic hypothermia.

Adolescent↗
PubMed1998

Hyperglycemia induces progressive changes in the cerebral microvasculature and blood-brain barrier transport during focal cerebral ischemia.

Hyperglycemia generally enhances cerebral ischemic injury. Most attention on a mechanism has focused on the adverse effect of increased lactate production (acidosis) leading to neuronal injury. The effects of hyperglycemia on another possible primary target, the cerebral microvasculature, is examined in this study. Focal cerebral ischemia was achieved by thread occlusion of the middle cerebral artery (MCA). Preischemic hyperglycemia was induced by intraperitoneal administration of 50% of D-glucose solution. In contrast to normoglycemic controls, glucose-injected rats showed a well demarcated pale infarct after 2 or 4 hours of ischemia reflecting a reduction in cerebral plasma volume (CPV) to 73 +/- 9 and 55 +/- 6% of contralateral by 2 and 4 hours respectively. Cerebral blood flow (CBF) measured by laser-Doppler flowmetry indicated that after the initial decline in CBF with MCA occlusion, hyperglycemia led to a further progressive reduction during ischemia. Blood-brain barrier transport measured by permeability surface area (PS) product for glutamine was reduced in both normoglycemic and hyperglycemic rats. However, the decline was greater in the hyperglycemic rats. Hyperglycemia induces progressive cerebrovascular changes and affects blood-brain barrier transport during focal cerebral ischemia. These changes may contribute to the adverse effects of hyperglycemia in stroke.

Animals↗
PubMed1998

Immunohistochemical study of clathrin in distal myopathy with rimmed vacuoles.

Clathrin-coated vesicles are involved in three receptor-mediated intracellular transport pathways: export from the Golgi apparatus, transfer of lysosomal enzymes from the Golgi apparatus to lysosomes, and endocytosis at the plasma membrane. Seeking evidence of transport abnormalities in distal myopathy with rimmed vacuoles (DMRV), we performed immunohistochemistry for clathrin in muscle biopsy specimens from patients with this disorder or other neuromuscular disorders, and also in control muscle samples resected in orthopedic procedures. While most myofibers from control muscle did not stain for clathrin, some fibers revealed finely granular sarcoplasmic staining. In specimens from patients with Duchenne and Becker muscular dystrophy, amyotrophic lateral sclerosis, peripheral neuropathy, and DMRV, numerous clathrin-positive granules were often scattered through the sarcoplasm and seen to a lesser extent in subsarcolemmal regions. Quantitative immunohistochemical assessment showed more reactivity for clathrin in DMRV than in controls and other diseased muscles, particularly in atrophic fibers and type 2 fibers. Not all strongly clathrin-positive muscle fibers contained rimmed vacuoles, although most fibers with vacuoles were clathrin positive. The result suggests that the lysosome system is activated and receptor-mediated intracellular transport pathways function appropriately in the muscles of DMRV patients.

Adolescent↗
PubMed1998

Adaptive modifications of post-saccadic smooth pursuit eye movements and their interaction with saccades and the vestibulo-ocular reflex in the primate.

Adaptation of the horizontal smooth pursuit eye movement was examined using step-ramp moving target paradigms in chronically prepared Macaca fuscata. Monkeys were trained to pursue a small target which moved in the horizontal plane in a 3 degrees step-10 degrees/s ramp or a 0 degrees step-10 degrees/s ramp mode for 300-400 ms. When the target moved from central fixation point in a step-ramp mode, the monkeys usually responded with an initial pursuit eye movement (latency, 100-120 ms) which reached to a nearly constant velocity of 4 degrees/s in 50 100 ms, followed by a 1-3.5 degrees catch-up saccade (latency, 170-230 ms). The catch-up saccade was followed by a 7-8 degrees/s post-saccadic pursuit. The post-saccadic pursuit velocity was measured 40-90 ms after the end of the catch-up saccade. When the target velocity was doubled (20 degrees/s) for 100-200 ms immediately after the onset of the catch-up saccade, the post-saccadic pursuit velocity increased by 40%. When the target velocity was decreased by half (5 degrees/s) immediately after the onset of the catch-up saccade for 150 ms, the post-saccadic pursuit velocity decreased by 30%. These increases or decreases of post-saccadic pursuit were observable within just 50-150 trials. The adaptation of post-saccadic pursuit occurred independent of the position of the target. The amplitude and latency of the catch-up saccade also increased correspondingly when the post-saccadic pursuit velocity was adaptively increased. Adaptation of smooth pursuit did not affect the dynamics of reflex eye movements, including the horizontal vestibulo-ocular reflex (HVOR) gain and phase measured by 0.33 Hz-10 degrees (peak-to-peak) turntable oscillations in darkness. Conversely, adaptation of the HVOR gain induced by a 2 h sustained oscillation of the turntable and screen in reversed direction at 0.33 Hz-10 degrees affected little the velocity of post-saccadic pursuit or the amplitude of the catch-up saccade. These results suggest that different neural mechanisms are respectively involved for the adaptation of horizontal smooth pursuit and HVOR in the primate.

Adaptation, Physiological↗
PubMed1998

Effects of niravoline (RU 51599), a selective kappa-opioid receptor agonist on intracranial pressure in gradually expanding extradural mass lesion.

It has recently been reported that kappa-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and animals. We investigated the effect of niravoline (RU 51599), a selective kappa-opioid receptor agonist in the treatment of intracranial hypertension. Acute intracranial hypertension was induced in cats by continuous inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 3 h. At this point, inflation was discontinued and the balloon remained expanded for an additional hour after which it was deflated. In the post-deflation period, monitoring continued for 1 h. The control group (n = 8) received ringer's lactate solution only, while the treatment group (n = 8) received an intravenous (IV) injection of 1.0 mg/kg of niravoline, every hour at the beginning of balloon inflation, during balloon inflation, in post-inflation, and at deflation time (5 doses). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), blood gases, pupil size, serum electrolytes, and osmolality were measured in both groups. Brain water content was determined in a separate group of cats at the end of a 3-h extradural brain compression. Compared to the untreated group, the niravoline-treated group had a significantly lower ICP and higher CPP at the 2 and 3 h during balloon inflation, in post-inflation, and in post-deflation periods. Brain water content was significantly reduced in niravoline-treated animals. No significant change was observed in serum osmolality throughout the experiment. Our results indicate that the mechanism by which niravoline reduces ICP is partly via a reduction in brain water content. Also, the current findings suggest that in clinical situations in which ICP is elevated due to the pressure of an extradural mass, niravoline may effectively reduce ICP while maintaining adequate CPP until the mass is removed.

Animals↗