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Biomedical subjects

N Takagi

Publications and source records attributed to N Takagi.

At least 91 records · Page 5Linked to original sources
PubMed1997

Association of IGF2 and H19 imprinting with choriocarcinoma development.

We studied IGF2 and H19 expression, and methylation status of H19 gene in androgenetic moles and choriocarcinomas. The human placentae were examined similarly as a control. The CpG sites analyzed for methylation covered the 5' portion and the entire coding regions of H19. Although the paternal IGF2 and the maternal H19 allele were exclusively transcribed in full-term placentae, both H19 alleles were active in early placentate of 6-8 weeks gestation. The level of H19 expression in the mole was similar to that in normal placentae, which is compatible with the finding that half of the H19 gene was methylated and the remaining one was hypomethylated en masse in the complete mole. These imply the importance of regulating the level of H19 transcription not only for normal embryogenesis but also for the development of androgenetic moles. Choriocarcinomas were characterized by a low expression of IGF2 and a high expression of H19 with the transcripts being apparently intact in size. Biallelic expression of IGF2 or H19 was found frequently but not consistently in choriocarcinomas. Contrary to expectation, enhanced H19 expression was accompanied by hypermethylation of CpG sites over the entire gene region, apparently being at variance with the finding in normal placentae and androgenetic moles. The hypermethylation of CpG sites was also recognized in choriocarcinoma specimens surgically removed. The active H19 allele was unmethylated in placentae and probably so in androgenetic moles, but it was heavily methylated in choriocarcinomas. These findings provide the possibility that the mutated promoter is responsible for overcoming transcriptional suppression by CpG methylation in the H19 gene.

Blotting, Southern↗
PubMed1997

Preventive effect of a novel antifolate, MX-68, in murine systemic lupus erythematosus (SLE).

We evaluated the preventive effects of a novel nonpolyglutamatable antifolate, MX-68, on two experimental murine models of systemic lupus erythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-host disease (GVHD) mice, in comparison with classical antifolate methotrexate (MTX). The oral administration of 2 mg/kg MX-68, three times a week from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting from the development of lupus nephritis was also inhibited. However, MX-68 did not suppress the increase of serum anti-DNA or anti-TNP antibodies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVHD mice, MX-68 given three times a week from the day of first cell injection, for 9 weeks, dose-dependently delayed the appearance of proteinuria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DNA and anti-TNP antibodies was significantly inhibited, but this was not observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These beneficial effects of MX-68 were much greater than those of MTX in both models. These results suggest that MX-68 might be a more useful drug for the treatment of SLE.

2-Aminoadipic Acid↗
PubMed1997

Changes in cholinergic neurons and failure in learning function after microsphere embolism-induced cerebral ischemia.

Central cholinergic neurons play an important role in learning and memory functions. The present study was undertaken to elucidate the pathological changes in learning function and acetylcholine metabolism of the cerebral cortex and hippocampus, following microsphere embolism in rats. Microspheres (48 microns) were injected into the right internal carotid artery of the rats. Learning function was determined using a passive avoidance task on the seventh day after the embolism. In the biochemical study, acetylcholine and choline contents, and choline acetyltransferase activity were measured in the cerebral cortex and hippocampus. Cortical acetylcholinesterase-containing fibers were quantitatively estimated in the embolized rat. Passive avoidance was impaired in the microsphere-embolized rat. Microsphere embolism decreased the acetylcholine concentration and choline acetyltransferase activity in the cerebral cortex and hippocampus. In the histochemical study, the length of cortical acetylcholinesterase-containing fibers was decreased, but cell density was unchanged in the ipsilateral hemisphere of the microsphere-embolized rat. The results suggest that microsphere embolism induces severe damage to cholinergic neurons, which may be related to the impairment of learning function in the ischemic brain.

Acetylcholine↗
PubMed1997

Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats.

1. The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. 2. Cerebral ischaemia was induced by administration of 900 microspheres (48 microns) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30 mg kg-1 nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. 3. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. 4. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. 5. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain.

Acetylcholine↗
PubMed1997

Nodular granulomatous phlebitis of the skin: a fourth type of tuberculid.

We present five cases of granulomatous phlebitis of the skin and compare them with a case of miliary tuberculosis with granulomatous phlebitis. All five patients were hypersensitive to purified protein derivative, but without active tuberculosis. Although anti-tuberculous drugs were effective, no tubercle bacilli were isolated from the skin. Clinically, subcutaneous nodules were felt along the course of the leg vein. Histologically, epithelioid cell granulomas with Langhans' giant cells were observed within the walls of the cutaneous veins. In a later stage, granulomatous panniculitis was often associated. Using the polymerase chain reaction method. Mycobacterium tuberculosis DNA was detected in four of the five cases of granulomatous phlebitis of the skin. Granulomatous phlebitis of the skin seems to represent a relatively early phase of delayed-type hypersensitivity reactions to Mycobacterium tuberculosis and may represent a distinct entity different from other types of tuberculid-a new tuberculid. Nevertheless, before making the diagnosis, the possibility of true tuberculosis must always be excluded. Nodular granulomatous phlebitis of the skin would be an appropriate name for the newly described condition.

Aged↗
PubMed1997

Transient ischemia differentially increases tyrosine phosphorylation of NMDA receptor subunits 2A and 2B.

Activation of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the events leading to ischemia-induced neuronal cell death. Recent studies have indicated that the properties of the NMDA receptor channel may be regulated by tyrosine phosphorylation. We have therefore examined the effects of transient cerebral ischemia on the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in different regions of the rat brain. Transient (15 min) global ischemia was produced by the four-vessel occlusion procedure. The tyrosine phosphorylation of NR2A and NR2B subunits was examined by immunoprecipitation with anti-tyrosine phosphate antibodies followed by immunoblotting with antibodies specific for NR2A or NR2B, and by immunoprecipitation with subunit-specific antibodies followed by immunoblotting with anti-phosphotyrosine antibodies. Transient ischemia followed by reperfusion induced large (23-29-fold relative to sham-operated controls), rapid (within 15 min of reperfusion), and sustained (for at least 24 h) increases in the tyrosine phosphorylation of NR2A and smaller increases in that of NR2B in the hippocampus. Ischemia-induced tyrosine phosphorylation of NR2 subunits in the hippocampus was higher than that of cortical and striatal NR2 subunits. The enhanced tyrosine phosphorylation of NR2A or NR2B may contribute to alterations in NMDA receptor function or in signaling pathways in the postischemic brain and may be related to pathogenic events leading to neuronal death.

Animals↗
PubMed1997

Transient global ischemia alters NMDA receptor expression in rat hippocampus: correlation with decreased immunoreactive protein levels of the NR2A/2B subunits, and an altered NMDA receptor functionality.

We investigated the gene expression levels, the immunoreactive protein prevalence, and the functional activity of N-methyl-D-aspartate (NMDA) receptor complexes at early times after severe global ischemia challenge in rats. The mRNA expression levels for the NR2A and NR2B subunits of NMDA receptors changed to different degrees within different subregions of the hippocampus after reperfusion with respect to sham-operated control. No significant change in expression was observed in the vulnerable CA1 subfield at or before 6 h after challenge for either receptor subunit, although changes in expression in other hippocampal subfields were observed. At 12 and 24 h after challenge, significant decreases in expression for both subunits were found in the vulnerable CA1 subfield, as well as in other hippocampal regions. At the protein level, a significant decrease in the amount of NR2A/NR2B immunoreactivity in the total hippocampus was observed at both 6 and 24 h after reperfusion compared with sham control. Electrophysiological assessment of single-channel NMDA receptor activity in the CA1 subfield indicates that the main conductance state of NMDA receptor channels is maintained 6 h after challenge, although by 18-24 h after challenge, this main conductance state is rarely observed. The NMDA receptor component of the excitatory postsynaptic field potential was found to be significantly diminished from sham control 24 h after challenge, such that only approximately 10% of the sham response remained, but was not significantly altered from sham control at 6 h after challenge. These results indicate that decreases in the expression levels, the immunoreactive protein prevalence, and that alterations in the functionality of NMDA receptors occur in the hippocampus at early times after severe transient global ischemia.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Growth inhibition of oral bacteria related to denture stomatitis by anti-candidal chalcones.

In the antimicrobial therapy of denture stomatitis, it is desirable to inhibit the growth of not only the primary causative organism, Candida albicans, but also other oral bacteria closely associated with the condition. Three synthetic anti-candidal chalcones were characterized and compared for their additional activity in inhibiting these causative bacteria. Among the tested chalcones, 2,4,2'-trihydroxy-5'-methylchalcone showed the highest activity for different Gram-positive bacteria. It inhibited the growth of streptococci, staphylococci and lactobacilli at 25.0-50.0 micrograms/mL which was lower than or comparable to its minimum inhibitory concentration for candida. It functioned with a bactericidal action and leaked 260 nm-absorbing substances from the streptococcal cells. The antimicrobial activity of 2,4,2'-trihydroxy-5'-methylchalcone against both primary and secondary causative agents suggests it could be useful as a potent therapeutic agent in denture stomatitis.

Anti-Bacterial Agents↗
PubMed1997

A novel antifolate, MX-68, inhibits the development of autoimmune disease in MRL/lpr mice.

We compared a novel unpolyglutamable antifolate, MX-68, with polyglutamable antifolate, methotrexate (MTX), for treatment of an autoimmune kidney disease which develops spontaneously in MRL/Mp-lpr/lpr (MRL/lpr) mice. Oral administration of either MX-68 or MTX was commenced in 8-week-old female mice and continued 3 times a week until they reached 30 weeks of age. MX-68 delayed the onset of proteinuria and prolonged life span dose-dependently. Furthermore, it suppressed the elevation of serum blood urea nitrogen and cholesterol levels. MX-68 was as effective as MTX at ameliorating events which accompany the development of lupus nephritis, despite that MX-68 did not undergo polyglutamation. These ameliorative effects of MX-68 and MTX did not occur via inhibition of either autoantibody production or cell proliferation. Neither compound suppressed age-dependent elevation of immune complexes or antibodies for single-stranded DNA and TNP in serum nor did they influence the associated enlargement of lymph nodes and spleen. We conclude that MX-68 is beneficial for the treatment of autoimmune kidney disease in mice and may be useful for other related diseases such as systemic lupus erythematosus.

2-Aminoadipic Acid↗
PubMed1997

Immunosuppressive properties of MX-68, a novel unpolyglutamatable antifolate.

MX-68 is a novel unpolyglutamatable antifolate. We here reported the in vitro and in vivo immunosuppressive properties of MX-68 compared with a polyglutamatable antifolate, methotrexate (MTX). MX-68 showed potent suppressive effects on mitogen-induced mouse splenic lymphocyte proliferation as well as immunoglobulin production from LPS-stimulated mouse splenic B cells. In in vivo studies, MX-68 significantly suppressed antigen-specific antibody production of both T cell-dependent antigen and T cell-independent antigen. Moreover, MX-68 inhibited a sheep red blood cell (SRBC)-induced delayed-type hypersensitivity (DTH) reaction by administration starting from the day of antigen immunization, but did not suppress the effector phase of the DTH reaction. MTX showed suppressive activities similar to MX-68 in all experiments. Interestingly, although MX-68 demonstrated somewhat stronger suppressive effects than MTX in vivo, the results from in vitro studies were reversed. These results suggest that polyglutamation is not always required to suppress immune responses and that MX-68 is a slightly stronger immunosuppressive drug than MTX in mice.

2-Aminoadipic Acid↗
PubMed1997

Effects of nebracetam on synaptosomal monoamine uptake of striatal and hippocampal regions in rats.

Effects of nebracetam, a novel nootorpic agent, on the synaptosomal uptake of neurotransmitter monoamines of the brain regions were examined. Striatal and hippocampal synaptosomes were isolated by the Percoll gradient method, and the striatal dopamine uptake and hippocampal serotonin uptake were measured in the presence of different concentrations (1 to 1000 microM) of nebracetam in vitro. A significant reduction in dopamine uptake in the striatum and serotonin uptake in the hippocampus was seen at concentrations of 100 microM or above. In in vivo microdialysis study, there were no appreciable changes in the extracellular concentrations of striatal dopamine and hippocampal serotonin when this agent at a dose of 30 mg/kg, which was effective in improving ischemic brain energy metabolism, was applied i.p. to the rat. The ineffectiveness of nebracetam in the in vivo microdialysis may be due to low levels of the concentration of nebracetam when the agent was administered i.p. at a dose of 30 mg/kg, since the brain blood concentration of this agent is pharmacokinetically estimated to be no more than 15 microM when this dose of nebracetam is employed. Thus, it is unlikely that this agent at a pharmacologically effective dose alters dopamine or serotonin uptake in the brain nerve terminal under normal conditions.

Animals↗
PubMed1997

[Extended total aortic arch replacement involving the proximal descending aorta through a median sternotomy].

From January 1986 to September 1995, total aortic arch replacement (TAR) for aortic dissection was performed using selective cerebral perfusion in 151 patients. In 18 patients, the surgical procedures of extended aortic arch replacement (EAR) involving the proximal descending aorta through a median sternotomy were applied. To evaluate the outcome of EAR, the early and late results were compared with those of non-extended aortic arch replacements (NAR) through a median sternotomy (n = 66). The early mortality rates for EAR and NAR were 5.6% and 16.7%, respectively (NS); the lower rate for EAR may be due to the fact that EAR were performed more recently than NAR. The differences between EAR and NAR with respect to the amount of blood transfused intraoperatively and the respiratory index at 12 hours after surgery were not statistically significant. In addition, the extracorporeal bypass time in EAR was no longer than that in NAR. Thus, as compared with the NAR procedure, the EAR procedure did not have a negative effect on early outcome. Regarding late results, the actuarial survival rates after EAR and NAR, respectively were 87% and 72% at 1 year, 87% and 69% at 3 years (NS). The early thrombo-occlusion rates of the remaining false lumens after TAR in broad aortic dissections were 56% after EAR and 33% after NAR (p = 0.21). These results suggest that EAR may be a more useful procedure in some patients requiring TAR.

Aged↗
PubMed1997

[A case of nephrotic syndrome after bone marrow transplantation].

We reported a 27-year-old man who developed nephrotic syndrome 12 months after a bone marrow transplantation from his HLA-identical sister for chronic myelocytic leukemia. Anti-nuclear antibodies had been serially investigated after the bone marrow transplantation. They were detected in his serum 5 months before the appearance of proteinuria, but he tested negative at the onset of nephrotic syndrome. Histological analysis of the renal biopsy revealed subepithelial and subendothelial immune deposits in the glomerular basement membrane with increased mesangial matrix and cells. These findings suggested immune complex glomerulonephritis due to chronic graft-versus-host disease (GVHD) after bone marrow transplantation. In murine experimental chronic GVHD, anti-nuclear antibodies, which generate immune complexes that deposit or form in the kidney have been detected.

Adult↗
PubMed1997

Regulation of cardiac angiotensinogen mRNA in vivo and in vitro.

In this study, to investigate the mechanism of hypertension-associated induction of cardiac angiotensinogen in vivo and in vitro, we studied the regulation of angiotensinogen mRNA in the hearts of genetically hypertensive rats and in the rat cardiomyocytes. Levels of cardiac angiotensinogen mRNA were significantly increased in the hypertensive rats. Steady state mRNA levels for angiotensinogen mRNA in cardiomyocytes were increased by angiotensin II and mechanical stretch. The addition of an angiotensin II type 1 receptor antagonist (CV11974) and a transcriptional inhibitor (actinomycin D) completely blocked the induction of angiotensinogen mRNA by angiotensin II in cardiomyocytes. The addition of CV11974 significantly, but not completely, inhibited the induction of angiotensinogen mRNA by mechanical stretch. Actinomycin D completely blocked the induction of angiotensinogen mRNA by stretch in cardiomyocytes. An angiotensin II type 2 receptor antagonist (PD123319) and a protein synthesis inhibitor (cycloheximide) did not affect the induction. These results indicate that the expression of cardiac angiotensinogen mRNA is activated by the development of hypertensive cardiac hypertrophy, and that angiotensin II and mechanical stretch activates the angiotensinogen gene via the angiotensin II type 1 receptor-pathway in cardiomyocytes.

Angiotensinogen↗
PubMed1996

Microsphere embolism-induced changes in presynaptic function of the cerebral cortex in rats.

The present study was undertaken to elucidate pathophysiological changes in the cortical presynaptic function, K(+)-stimulated calcium influx, noradrenaline release and noradrenaline uptake, on the 1st and 3rd days after microsphere embolism in rats. Voltage-dependent calcium channels were characterized pharmacologically using three types of calcium channel blockers, L-type (nifedipine and diltiazem), N-type (omega-conotoxin GVIA), and P-type channel (omega-agatoxin IVA) blockers. K(+)-stimulated calcium influx of the normal rat synaptosome was inhibited by 100 nM omega-agatoxin IVA, but not by 10 microM nifedipine, 10 microM diltiazem and 100 nM omega-conotoxin GVIA. Calcium influx of the cortical nerve terminals of the right hemisphere was decreased on the 1st and 3rd days after the embolism. Noradrenaline release and uptake were also decreased on the 1st and 3rd days after the embolism. However, the percent release of noradrenaline was not altered. The results suggest that P-type channels are predominant in the cerebrocortical nerve terminals in rats and that calcium influx, noradrenaline release and uptake in the cerebrocortical nerve terminals are decreased by microsphere embolism. The decrease in noradrenaline release may be mainly due to a reduction in the activity of noradrenaline uptake in cerebrocortical nerve terminals of the microsphere-embolized rat.

Animals↗
PubMed1996

Genomic imprinting and chromosomal localization of the human MEST gene.

We have isolated a human homologue (MEST) of the mouse mesoderm-specific transcript (Mest) gene that shares about 70% nucleotide sequence homology. Northern blot analysis showed that the MEST gene was expressed in all major fetal organs and tissues so far examined, i.e., amnion, brain, heart, lung, stomach, gut, adrenal, kidney, muscle, and liver, which does not contradict with mesoderm-specific expression. MEST was abundantly expressed in hydatidiform moles of androgenetic origin, whereas it was barely detectable in dermoid cysts of parthenogenetic origin. Thus, it seems likely that the MEST gene, mapped to 7q32 by fluorescence in situ hybridization, is maternally repressed as the mouse homologue.

Amino Acid Sequence↗