Search PubMed⌕ Search

Biomedical subjects

K Shimada

Publications and source records attributed to K Shimada.

At least 433 records · Page 24Linked to original sources
PubMed1998

Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.

We have found that a hexadeoxyribonucleotide (5'TGGGAG3', R-95288), Koizumi, M. et al. Bioorganic & Medicinal Chemistry, 1997, 5, 2235, bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5'-end and a 2-hydroxyethylphosphate at the 3'-end, has high anti-HIV-1 activity and the least cytotoxicity in vitro and in vivo. In order to synthesize more potent hexadeoxyribonucleotides, we substituted phosphodiester (P-O) bonds in the 6-mer with the least phosphorothioate (P-S), phosphoramidate (P-N), or methylphosphonate (P-Me) bonds. When more than two P-N or P-Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV- activity, in spite of quadruplex structure formation. However, when P-S bonds were substituted for P-O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P-N or P-Me bonds. The results suggest that the formation of a quadruplex structure is not always sufficient for anti-HIV-1 activity of the 6-mer, and that net negative charges derived from P-O or P-S bonds in the quadruplex are important for anti-HIV-1 activity. Moreover, among various phosphate-modified ODNs, we found that the anti-HIV-1 activity of ODN PS7 with only one P-S bond was the same as that of R-95288, both having a high stability in human plasma.

Anti-HIV Agents↗
PubMed1998

Role of retinoic acid in regulation of mRNA expression of CaBP-D28k in the cerebellum of the chicken.

In contrast to vitamin D3-dependent gene expression of calbindin (CaBP-D28k) in intestine and kidney, the cerebellar mRNA expression seems independent of vitamin D3. The present study was conducted to elucidate correlation of mRNA expression of CaBP-D28k and vitamin D3 receptor (VDR) in the kidney and cerebellum of the developing chick by Northern blot analysis, localization of CaBP-D28k mRNA within the cerebellum by in situ hybridization, and effect of retinoic acid in ovo on CaBP-D28k mRNA levels. CaBP-D28k mRNA levels were low in the cerebellum until embryonic day 16 (E16) but markedly increased on E18 and reached plateau levels on E20. VDR mRNA levels were low until E16 and significantly increased on E18 but decreased on E20 and remained low on 1 and 7 days after hatching. In the mesonephros, CaBP-D28k mRNA levels were high until E16 but abruptly decreased on E18, while VDR mRNA levels remained relatively constant throughout the examined period between E10 and 20. In situ hybridization analysis clearly demonstrated CaBP-D28k mRNA signals within the Purkinje cells of the cerebellum in the embryo on E12-E18. Although 1.25 dihydroxyvitamin D3 [1.25(OH)2D3, 3 x 10(-10) M injected in ovo on E15 increased CaBP-D28k mRNA levels in the mesonephros on E16 but had no effect on those in the cerebellum. On the contrary, in ovo injection of retinoic acid (10(-10) and 10(-8) M) caused no effect on CaBP-D28k mRNA levels in the mesonephros but significantly increased those in the cerebellum. The results indicate a regulatory role of retinoic acid on mRNA expression of CaBP-D28k in the cerebellar Purkinje cells of the chicken embryo.

Animals↗
PubMed1998

Changes of AVT levels in plasma, neurohypophysis and hypothalamus in relation to oviposition in the laying hen.

Arginine vasotocin (AVT) is a neurohypophysial hormone involved in the reproductive function in avian species. We measured AVT concentrations in the neurohypophysis and plasma in relation to indomethacin blocked oviposition and to prostaglandin (PG) E2-induced premature oviposition in the hen. In addition, AVT concentration in the hypothalamus was measured in relation to spontaneous oviposition. In the control group the concentration of AVT decreased in the neurohypophysis and increased in plasma at oviposition. In hens that were administrated indomethacin, oviposition was delayed for several hours and no changes in the levels of AVT in neurohypophysis and plasma were observed at the predicted time of oviposition. Premature oviposition was induced within 5 min after the administration of PGE2. The levels of AVT decreased in the neurohypophysis and increased in plasma at the PGE2-injected premature oviposition. The increases of AVT levels in paraventricular and supraoptic nuclei were observed 2 and 5 h after spontaneous oviposition. The results indicate that oviposition causes an increase in the release of AVT from neurohypophysis and suggest that the synthesis of hypothalamic AVT may be stimulated by oviposition.

Animals↗
PubMed1998

Angiotensin-Converting Enzyme Gene Polymorphism and Plasminogen Activator Inhibitor 1 Levels in Subjects with Cerebral Infarction.

It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary artery disease, but its relation to cerebral infarction is still controversial. Plasminogen activator inhibitor 1 (PAI-1) is also a predictor of risk of atherothrombotic disease. In this study we investigated the association of the ACE gene polymorphism and plasma PAI-1 levels in subjects with cerebral infarction. We evaluated the genotype of the ACE gene in 26 subjects with and 28 subjects without a history of ischemic stroke. The ACE genotype was analyzed by the polymerase chain reaction. Plasma PAI-1 antigen levels were measured by ELISA. There were no differences in accepted risk factors between the groups with or without cerebral infarction. However, the frequency of the D allele was significantly higher in subjects with cerebral infarction (0.63) than in those without infarction (0.39) (chi(2) = 6.306, P = 0.012). The frequency of the DD genotype of the ACE gene was also significantly higher in subjects with than in those without cerebral infarction (DD: 46.2%, ID: 34.6%, II: 19.2% vs. DD: 14.3%, ID: 50.0%, II: 35.7%, chi(2) = 6.689, P = 0.035). Plasma PAI-1 levels were not significantly different between groups with and without cerebral infarction. There was no association between the ACE genotype and PAI-1 levels. The DD genotype of the ACE gene is associated with cerebral infarction, which is independent of plasma PAI-1 level.

Journal Article↗
PubMed1998

Effect of a Change in the Sleep/Wake Cycle on the Diurnal Variation of Fibrinolytic Parameters.

The mechanism underlying the circadian rhythm of fibrinolysis is not well understood. To evaluate the influences of wakefulness and of the intrinsic circadian rhythm on fibrinolytic activity, we examined diurnal changes (8:00 am vs. 8:00 pm) in plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator (t-PA) antigen levels, and t-PA activity, as well as in plasma serum cortisol levels, in 10 healthy males (21 +/- 2 years) for two consecutive days. On the first day, subjects remained awake all day and night. They slept during the daytime (8:30 am to 5:30 pm) on the following day. PAI-1 activity and cortisol levels were significantly decreased, and t-PA activity tended to increase during the daytime on the first day. On the morning following overnight wakefulness, PAI-1 activity and cortisol levels did not return to the levels of the previous morning. On the second day, the afternoon decrease in PAI-1 activity, but not cortisol levels, was still observed, although its magnitude was substantially attenuated. No significant diurnal changes were observed in the levels of t-PA antigen throughout the study period. These findings suggest that the diurnal variation of fibrinolytic activity may be governed by an intrinsic circadian rhythm of PAI-1, which can be modified by a change in the time of wakefulness.

Journal Article↗
PubMed1998

Grb10/GrbIR as an in vivo substrate of Tec tyrosine kinase.

BACKGROUND: Tec is a member of the recently emerging subfamily among nonreceptor protein-tyrosine kinases (PTKs). Although many members of this family have been shown to be involved in a wide range of cytokine-mediated signalling systems, the molecular mechanism by which they exert in vivo effects remains obscure. To gain insights into the downstream pathways of Tec, we here looked for Tec-interacting proteins (TIPs) by using the yeast two-hybrid screening. RESULTS: One of TIPs turned out to be Grb10/GrbIR, which carries one pleckstrin homology domain and one Src homology 2 domain. Grb10/GrbIR was known to bind receptor PTKs in a ligand-dependent fashion, but not to be phosphorylated on tyrosine residues. In a transient expression system in human kidney 293 cells, however, Grb10/GrbIR becomes profoundly tyrosine-phosphorylated by Tec, but not by Syk, Jak2 or insulin receptor. We also reveal that expression of Grb10/GrbIR suppresses the cytokine-driven and Tec-driven activation of the c-fos promoter. CONCLUSION: Our results indicate a novel role of Grb10/GrbIR as an effector molecule to a subset of nonreceptor PTKs.

Amino Acid Sequence↗
PubMed1998

Sequence-specific DNA binding activity in the RAE28 protein, a mouse homologue of the Drosophila polyhomeotic protein.

The rae28 gene, a mouse homologue of the Drosophila polyhomeotic gene, is involved in the maintenance of the transcriptional repression states of Hox genes. In this study we synthesized the glutathione S transferase-RAE28 (GST-RAE28) fusion protein and examined sequence-specific DNA binding activity in the RAE28 protein by using the selected and amplified binding site method. After five rounds of enrichment, the eluted DNAs were amplified, cloned and sequenced. The sequences of individual oligonucleotides included the following consensus sequences; 5'-ACCA-3', 5'-ACCCA-3', 5'-CTATCA-3' and 5'-TGCC-3'. The oligonucleotides including these consensus sequences were show to have significant affinity with the GST-RAE28 fusion protein. The RAE28 protein was recently shown to form multimeric protein complexes with other members of mouse Pc-G proteins in the nucleus. These findings strongly suggest that the RAE28 protein constitutes a sequence-specific DNA binding domain in multimeric Pc-G protein complexes.

Animals↗
PubMed1998

Promoter of mDMAHP/Six5: differential utilization of multiple transcription initiation sites and positive/negative regulatory elements.

We analyzed the expression of mouse DMAHP / Six5 (the myotonic dystrophy-associated homeodomain protein gene) during embryogenesis and in various tissues by northern blotting. Expression was observed as early as embryonic day 7 (E7) and continued to E17. Abundant expression was observed in neonatal heart and skeletal muscle with potential links to the phenotype of myotonic dystrophy. The transcription initiation sites of the gene were analyzed in mouse E11 and E15 embryos and in adult skeletal and heart muscle. Three major transcription initiation sites were identified, the proximal site was specific to the early E11 embryo, while the other two were common among the heart and skeletal muscle and E11 and E15 embryos. All transcription initiation sites were downstream of the corresponding CTG repeat locus of the mouse gene (-1195), excluding a possible inclusion of the CUG repeat sequence in mRNA leading to abnormal splicing or to translation of aberrant protein. For analysis of the regulatory elements in the promoter region, we used P19 embryonal carcinoma cells which abundantly express mouse DMAHP / Six5. Multiple positive and negative elements were identified in the promoter region. All positive elements were Sp1/Sp3 binding sites and one of the negative elements was a novel factor binding site. The transcription initiation sites and regulatory elements are conserved between human and mouse DMAHP.

Animals↗
PubMed1998

Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients.

BACKGROUND: Nonfunctioning islet cell tumors (NFICTs) usually reach a large size prior to detection, at which stage patients have some symptoms or signs. Recently, NFICTs have been discovered in asymptomatic patients with increasing frequency owing to advances in diagnostic imaging techniques. This study investigated clinical, imaging and pathological features in recent cases of NFICT. METHODS: The medical records, radiographs and pathological specimens of 16 patients with NFICT who were evaluated between April 1991 and March 1996 were reviewed. RESULTS: Tumor sizes ranged from 0.8 to 17 cm (average, 5.2 cm). Five patients (31%) had some symptoms or signs at the time of diagnosis; however, the other 11 (69%) had no symptoms. Of 10 patients with a tumor of size 5 cm or less, nine were asymptomatic and all tumors were histologically benign. In contrast, in six patients with a tumor larger than 5 cm, four had some symptoms and five tumors were malignant. The detection rates of pancreatic tumor mass on ultrasonography and computed tomography were 94% (15/16) each. All 14 patients in whom the tumor was completely resected survived without recurrence; however, the remaining two patients with liver metastases died following recurrence. CONCLUSIONS: US and CT are useful in detecting NFICTs even if the tumor is small and the patient is asymptomatic. The detection of NFICTs of small size and their complete removal are essential for a successful cure.

Adenoma, Islet Cell↗
PubMed1998

Genetic variation in the promoter region of the beta-fibrinogen gene is associated with ischemic stroke in a Japanese population.

Evidence suggests that an allelic variation in the beta fibrinogen gene may confer an increased risk of coronary artery disease and stroke. The role of the beta fibrinogen gene polymorphism and fibrinogen levels in ischemic stroke has not been determined in Japanese, who are more prone to stroke than to coronary artery disease compared with Caucasians. We investigated the associations between ischemic stroke, plasma fibrinogen level, and a HaeIII restriction fragment length polymorphism (G/A(-455)) located at -455 bp from the start of transcription of the beta fibrinogen gene in 85 hypertensive patients with ischemic stroke (stroke group), 85 hypertensive patients without ischemic stroke (nonstroke group) and in 84 normotensive subjects matched for age, sex, and smoking status recruited at an annual health examination (normotensive group). The frequency of non-cutting allele (designated A(-455) allele) in the control group was 0.07 [95% CI: 0.03-0.11]; this value was significantly lower than that previously reported in Caucasians (0.19-0.26). The A(-455) allele frequency of the nonstroke group and stroke group were 0.08 [95% CI: 0.04-0.12] and 0.15 [95% CI: 0.10-0.21]. A(-455) allele frequency of the stroke group was significantly higher than that of the control group chi2 = 5.63, P= 0.018) and the nonstroke group chi2 = 4.00, P= 0.043). The mean +/- SD fibrinogen level was significantly higher in the stroke group than that in the normotensive group (277 +9/- 64 mg/dl versus 257 +/- 52 mg/dl, P < 0.03), but that of the nonstroke group was not significantly different compared with both normotensive and stroke groups. In conclusion, the positive association between the fibrinogen genotype G/A(-455) and ischemic stroke in hypertensive patients was independent of other risk factors. These results suggest that fibrinogen A(-455) allele may be an independent risk factor for ischemic stroke in the Japanese population.

Age Factors↗
PubMed1998

The 27-bp repeat polymorphism in intron 4 of the endothelial cell nitric oxide synthase gene and ischemic stroke in a Japanese population.

Endothelium-derived nitric oxide formed by endothelial constitutive nitric oxide synthase (ecNOS) mediates endothelium-dependent vasodilation and antithrombotic action. We analyzed the distribution of a polymorphism of ecNOS (27-bp repeat in intron 4) in 127 ischemic stroke patients (18 with atherothrombotic, 58 with lacunar, and 51 with silent lacunar stroke) and 91 control subjects. When we assigned the four repeats as allele a, and five repeats as allele b, there was no significant difference between the genotype distribution and allele frequencies in the stroke group and in the control group (0.862 versus 0.868 for the b allele frequency). Moreover, there was also no significant difference in the genotype distribution or allele frequencies among the three stroke subgroups (b allele frequency: 0.889 for atherothrombotic stroke; 0.862 for lacunar stroke; 0.853 for silent lacunar stroke). These findings suggest that there is no overt association between this ecNOS gene polymorphism and ischemic stroke. We found no evidence that this polymorphism may be a genetic factor for the onset of cerebrovascular disease in this Japanese population.

Aged↗
PubMed1998

Plasma levels of natriuretic peptides and adrenomedullin in elderly hypertensive patients: relationships to 24 h blood pressure.

OBJECTIVE: The aim of this study was to investigate the relationships between levels of natriuretic peptides and adrenomedullin and 24 h blood pressure levels in elderly hypertensives. DESIGN AND METHODS: We performed both 24 h ambulatory blood pressure monitoring and measurement of plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and adrenomedullin in 118 asymptomatic hypertensive elderly (> 60 years old) patients. We classified the subjects into groups with isolated clinic hypertension (n = 40) and sustained hypertension (n = 78). We also measured the levels of these peptides in 37 elderly normotensive subjects. RESULTS: Plasma ANP and BNP levels were slightly increased in patients with isolated clinic hypertension compared with elderly normotensives. Among the hypertensives, plasma ANP and BNP levels were more closely related to 24 h blood pressure levels than to office blood pressure levels. Sustained hypertensives showed significantly increased plasma levels of ANP and BNP compared with isolated clinic hypertensives, while adrenomedullin levels were similar in the two groups. Elderly hypertensives with left ventricular hypertrophy detected by electrocardiography had significantly higher levels of ANP and BNP, and higher BNP/ANP ratios than those without left ventricular hypertrophy, while there was no significant difference in adrenomedullin levels between the two groups. CONCLUSIONS: Our results suggest that measurements of ANP and BNP may be useful in detecting left ventricular hypertrophy and in differentiating isolated clinic hypertension from sustained hypertension in elderly hypertensive patients.

Adrenomedullin↗