Biomedical subjects

K Hidaka

Publications and source records attributed to K Hidaka.

At least 73 records · Page 4Linked to original sources

PubMed1995

Full-length cDNA cloning and distribution of human dopamine D4 receptor.

Dopamine D4 receptor is the focus of interest in terms of pharmacological profile and possible relation to the disease. Using poly A+RNA from human retina as a template, we succeeded in cloning of full-length cDNA of the human dopamine D4 receptor by improved reverse transcription-polymerase chain reaction (RT-PCR). From the RT-PCR products, two polymorphic variants which had two and four tandem repeats in the putative third cytoplasmic loop were obtained. Transient expression of the full-length cDNA in COS-1 cells produced [3H]spiperone binding sites with a high affinity. These results confirmed the existence of the D4 receptor mRNA containing a different number of polymorphic tandem repeats in native human tissues. The RT-PCR method demonstrated the restricted distribution of the D4 mRNA in human tissues and brain regions. The mRNA was detected at the highest level in the retina, followed by the brain, placenta, and kidney. Among brain regions, relatively low levels for mRNA of the human D4 receptor were observed in the nigrostriatal pathway compared with the mesolimbic system. The distribution of the mRNA in human brain suggests that the D4 receptor plays a different role in the central nervous system compared with the D2 receptor.

Base Sequence↗

PubMed1995

Chemosensitisation of spontaneous multidrug resistance by a 1,4-dihydropyridine analogue and verapamil in human glioma cell lines overexpressing MRP or MDR1.

Multidrug resistance phenotypes in human tumours are associated with the overexpression of the 170 kDa P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene, and also with that of the non-P-glycoprotein-mediated multidrug resistance gene, MRP, which encodes a 190 kDa membrane ATP-binding protein. We have previously reported that overexpression of MRP appears to be responsible for spontaneous multidrug resistance in some human glioma cell lines (Abe et al., Int. J. Cancer, 58, 860-864, 1994). In this study, we investigated whether chemosensitising agents of P-glycoprotein-mediated multidrug resistance such as verapamil, a biscoclaurine alkaloid (cepharanthine), and a dihydropyridine analogue (NIK250) could also reverse multidrug resistance in human glioma cells. The glioma cell lines were the two MRP-expressing cell lines, T98G and IN500, an MDR1-expressing cell line, CCF-STTG1, and the MRP1 MDR1-non-expressing cell line, IN157. Verapamil and NIK250 almost completely reversed drug resistance to vincristine, etoposide and doxorubicin in T98G cells, while they also reversed drug resistance to vincristine and etoposide, but only partially to doxorubicin in IN500 cells. Cepharanthine as well as verapamil and NIK250 reversed vincristine resistance in CCF-STTG1 cells, but cepharanthine only partially reversed drug resistance in T98G and IN500 cells. The cellular accumulation of [3H]etoposide increased about 2- and 3-fold compared with control in T98G cells in the presence of verapamil and NIK250 respectively. Furthermore, the release of doxorubicin from the nuclei of T98G cells was blocked by NIK250. However, NIK250 and verapamil caused no apparent increase in vincristine accumulation in T98G cells. NIK250 or verapamil might exert inhibitory effects upon MRP function, resulting in a reversal of MRP-mediated spontaneous multidrug resistance in cultured human glioma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

Scanning electron microscopic observation of pancreatic ducts in WBN/Kob rats.

To elucidate changes of pancreatic ducts in chronic pancreatitis, we observed pancreatic tissues with light microscopy and scanning electron microscopy, and corrosion casts of pancreatic ducts with scanning electron microscopy, in male WBN/Kob rats, considered a spontaneously occurring chronic pancreatitis model. At 3 months of age, hemorrhage and increased fibrosis were found in part of the pancreatic tail. After 3 months of age, pancreatic ductal lumina exhibited a winding form and inner surfaces showed long cilia and crater-like depressions. Fibrous tissues gradually extended into exocrine tissues and islets after 6 months of age. Most pancreatic ductal lumina developed a helical form with many deep depression at 14 months of age. It is suggested that increased pancreatic ductal pressure causes these findings.

Animals↗

PubMed1995

Biomodulation by hyperthermia of topoisomerase II-targeting drugs in human colorectal cancer cells.

We examined whether heat stress could enhance the sensitivity of human colon cancer WiDr cells to topoisomerase II-targeting anticancer agents, etoposide (VP-16) and teniposide (VM-26), and also determined the most effective timing for the drug administration after exposure to hyperthermia. Both topoisomerase II contents and topoisomerase II activity were significantly increased in WiDr cells 3 to 12 h after heat stress at 43 degrees C for 1 h, in comparison with those immediately after the heat stress. Cytotoxicity by VP-16 was most significantly enhanced 3 to 12 h after exposure to 43 degrees C for 1 h, but no synergistic effect was observed when the drug was administered immediately after the heat stress. A combination of VM-26 with heat stress, but not that of a topoisomerase I-targeting camptothecin derivative (CPT-11), or vincristine, showed a synergistic cytotoxic effect on WiDr cells. VP-16 alone induced cellular accumulation at the G2 + M phase, whereas the combination of VP-16 and heat stress further increased the cell population at the G2 + M phase, and decreased S-phase cells. A possible application of the combination of VP-16 and hyperthermia in clinical use is discussed.

Adenocarcinoma↗

PubMed1995

Inhibition by erythromycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP-dependent protein kinase.

The long-term low-dose administration of erythromycin is effective in treating chronic inflammatory diseases of the lower respiratory tract. The aim of this study was to clarify the mechanism for this therapeutic effect of erythromycin. We measured its effect on the production of superoxide anion (O2-) by polymorphonuclear leukocytes (PMN) that was induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or by phorbol myristate acetate (PMA). 25 microM erythromycin inhibited fMLP-induced O2- production by about 50%, but not PMA-induced O2- production. Moreover, this inhibition was overcome by adding an inhibitor of cyclic AMP-dependent protein kinase (PKA), H-89. The fMLP-induced O2- production was also inhibited by isoproterenol, a beta-adrenergic agonist, and by dibutyryl cyclic AMP, a cell membrane permeating analogue of cyclic AMP. The inhibition was also overcome by the addition of H-89. Therefore, the effect of erythromycin seemed to be, in part, mediated through the activation of PKA. The inhibition by erythromycin of O2- generation by PMN may contribute to the beneficial effect of this drug in treating chronic respiratory diseases.

Adrenergic beta-Agonists↗

PubMed1995

Synthesis and structure-activity studies of a series of 1-oxa-2,8-diazaspiro[4.5]decan-3-ones and related compounds as M1 muscarinic agonists.

A series of novel 2,8-dialkyl-1-oxa-2,8-diazaspiro[4.5]decan-3-ones and 2,8-dimethyl-1,2,8-triazaspiro[4.5]-decan-3-one (13), related to M1 muscarinic agonists YM796 and RS86, were synthesized by using Michael addition reaction of hydroxyurea or methylhydrazine to alpha, beta-unsaturated esters followed by cyclization reaction. These compounds were assessed for binding affinities for M1 and M2 receptors and in vivo muscarinic activity: namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks and induction of hypothermia, tremor, and salivation. 2,8-Dimethyl-1-oxa-2,8-diazaspiro[4.5]decan-3-one (6a) exhibited high affinities for both M1 and M2 receptors, showed antiamnesic activity (0.1 mg/kg, s.c.) and induced hypothermia (3 mg/kg, s.c.). In addition, 6a stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M1 muscarinic receptors. The alteration of the methyl group at N2 of 6a increased the selectivity in binding affinities for M1 over M2 receptors, but resulted in loss of M1 agonistic activity or antiamnesic activity. Compound 13 exhibited only low affinity for M1 receptors, suggesting that a basic nitrogen atom is not tolerated in M1 receptor binding as a substitute for an oxygen atom or a carbonyl group at the 1-position of 6a or RS86. None of these derivatives exhibited high selectivity for antiamnesic effect over induction of hypothermia compared to YM796.

Animals↗

PubMed1995

Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists.

2,8-Dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one (17), designed by incorporating the tetrahydrofuran ring moiety of muscarone into an 8-azaspiro[4,5]decane skeleton, and related 1-oxa-8-azaspiro[4.5]decanes were synthesized and assessed as M1 muscarinic agonists for the symptomatic treatment of dementia of Alzheimer's type. The compounds were tested for central muscarinic M1 and M2 receptor affinity and in vivo muscarinic activities: namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks, and induction of hypothermia, tremor, and salivary secretion. Compound 17 exhibited potent muscarinic activities in vitro and in vivo with no selectivity. Systematic modifications of 17 were conducted, and a number of compounds, including the 2-ethyl analogue (18), 3-methylene analogue (29), 3-dithioketal analogues (26, 28), and 3-oxime analogue (37) were found to display preferential affinity for M1 receptors over M2 receptors and, in addition, to exhibit potent antiamnesic activity sufficiently separated from hypothermia-inducing activity, taken as an index of cholinergic side effects, compared with the reference compound RS86 (1). Structure-activity relationships are discussed in comparison with those for muscarone analogues. Of these compounds only two, 2-ethyl-8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one (18) and 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (29), stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M1 muscarinic receptors. The optical resolution of 18 and 29 was performed. Eudismic ratios of both compounds in binding affinity were low, but M1 agonist activity resided preferentially in the (-)-isomers. The absolute configuration of (-)-29 was determined by X-ray crystal structure analysis to be S, being the same as that of muscarone. Based on the in vivo selectivity, (-)-29 was selected for clinical studies.

Alkanes↗

PubMed1995

[Determination of gene mutation of silent serum cholinesterase and its epidemiologic characters in the Japanese].

We detected 121 individuals with silent type of serum cholinesterase from 36 families in Japan. DNA analysis totaling 37 members of eleven blood unrelated families were carried out by four useful methods, namely, 1) PCR-SSCP analysis, 2) dot blot hybridization (DBH) with the use of synthetic oligonucleotide probe, 3) restriction endonuclease analysis (REA) and 4) direct sequencing analysis. Their mutations were classified into four groups, namely, 1) a G-->C transversion at codon 365, 2) a frameshift mutation with insertion of an extra A at codon 315, 3) an A-->G transition at codon 128 and 4) a C-->A transition at codon 400. The three procedures including (PCR-SSCP, DBH, REA) without the use of radio labeled materials (non-RI) are recommendable for the analyses. However, the direct sequencing analysis of bases with RI might be, at present, necessary for the final identification.

Asian People↗

PubMed1995

Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan.

Apolipoprotein (apo) E modulates the catabolism of chylomicrons and of very low density lipoprotein remnants. It has three major isoforms (apo E2, E3, E4) and some rare variants. To detect the variants of apo E, blood specimens from 1269 Japanese subjects were analyzed using isoelectric focusing with immunoblotting. The E5 and E7 variants were identified by IEF in 2 and 18 subjects, respectively. Both E5 (Glu3-->Lys) carriers were confirmed by PCR-mediated site-directed mutagenesis, and all E7 (Glu244-->Lys, Glu245-->Lys) carriers were confirmed by the amplification refractory mutation system. The relative frequencies of the epsilon 5 and epsilon 7 alleles were 0.001 and 0.007, respectively. High concentrations of total cholesterol (> 220 mg/dl) were detected in five of the subjects expressing apo E7 and one subject expressing apo E5, and eight subjects heterozygous for apo E7 showed elevated plasma triglyceride concentrations (> 150 mg/dl). In 621 healthy subjects, the mean triglyceride concentration in subjects with apo E7/3 appeared to be higher than in those with apo E3/3, but the difference was not statistically significant.

Adolescent↗

PubMed1995

[Comparison of complement activation between tuberculous and malignant pleuritis].

Complement activation products in pleural effusions were studied to clarify the causes of tuberculous and malignant pleuritis. Pleural SC5b-9, an activation product of complement common pathway, was significantly higher in tuberculous effusions than in malignant ones. In the tuberculous effusions, the levels of SC5b-9 and LDH (a marker of tissue damage) were significantly correlated, but in the malignant effusions these two values were not correlated. In the tuberculous effusions, SC5b-9 and Bb values were significantly correlated, but SC5b-9 and C4d were not, and nor were SC5b-9 and immune complex. In the malignant effusions, SC5b-9 and Bb values were low and were not significantly correlated. These results suggest that complement activation plays a significant role in tuberculous pleuritis, but not in malignant pleuritis.

Antigen-Antibody Complex↗

PubMed1994

Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies.

Previous reports have shown that (+/-)-YM796 (2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane) exhibits M1 agonistic activity and ameliorates cognitive impairment, and that the (-)-S isomer is active in in vitro studies. We report here the characterization of the (-)-S isomer, YM796 ((-)-(S)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane L-tartrate monohydrate), and its (+)-R isomer in in vivo pharmacological studies in comparison with the cholinesterase inhibitors tacrine, amiridine and E-2020. YM796 (0.031-0.5 mg/kg p.o.), like the racemate, reversed the cognitive impairment in passive avoidance tasks of rats with nucleus basalis magnocellularis lesions, whereas (+)-R-YM796 was ineffective in this experimental amnesia. YM796 exhibited only weak effects on mouse salivation and hypothermia, a peripheral cholinergic response and a central cholinergic response, respectively. The (+)-R isomer, however, failed to induce these cholinergic responses. YM796 also ameliorated the memory deficits induced by scopolamine in rats and electroconvulsive shock in mice. The potency of YM796 in these experimental amnesia models was over a 100 times greater than that of tacrine, over 10 times greater than that of E-2020, and 6 times greater than that of amiridine. In salivary secretion and hypothermia, YM796 was 2-4 times weaker than tacrine and E-2020, and 1-2 times stronger than amiridine. Thus, YM796's ratio of anti-amnesic effects to salivary secretion and hypothermia was much greater than that of the cholinesterase inhibitors tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Characterization of two new human apolipoprotein A-I variants: apolipoprotein A-I Tsushima (Trp-108-->Arg) and A-I Hita (Ala-95-->Asp).

Two unrelated subjects with new variants of apolipoprotein (apo) A-I were found during screening with isoelectric focusing (IEF) gel analysis. In the first case, apo A-I Tsushima, sequencing following amplification by the polymerase chain reaction (PCR) revealed a residue 108 missense mutation (TGG-->CGG, Trp-->Arg) in exon 4. The proband of apo A-I Tsushima was heterozygous for this mutation. The second case, apo A-I Hita, revealed a residue 95 missense mutation (GCC-->GAC, Ala-->Asp) in exon 4. The proband of apo A-I Hita was compound heterozygous with apo A-I (Ala-37-->Thr). These two subjects exhibited normal plasma concentrations of apo A-I and HDL cholesterol. In screening normal high school students (n = 198), we used a PCR-mediated site-directed mutagenesis to rapidly detect the substitution of G to A at codon 37 because the apo A-I (GC-->ACC, Ala-37-->Thr) mutation is unrelated to the charge difference on IEF. The frequency of the A allele was 0.04: the substitution G to A at codon 37 did not affect the plasma concentrations of lipids and lipoproteins.

Aged↗

PubMed1994

6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: structure-activity relationships for the AMPA-type non-NMDA receptor.

A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their activity to inhibit [3H]AMPA binding from rat whole brain. From the structure-activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) showed the most potent activity for the AMPA receptor. Compound 11 was evaluated for selectivity versus other excitatory amino acid receptors, and its action against AMPA at its receptor in the rat striatum was characterized. These data showed that compound 11 was a selective antagonist for the AMPA receptor with a Ki value of 0.084 microM, being approximately equipotent with 2,3-dihydro-6-nitro-7-sulfamoylbenzo(f)quinoxaline (3) (NBQX; Ki = 0.060 microM). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).

Acoustic Stimulation↗

PubMed1994

A case of hepatocolic fistula after percutaneous drainage for a gas-containing pyogenic liver abscess.

We describe a rare case of gas-containing pyogenic liver abscess which penetrated the adjacent colon, forming a hepatocolic fistula, after percutaneous transhepatic abscess drainage (PTAD) had been performed. To the best of our knowledge, this is the first report of hepatocolic fistula associated with a gas-forming liver abscess in a diabetic patient, with radiological and surgical confirmation of the fistula.

Colonic Diseases↗

PubMed1994

Successive time courses of strength development and steroid hormone responses to heavy-resistance training.

Subjects (5 males, 5 females) performed heavy-resistance exercise at a constant stimulus 3 days/wk for 8 wk. Work rates were then increased to higher but constant levels for an additional 8 wk. Half times of the first training period were 14 and 10 days for the bench press and parallel squat, respectively. The second time course resulted in only one-third of the overall magnitude of strength increases for both exercises as the first, and the kinetics were slower in the parallel squat but similar in the bench press (half time 13 days). Skeletal muscle fiber area was significantly increased (19%) in fast-twitch fibers by the end of the second training period. Postexercise elevations in serum cortisol and prolactin were seen only in the male subjects. Because the males trained at considerably higher work loads than the females, these results imply that absolute amounts of resistance may be an essential requirement for inducing certain hormonal responses. Serum cortisol levels in males after exercise were blunted by the 5th wk of the first time course. For serum testosterone, neither resting nor higher post-exercise concentrations were different at any point of the training periods for either sex. We conclude that the strength time course results are not inconsistent with current thought on factors contributing to strength accumulation. The absence of a specific serum androgenic response with strength development may be related to the fact that the constant exercise stimulus is not conducive to establishing clear-cut hormone-strength relationships.

Adult↗

PubMed1994

Effect of radiosurgery using Leksell gamma unit on metastatic brain tumor--autopsy case report.

A 77-year-old male presented with gradual development of right hemiparesis. Postcontrast computed tomography (CT) revealed enhanced lesions in the left parietal and right paraventricular areas. Stereotactic brain biopsy led to a histological diagnosis of metastatic carcinoma. The lesions were treated by radiosurgery using the Leksell gamma unit. CT showed reduced size of the lesions after irradiation. The primary lesion could not be found and he died from pneumonia. Autopsy 3 weeks after the irradiation disclosed histological tumor necrosis, with greater tumor cell kill effects toward the center of the tumor.

Aged↗

PubMed1994

Protein-free culture of the human pancreatic cancer cell line, SUIT-2.

A human pancreatic cancer cell line (SUIT-2), usually cultured in serum-supplemented medium (DMEM/FBS), was adapted to protein-free conditions using a 1:1 mixture of DMEM and Ham's F12 medium (DMEM/F12). The cells have been maintained in DMEM/F12 for more than 2 years, with over 50 passages. The SUIT-2 cells grew in DMEM/F12 with a doubling time of 35.7 h, which was similar to that in DMEM/FBS (35.0 h). The cellular morphology was similar in both media. Type IV collagenolytic activity was detected in the conditioned media from cells grown in DMEM/F12. The secretion of CEA and CA19-9 initially decreased in DMEM/F12. CEA was not detected after passage 5 (p5) but the concentration of CA19-9 did not decrease further after the first few serial passages in protein-free medium. Xenografts of SUIT-2 cells cultured in DMEM/F12 remained tumorigenic and could form metastatic tumors in nude mice. In conclusion, SUIT-2 cells grown in protein-free media continued to produce CA19-9 and type IV collagenase in vitro and formed metastatic tumors in vivo.

Animals↗

PubMed1994

Pravastatin-induced changes in receptor-mediated metabolism of low density lipoprotein in guinea pigs.

The effect of pravastatin, an inhibitor of HMG-CoA reductase, on the metabolism of human low density lipoprotein (LDL) was examined in guinea pigs. Pravastatin treatment significantly reduced plasma levels of total cholesterol and LDL-cholesterol by 15.6 mg/dl (38.8%) and 12.7 mg/dl (42.9%), respectively. We investigated the metabolism of LDL in pravastatin-treated and untreated guinea pigs using the simultaneous intravenous injection of 131I-labeled LDL and 125I-labeled, galactose-treated LDL to quantify the LDL receptor pathway. Pravastatin increased the fractional catabolic rate (FCR) of the LDL receptor-dependent pathway. The treatment with pravastatin did not alter the FCR of the LDL receptor-independent pathway. The FCR of the LDL receptor-dependent pathway was higher for LDL isolated from pravastatin-treated subjects than for LDL isolated from control subjects. These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the LDL receptor-mediated pathway.

Animals↗