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Biomedical subjects

Y Nonaka

Publications and source records attributed to Y Nonaka.

At least 19 recordsLinked to original sources
PubMed2001

Reverse aromatic cope rearrangement of 2-allyl-3-alkylideneindolines driven by olefination of 2-allylindolin-3-ones: synthesis of alpha-allyl-3-indole acetate derivatives.

The reverse aromatic Cope rearrangement of 2-allyl-3-alkylideneindolines obtained by Horner-Wadsworth-Emmons olefination of 2-allylindolin-3-ones was performed. When 2-allylindolin-3-ones were treated with phosphonium ylides in refluxing toluene, domino Wittig reaction and reverse aromatic Cope rearrangement took place to give alpha-allyl-3-indole acetate derivatives in good yields. The aromatization as a new driving force in the Cope rearrangement is preferable to the conjugation with the carbonyl and cyano groups and also to the alkyl substitution pattern, which are well-known driving forces.

Journal Article↗
PubMed2001

DNA-damaging carcinogen 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) induces apoptosis via caspase-9 in primary cultured rat hepatocytes.

The mechanism of cytotoxicity induced by the DNA-damaging carcinogen 3-amino-1,4-dimethyl-5H-pyrido[4,3-b] indole (Trp-P-1) was investigated in primary cultured rat hepatocytes. Cytotoxicity was caused by intact Trp-P-1 and not by metabolically activated derivatives prepared using a recombinant yeast strain AH22/pAMR2 expressing rat cytochrome P450 1A1, and not by metabolically activated derivatives. We also found internucleosomal DNA fragmentation 6 h after treatment with 30 microM Trp-P-1, indicating that the cytotoxicity was due to the induction of apoptosis. After treatment with Trp-P-1, c-Myc protein level increased in a time-dependent manner and p53 protein also increased transiently with a subsequent increase in Bax protein level. This apoptotic pathway required the activation of caspase-9 as an initiator after leakage of cytochrome c into the cytosol from mitochondria and the activation of caspase-3 and -7 as executioners, but not caspase-1, -6 or -8 as measured using the corresponding peptide inhibitors and substrates or western blotting. The activated caspases in turn cleaved poly(ADP-ribose) polymerase as an intracellular substrate. Furthermore, we detected NUC18-like endonuclease activity during apoptosis induced by Trp-P-1. These findings suggest that this apoptosis may have a role against heterocyclic amine-type carcinogens in normal cells.

Animals↗
PubMed2001

Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo.

Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5'-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5'-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5'-DFUR between in vitro and in vivo was ascribed to up-regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5'-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route.

Administration, Oral↗
PubMed2001

Salt-inducible kinase is involved in the ACTH/cAMP-dependent protein kinase signaling in Y1 mouse adrenocortical tumor cells.

The involvement of salt-inducible kinase, a recently cloned protein serine/threonine kinase, in adrenal steroidogenesis was investigated. When Y1 mouse adrenocortical tumor cells were stimulated by ACTH, the cellular content of salt-inducible kinase mRNA, protein, and enzyme activity changed rapidly. Its level reached the highest point in 1-2 h and returned to the initial level after 8 h. The mRNA levels of cholesterol side-chain cleavage cytochrome P450 and steroidogenic acute regulatory protein, on the other hand, began to rise after a few hours, reaching the highest levels after 8 h. The salt-inducible kinase mRNA level in ACTH-, forskolin-, or 8-bromo-cAMP-treated Kin-7 cells, mutant Y1 with less cAMP-dependent PKA activity, remained low. However, Kin-7 cells, when transfected with a PKA expression vector, expressed salt-inducible kinase mRNA. Y1 cells that overexpressed salt-inducible kinase were isolated, and the mRNA levels of steroidogenic genes in these cells were compared with those in the parent Y1. The level of cholesterol side-chain cleavage cytochrome P450 mRNA in the salt-inducible kinase-overexpressing cells was markedly low compared with that in the parent, while the levels of Ad4BP/steroidogenic factor-1-, ACTH receptor-, and steroidogenic acute regulatory protein-mRNAs in the former were similar to those in the latter. The ACTH-dependent expression of cholesterol side-chain cleavage cytochrome P450- and steroidogenic acute regulatory protein-mRNAs in the salt-inducible kinase-overexpressing cells was significantly repressed. The promoter activity of the cholesterol side-chain cleavage cytochrome P450 gene was assayed by using Y1 cells transfected with a human cholesterol side-chain cleavage cytochrome P450 promoter-linked reporter gene. Addition of forskolin to the culture medium enhanced the cholesterol side-chain cleavage cytochrome P450 promoter activity, but the forskolin-dependently activated promoter activity was inhibited when the cells were transfected with a salt-inducible kinase expression vector. This inhibition did not occur when the cells were transfected with a salt-inducible kinase (K56M) vector that encoded an inactive kinase. The salt-inducible kinase's inhibitory effect was also observed when nonsteroidogenic, nonAd4BP/steroidogenic factor-1 -expressing, NIH3T3 cells were used for the promoter assays. These results suggested that salt-inducible kinase might play an important role(s) in the cAMP-dependent, but Ad4BP/steroidogenic factor-1-independent, gene expression of cholesterol side-chain cleavage cytochrome P450 in adrenocortical cells.

Adrenal Cortex Neoplasms↗
PubMed2001

Differential regulation of 3beta-hydroxysteroid dehydrogenase type II and 17alpha-hydroxylase/lyase P450 in human adrenocortical carcinoma cells by epidermal growth factor and basic fibroblast growth factor.

Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) are pluripotent growth factors that stimulate both the proliferation and steroidogenesis of adrenocortical cells. Here we demonstrate that EGF and bFGF specifically induce mRNA of 3beta-hydroxysteroid dehydrogenase type II (3betaHSD II) and suppress that of 17alpha-hydroxylase/lyase P450 (CYP17) in human adrenocortical H295R cells. The induction of 3betaHSD II mRNA did not occur until 6 h after the growth factor treatment and was completely abolished in the presence of a protein synthesis inhibitor, cycloheximide (CHX), suggesting that the induction required de novo protein synthesis. The CYP17 mRNA suppression began at almost the same time as the induction of the 3betaHSD II mRNA. Interestingly, the CYP17 mRNA level was increased by the CHX treatment. Both the 3betaHSD II and CYP17 mRNAs were repressed by treatment with a calmodulin kinase II (CaMK II) inhibitor, KN-93, and were enhanced by a mitogen-activated protein kinase (MAPK) inhibitor, PD98059. The PD98059-mediated induction of the 3betaHSD II mRNA was completely blocked by the CHX treatment. Interestingly, treatment with EGF in the presence of both PD98059 and CHX produced a greater increase in the CYP17 mRNA than did treatment in the presence of PD98059 alone. These results suggest that CHX-sensitive factor(s) and CaMK II- and MAPK-signaling pathways may have important roles in both induction of 3betaHSD II and suppression of CYP17 by EGF or bFGF in H295R cells.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

[A case of a persistent primitive proatlantal intersegmental artery with a ruptured basilar bifurcation aneurysm].

A case of persistent primitive proatlantal intersegmental artery (PPPIA) associated with a ruptured basilar bifurcation aneurysm was reported. A 44-year-old male with sudden headache was admitted to our hospital. CT scan revealed subarachnoid hemorrhage. Cerebral angiography revealed anomalous anastomosis between the internal carotid artery and the vertebral artery at the proatlantal region. This anastomosis branched off from the left internal carotid artery at the C4 level and joined the horizontal portion of the left vertebral artery. It was thought to be PPPIA. Angiography also revealed an aneurysm of the basilar bifurcation which was responsible for the patient's subarachnoid hemorrhage. The aneurysm was successfully treated by endovascular embolization with Guglielmi detachable coils in an acute stage, and resulted in good outcome. PPPIA with basilar bifurcation aneurysm has not been presented or reported in the literature to date. To our knowledge, this is the first report of such an association of vascular anomalies. The frequency of PPPIA combined with the intracranial aneurysm is relatively high, whereas the occurrence of PPPIA is extremely rare. Therefore, it was suggested that some congenital and/or hemodynamic factors changed by PPPIA may affect the pathogenesis of intracranial aneurysms.

Adult↗
PubMed2000

Pure acute subdural haematoma without subarachnoid haemorrhage caused by rupture of internal carotid artery aneurysm.

A 52-year-old female presented with disturbance of consciousness and clinical signs of tentorial herniation. Computed tomography showed a pure acute subdural haematoma (SDH) over the left convexity without subarachnoid haemorrhage. Cerebral angiography showed a saccular aneurysm at the junction of the left internal carotid artery and the posterior communicating artery. Surgery to remove the haematoma and clip the aneurysm showed the rupture point was located in the anterior petroclinoid fold (subdural space). The patient recovered without neurological deficits. Pure SDH caused by ruptured aneurysm is rare. Rupture of an aneurysm adhered to either the dura or falx and located in the subdural space may cause pure SDH. Therefore, ruptured intracranial aneurysm should be considered as a cause of non-traumatic SDH. Immediate removal of the SDH and aneurysmal clipping is recommended in such patients, even those in poor neurological condition.

Aneurysm, Ruptured↗
PubMed2000

Molecular cloning of NADPH-cytochrome P450 oxidoreductase from silkworm eggs. Its involvement in 20-hydroxyecdysone biosynthesis during embryonic development.

Using RT-PCR, a cDNA fragment of NADPH-cytochrome P450 oxidoreductase from silkworm, Bombyx mori, was cloned from three-day-old nondiapause eggs. RACE was used to isolate the ends of the DNA. The full-length cDNA obtained was composed of 3471 bp with an open reading frame encoding a protein of 687 amino-acid residues with a relative molecular mass of 77 700. The protein, fused with glutathione S-transferase, was expressed in Escherichia coli and purified to homogeneity. The fused protein not only had NADPH-dependent cytochrome c-reducing activity, but also acted as an electron carrier from NADPH to bovine adrenal 21-hydroxylase P450 in the steroid hydroxylation reaction, confirming that the protein is the silkworm NADPH-cytochrome P450 oxidoreductase. Ecdysone 20-hydroxylase activity in the nondiapause egg microsomes increased until the fourth day after oviposition, and then decreased, little being detected on the ninth day. An antibody raised against the P450 reductase inhibited the ecdysone hydroxylation. Immunoblot analyses of the microsomes indicated that the P450 reductase protein appeared distinctly in the three-day-old nondiapause eggs and, in contrast to the developmental pattern of ecdysone hydroxylase activity, continued to increase as the embryos developed. These results suggest that ecdysone hydroxylation in the early stage of embryogenesis is dependent on the presence of both P450 reductase and ecdysone 20-hydroxylase P450, but its gradual reduction in the later stage may be due to the decrease in the level of ecdysone 20-hydroxylase P450.

Amino Acid Sequence↗
PubMed2000

Delayed CSF pseudocyst following shunt malfunction after myelomeningocele repair.

We report a case of delayed cerebrospinal fluid (CSF) pseudocyst following shunt malfunction in a 20-year-old patient with myelomeningocele. Magnetic resonance (MR) images and a radioimmunoassay shunt-gram detected the CSF fistula at the old scar of the myelomeningocele repaired 20 years before. Since the revision of the shunt system failed to keep the pseudocyst, the lesion was successfully directly repaired. Treatment of the delayed CSF pseudocyst following shunt malfunction thus requires a radical operation of the lesion.

Adult↗
PubMed2000

[Efficacy and safety of cefozopran (CZOP) monotherapy and combination therapy with CZOP and amikacin (AMK) for infections accompanying hematological diseases].

We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for infections in patients with hematological diseases. Efficacy was evaluated in 71 patients of monotherapy group and 70 patients of combination therapy group. Underlying diseases were mostly leukemia and lymphoma. Infections included sepsis, suspected sepsis, pneumonia and so on. Efficacy in CZOP monotherapy was excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients (7.5%) and the efficacy rate was 65.7%. On the other hand, in combination therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%) and the efficacy rate was 56.1%. Side effects such as eruption were noted in 2 patients. Abnormal laboratory findings were noted in 9 patients. All side effects as well as abnormal laboratory findings were minimal. It was concluded that CZOP monotherapy was effective in the treatment of various infections accompanying hematological diseases.

Adolescent↗
PubMed1999

Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal.

PCR-coupled cDNA subtraction hybridization was adapted to identify the genes expressed in the adrenocortical tissues from high salt diet-treated rat. A novel cDNA clone, termed salt-inducible kinase (SIK), encoding a polypeptide (776 amino acids) with significant similarity to protein serine/ threonine kinases in the SNF1/AMPK family was isolated. An in vitro kinase assay demonstrated that SIK protein had autophosphorylation activity. Northern blot revealed that SIK mRNA levels were markedly augmented by ACTH treatment both in rat adrenal glands and in Y1 cells. SIK may play an important role in the regulation of adrenocortical functions in response to high plasma salt and ACTH stimulation.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Metabolic studies using recombinant escherichia coli cells producing rat mitochondrial CYP24 CYP24 can convert 1alpha,25-dihydroxyvitamin D3 to calcitroic acid.

Previously we expressed rat 25-hydroxyvitamin D3 24-hydroxylase (CYP24) cDNA in Escherichia coli JM109 and showed that CYP24 catalyses three-step monooxygenation towards 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3 [Akiyoshi-Shibata, M., Sakaki, T., Ohyama, Y., Noshiro, M., Okuda, K. & Yabusaki, Y. (1994) Eur. J. Biochem. 224, 335-343]. In this study, we demonstrate further oxidation by CYP24 including four- and six-step monooxygenation towards 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3, respectively. When the substrate 25-hydroxyvitamin D3 was added to a culture of recombinant E. coli, four metabolites, 24, 25-dihydroxyvitamin D3, 24-oxo-25-hydroxyvitamin D3, 24-oxo-23, 25-dihydroxyvitamin D3 and 24,25,26,27-tetranor-23-hydroxyvitamin D3 were observed. These results indicate that CYP24 catalyses at least four-step monooxygenation toward 25-hydroxyvitamin D3. Furthermore, in-vivo and in-vitro metabolic studies on 1alpha,25-dihydroxyvitamin D3 clearly indicated that CYP24 catalyses six-step monooxygenation to convert 1alpha,25-dihydroxyvitamin D3 into calcitroic acid which is known as a final metabolite of 1alpha,25-dihydroxyvitamin D3 for excretion in bile. These results strongly suggest that CYP24 is largely responsible for the metabolism of both 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3.

Animals↗
PubMed1999

[Chlamydia pneumoniae infection and Mycoplasma pneumoniae infection in pediatric patients].

We evaluated a total of 1104 pediatric patients with acute lower respiratory tract infection for C. pneumoniae infection and M. pneumoniae infection by serology during July 1995 to December 1998. A microimmunofluorescence test was used for diagnosis of C. pneumoniae infection and a high density particle agglutination test for that of M. pneumoniae infection. Acute C. pneumoniae infection was found in 149 patients (13.5%), acute M. pneumoniae infection in 118 patients (10.7%), and dual infection in 27 patients (2.4%). Among 305 patients with pneumonia, M. pneumoniae infection (83 patients, 27.2%) was more common than C. pneumoniae infection (47 patients, 15.4%). However among 799 patients with bronchitis. C. pneumoniae infection (102 patients, 12.8%) was more common than M. pneumoniae infection (35 patients, 4.4%). Patients with C. pneumoniae infection were more younger and more frequently wheezing than patients with M. pneumoniae infection. These findings demonstrate that C. pneumoniae infection in very common pathogen of pediatric lower respiratory tract infection as M. pneumoniae infection in Japan.

Acute Disease↗
PubMed1999

[Study of optimal CHOP dose ranges for elderly patients with non-Hodgkin's lymphoma].

Two groups of intermediate-to high-grade non-Hodgkin's lymphoma patients aged 65 years and over were enrolled in a dose-range study of CHOP therapy utilizing 5 doses (1/2, 7/12, 2/3, 5/6, full CHOP): 11 patients 65-79 years of age (group A) and 9 patients 80 years or older (group B). The patients were enrolled consecutively; the study was designed so that if 3 patients completed 3 cycles of CHOP on schedule without major problems, the next highest dose was administered. If 2 patients experienced any major problems during 6 cycles at a given dose, treatment was discontinued and the dose prior to that particular dose was regarded as the optimal dose. The 6 treatment cycles were completed by 3 of 3 (2/3 CHOP), 3 of 4 (5/6 CHOP), and 1 of 4 (full CHOP) group A patients; and by 3 of 3 (1/2 CHOP), 2 of 3 (7/12 CHOP) and 1 of 3 (2/3 CHOP) group B patients. The results indicated that the optimal doses for group A and B were five-sixths and seven-twelfths of the standard CHOP dose, respectively.

Aged↗
PubMed1998

Structure/function relationship of CYP11B1 associated with Dahl's salt-resistant rats--expression of rat CYP11B1 and CYP11B2 in Escherichia coli.

Dahl's salt-resistant normotensive rats (DR rats) have been previously reported to express cytochrome P-450 (CYP11B1) containing five missense mutations [Matsukawa, N., Nonaka, Y., Higaki, J., Nagano, M., Mikami H., Ogihara, T. & Okamoto, M. (1993) J. Biol. Chem. 268, 9117-9121]. To investigate structure-function relationships of CYP11B, wild-type rat CYP11B1 and CYP11B2 and DR-CYP11B1 (mutant CYP11B1 in Dahl's salt-resistant rats) have been successfully expressed in Escherichia coli. Steroid 11beta-hydroxylase (11beta-OHase) activity observed with DR-CYP11B1 was similar to that of wild-type CYP11B1, while 18-hydroxylase (18-OHase) activity of DR-CYP11B1 was lower than that of wild-type CYP11B1. Mutant CYP11B1s containing a single or a double amino acid substitution associated with DR-CYP11B1 have been also expressed in E. coli to investigate effects of the substitutions on enzymatic activity. Each of the single mutant enzymes showed lower 18-OHase activity than wild-type CYP11B1, but not as low as DR-CYP11B1. A double mutant CYP11B1 with V381L and I384L showed 18-OHase activity at a similar low level to that of DR-CYP11B1. The 19-hydroxylation (19-OHase) activity of DR-CYP11B1 was about one-third of that of the wild-type enzyme and this low activity appeared due to the V443M mutation. These results suggest that three of five amino acid substitutions present in DR-CYP11B1 account for the decreased 18-OHase and 19-OHase activities. A decrease in these enzyme activities may be responsible for the normotension of the DR rats when fed a high-salt diet.

Amino Acid Sequence↗
PubMed1998

Cloning of a membrane-spanning protein with epidermal growth factor-like repeat motifs from adrenal glomerulosa cells.

The three zones of adrenal cortex are thought to arise from a single multipotential stem cell, but the mechanisms underlying the zonal differentiation during embryonic development of adrenal cortex are poorly understood. Employing subtraction cloning strategy, we isolated three distinct clones that were specifically expressed in the rat glomerulosa zone. One clone, named zona glomerulosa specific clone, encoded a membrane-spanning protein with a signal peptide at the N-terminus, six epidermal growth factor-like repeat motifs, and a transmembrane domain near the C-terminus. It was identified as a rat homolog of preadipocyte factor-1 (Pref-1), a factor involved in maintaining the undifferentiated status of preadipocyte. Immunohistochemical studies confirmed the presence of Pref-1 protein in the glomerulosa zone. Detailed examination revealed that the zone is divided into two layers; the first is a few-cells-thick layer present underneath the capsule (expressing both Pref-1 protein and aldosterone synthase cytochrome P450), and the second layer is beneath the first (containing Pref-1 protein but not aldosterone synthase). Moreover, another cell layer was found beneath the second layer and above the fasciculata zone, whose cells contained no Pref-1 protein, aldosterone synthase, or 11beta-hydroxylase. These findings suggest that a recently reported aldosterone synthase- and 11beta-hydroxylase-less cell layer between the two zones is composed of two kinds of cell: Pref-1 protein-positive and -negative cells. The level of Pref-1 message in the adrenal glands of animals having various pituitary-adrenal axis activities, as well as various plasma salt concentrations, correlated with the total number of glomerulosa cells. However, the specific content of Pref-1 message in a cell was fairly constant. When the adrenal gland was surgically enucleated and the remaining capsule regenerated, the level of Pref-1 transcript was significantly suppressed at the early phase. At this phase, only a minor population of the cortical cells expressed Pref-1 protein, most of these cells already expressing a fasciculata/reticularis-specific marker, inner zone antigen. These findings suggest that the capsular cells, mostly composed of the glomerulosa cells, may have potential for differentiating into other zones' cells, and the down-regulation of Pref-1 expression may be an important step in the adrenal zonal differentiation.

Adrenal Glands↗