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Y Nishii

Publications and source records attributed to Y Nishii.

At least 73 records · Page 4Linked to original sources
PubMed1991

On the mechanisms for the selective action of vitamin D analogs.

A variety of analogs of 1,25-(OH)2D3 with less calcemic activity and lower receptor binding affinity than 1,25-(OH)2D3 have been developed. However, these compounds have equal or greater ability to differentiate leukemia cells and psoriatic fibroblasts and to suppress PTH synthesis and secretion. The mechanism for this selectivity has not been elucidated. Because the lower potency of ergocalciferol compared to cholecalciferol in preventing or curing rickets in chicks was associated with a lower affinity of the avian vitamin D binding protein (DBP) for vitamin D2, we tested five analogs with low calcemic activity including 22-oxa-1,25-(OH)2D3 (OCT), MC903, 1,25-(OH)2-16 ene-23-yne D3, 1,25-(OH)2-26,27 dihomo-22-ene-D3, and 1,25-(OH)2-24-trihomo-22-ene-D3 for their affinity for rat serum DBP. All analogs had a low affinity for DBP, ranging from 50-3000 times less than that of 1,25-(OH)2D3. OCT also bound with low affinity to dog and human serum DBP. We tested with OCT the possible consequences of its low affinity for serum DBP. One of the functions of DBP is to prolong the lifetime of 1,25-(OH)2D3 in circulation. Quantification of the metabolic clearance rate (MCR) of OCT in 8 normal dogs using a single bolus injection technique showed that OCT was cleared at a rate of 48.2 +/- 7.5 ml/min, approximately 6-7 times more rapidly than 1,25-(OH)2D3 (6.8 +/- 0.4 ml/min). The estimated half-life of OCT in the circulation was 2.5 +/- 0.3 h compared to 7.0 +/- 0.6; n = 7 for 1,25-(OH)2D3. As our primary interest is the potential of OCT in treating the secondary hyperparathyroidism of CRF, we also measured the MCR of OCT in 5/6 nephrectomized dogs. Uremia does not affect the rate of clearance of OCT from the circulation (MCR: 56.8 +/- 4.5; t1/2 = 2.1 +/- 0.2 n = 4). Despite its shorter half-life, OCT suppressed PTH secretion in vivo in uremic dogs. The effects of low binding to DBP on the percentage uremic dogs. The effects of low binding to DBP on the percentage of free sterol were determined using an ultrafiltration procedure. We compared the proportion of free (unbound) OCT and 1,25-(OH)2D3 in 0.1% BSA-PBS with concentrations of human serum ranging from 0-25%. The proportion of OCT in the free form was significantly higher than that of 1,25-(OH)2D3 for every serum concentration tested. The physiological relevance of a higher percentage of free OCT was tested in normal human macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The activity of 22-oxacalcitriol in osteoblast-like (ROS 17/2.8) cells.

22-Oxacalcitriol (OCT), a synthetic vitamin D analog, can mimic the ability of 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] to differentiate leukemia and skin cells, to enhance the immune response and to suppress PTH secretion, but has much less calcemic activity. The mechanism for this selective action is not understood. OCT has been shown to have a diminished ability to mobilize calcium from bone in vivo, but in vitro findings are contradictory. Little is known about the effect of OCT on bone forming cells. Therefore, the present studies were designed to investigate the actions of OCT at the molecular level in the osteoblast-like cell line, ROS 17/2.8. 3H-OCT was bound to the vitamin D receptor (VDR) in intact cells at the same rate as 3H-1,25-(OH)2D3. As previously found for 1,25-(OH)2D3, the time course of specific binding of OCT was biphasic, with an initial plateau at 1 h and a further increase from 2-8 h. Scatchard analysis demonstrated that exposure to 3H-1,25-(OH)2D3 increased VDR from 24 fmol/mg protein at 2 h to 85 fmol/mg protein at 8 h. Exposure to 3H-OCT increased VDR from 22 to 76 fmol/mg protein, indicating that OCT is also capable of up-regulating the VDR in ROS 17/2.8 cells. In contrast to the lower affinity of OCT for VDR reported for chick intestine and HL-60 cells, the Kd for OCT in intact ROS 17/2.8 cells was identical to that for 1,25-(OH)2D3. The effect of OCT on osteocalcin secretion and alkaline phosphatase (ALP) activity in ROS 17/2.8 cells was also determined. Pretreatment for 24 h with either 1,25-(OH)2D3 or OCT resulted in a dose-dependent enhancement of osteocalcin secretion. A 2-fold stimulation by both compounds was observed with 10(-7)M. ALP activity was measured after a 72-h incubation with 10(-7)M 1,25-(OH)2D3 or OCT. Both compounds increased ALP activity to the same extent. Stimulation by OCT of VDR levels, ALP activity, and osteocalcin secretion were inhibited by the addition of 5 microM cycloheximide, indicating that these actions of OCT require new protein synthesis. Thus, OCT, like 1,25-(OH)2D3, up-regulates the vitamin D receptor, stimulates osteocalcin secretion, and increases ALP activity in ROS 17/2.8 cells, suggesting that the analog may be as active as 1,25-(OH)2D3 in stimulating bone formation in vivo. The low activity of OCT in mobilizing calcium from bone in vivo does not appear to be due to an inability of this compound to act on osteoblasts.

Alkaline Phosphatase↗
PubMed1991

A novel vitamin D3 analog, 22-oxa-1,25-dihydroxyvitamin D3, inhibits the growth of human breast cancer in vitro and in vivo without causing hypercalcemia.

Although 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been shown to inhibit the growth of certain malignant cells, its hypercalcemic effect has prevented clinical application. We have recently developed a novel vitamin D3 analog, 22-oxa-1,25-(OH)2D3 (OCT), that is capable of promoting differentiation and inhibiting proliferation without inducing hypercalcemia. The present study was undertaken to determine whether OCT could be applied for the treatment of breast cancer with or without estrogen receptor (ER). OCT inhibited the proliferation of both ER-positive (MCF-7, T-47D, and ZR-75-1) and ER-negative breast cancer cells (MDA-MB-231 and BT-20) in vitro in a time- and dose-dependent manner, as determined by cell number and [3H]thymidine uptake. The antiproliferative effect was observed with a concentration as low as 10(-11) M OCT, and treatment of MCF-7 cells with 10(-8) M OCT for 8 days caused more than a 50% reduction in cell number compared with that of vehicle-treated cells. OCT was approximately 1 order of magnitude more potent than 1,25-(OH)2D3 in inhibiting the proliferation of MCF-7 cells. The in vivo effect of OCT was examined in athymic mice implanted with ER-negative MX-1 tumor, which was established as the xenograft derived from human breast carcinoma. Intratumor administration of OCT three times a week remarkably delayed the growth of MX-1 tumor in a time- and dose-dependent manner. The antitumor effect of 1 microgram/kg BW OCT was greater than that of 500 microgram/kg BW adriamycin, and the relative tumor weights in each group on day 26 were 29.7% and 50.5% of that in the vehicle-treated group, respectively. The effects of OCT and adriamycin were additive, and the relative tumor weight after 26 days of combined treatment was 21.7% of that in the vehicle-treated group. Oral administration of OCT was also effective, and the relative tumor weight in the OCT-treated group (1 microgram/kg BW) was 54.6 +/- 0.1% (mean +/- SEM) of that in the vehicle-treated group. Neither intratumor nor oral administration of OCT raised the serum calcium level in these animals. These results demonstrate that OCT is a potent inhibitor of the proliferation of breast cancer cells with or without ER and that OCT inhibits the growth of breast cancer in vivo without inducing hypercalcemia. We suggest that OCT may provide a new strategy for the treatment of breast carcinoma regardless of ER status.

Animals↗
PubMed1991

Purification and characterization of thyroid hormone-responsive rat hepatic proteins.

Bernal et al. identified two proteins in rat hepatic nuclear extract, t- and n-proteins, that were enriched by thyroidectomy or T3 treatment, respectively. We purified these proteins, raised monospecific antibodies, and characterized them by Western blotting. Anti-n and anti-t-protein antibodies did not recognize t- and n-proteins, respectively. The n-protein was present in nuclear and cytosolic fractions, was present at low levels in the microsomal fraction, and was absent in the mitochondrial fraction of rat liver. The t-protein was more abundant in mitochondrial and microsomal fractions than in the nuclear fraction. The t-protein had the same molecular mass and shared immunological properties with peroxisomal enoyl-coenzyme-A (CoA) hydratase-3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme. The total cellular amount of n-protein increased 12 h after the administration of 1 microgram T3/100 g BW to thyroidectomized rats. Induction was obvious at 0.1 microgram T3/100 g BW after 24 h. Maximal induction was observed at 0.3 microgram T3/100 g BW. The n-protein was induced when thyroidectomized rat liver was perfused with 10(-7) M T3 for 6 h, excluding the possibility that the effect of T3 was mediated by an extrahepatic factor. The n-protein was detected in liver and brain, but not in kidney, heart, testis, or spleen. However, the amount of n-protein in brain was not thyroid hormone dependent. Hepatic n-protein does not correspond to any other T3-responsive protein in terms of its molecular mass and intracellular localization and may be a novel T3-responsive protein.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1991

Purification of human c-erb A beta protein.

Human thyroid hormone receptor (c-erb A protein) produced by Escherichia coli expression vector plasmid was purified sequentially using polyethylenimine precipitation of DNA, hydroxylapatite column chromatography, ammonium sulphate precipitation, Sephacryl S-300 gel filtration and mono Q-Sepharose column chromatography. These column procedures resulted in 41.3-fold purification of 3,5,3'-tri-iodo-L-thyronine (T3) binding activity over the initial E. coli extract. Purified protein as well as crude preparation showed high-affinity binding to T3. The c-erb A protein enriched by column purification was further purified by electroelution after electrophoresis. Rabbit antibody against the c-erb A protein was prepared and used for the Western blotting analysis. The antibody recognized c-erb A protein but not the bacterial proteins in crude E. coli extract. When partially purified rat hepatic nuclear thyroid hormone receptor was analysed, a 56 kDa receptor was specifically recognized by the antibody.

Antibodies↗
PubMed1991

[Pachydermoperiostosis--report of a case and review of 121 Japanese cases].

A case of 23 years old man with idiopathic pachydermoperiostosis is reported. He showed cutis verticis gyrata, clubbed fingers and periosteal new bone formation without any causative basic disorder. His serum level of FSH, LH, estradiol and estriol were elevated, but their significance was not clear. Histological examination of the skin from the forehead revealed sebaceous hyperplasia and dermal thickening, where deposit of alcian blue and colloidal iron positive substance were detected. The deformed forehead and eyelids were corrected by plastic surgery. One hundred and twenty one cases of pachydermoperiostosis reported so far in Japan are briefly reviewed. Most of them were male (94.1%), about one fourth had a family history. The principal features are: clubbing of the digits (88.4%), periosteal new bone formation (94.1%), coarsening of the facial features with furrowing of the skin of the face (72.7%) and cutis verticalis gyrata (59.5%). Arthralgia (40.5%), hyperhidrosis of the feet and hands (44.6%), gastric hypertrophy (8 cases), gastric ulcers (5 cases) and endocrine abnormalities (17 cases) were also reported.

Adult↗
PubMed1990

Cytochrome P-450-linked monooxygenase systems of bovine brain mitochondria and microsomes.

1. Cytochrome P-450-linked monooxygenase of mitochondria and microsomes of the cerebrum, cerebellum and pituitary gland of bovine brain were investigated biochemically and immunochemically. 2. The cytochromes P-450scc and P-450(11) beta, NADPH-ferredoxin reductase and adreno-ferredoxin were detected and their enzymatic activities of steroid hydroxylations were found in the bovine brain.

Animals↗
PubMed1990

Role of 1,25-dihydroxycholecalciferol in growth-plate cartilage: inhibition of terminal differentiation of chondrocytes in vitro and in vivo.

The effects of vitamin D metabolites on alkaline phosphatase [ALPase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1] activity, a marker of terminal differentiation, in chondrocyte cultures and growth plates in vivo were examined. In cultures of pelleted rabbit growth-plate chondrocytes, 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D3) increased the contents of DNA and macromolecules containing uronic acid (proteoglycans). It also decreased ALPase activity with an ED50 of less than 1 nM. Other vitamin D3 metabolites, such as 24,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol, had little effect on these biochemical parameters. In rachitic growth plates, the uronic acid content was half that in normal growth plates, whereas ALPase activity was 2.5 times that in normal growth plates. Administration of 1,25-dihydroxycholecalciferol at a low dose (0.1 micrograms per kg of body weight) to rachitic rats increased the uronic acid content 1.4-fold and decreased ALPase activity by 40%. This compound, like 24,25-dihydroxycholecalciferol (10 micrograms per kg of body weight), increased the calcium level of the blood. However, administration of 24,25-dihydroxycholecalciferol had little effect on the uronic acid and ALPase contents in growth plates. These observations suggest that 1,25-dihydroxycholecalciferol is a bioactive form of vitamin D that plays an important role in the control of chondrocyte terminal differentiation.

24,25-Dihydroxyvitamin D 3↗
PubMed1990

Somatostatin analogue (SMS 201-995) decreases plasma levels of corticotropin (ACTH) and corticotropin-releasing hormone in a patient with ectopic ACTH-producing tumors.

Effects of long-acting somatostain analogue (SMS 201-995) on plasma corticotropin (ACTH) and corticotropin-releasing hormone (CRH) levels were studied in a patient (63-year-old woman) with ectopic ACTH-producing tumors associated with type I multiple endocrine neoplasia (MEN-I). The patient had undergone bilateral adrenalectomy. Plasma CRH, as well as plasma ACTH, beta-endorphin and alpha-MSH, increased. The hormone levels were dramatically decreased by acute administration of SMS 201-995. Moderately higher doses of dexamethasone (0.05 or 0.1 mg/kg a day) did not decrease plasma CRH or ACTH. An extremely high dose of dexamethasone (0.2 mg/kg a day), however, decreased plasma ACTH, but failed to decrease plasma CRH. Acute administration of SMS 201-995 further lowered the level of plasma ACTH even in this condition. In addition to the decrease in ACTH, SMS 201-995 decreased plasma CRH. Chronic administration of SMS 201-995 continuously decreased plasma CRH, ACTH and beta-endorphin. The decrease in these hormone concentrations accompanied the disappearance of hyperpigmentation. These results suggested that SMS 201-995 inhibits hypersecretion not only of ACTH but also of CRH, and that the agent is therapeutically useful in normalizing the hypersecretion of these hormones.

ACTH Syndrome, Ectopic↗
PubMed1990

Prevention of immunological disorders in MRL/l mice by a new synthetic analogue of vitamin D3: 22-oxa-1 alpha,25-dihydroxyvitamin D3.

We examined the immunoregulating effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1 alpha,25(OH)2D3), a synthetic analogue of vitamin D3 with an oxygen atom at C22 in the side chain skeleton, on spontaneously developing autoimmune disorders in MRL/Mp-lpr/lpr (MRL/l) mice. The oral administration of the compound significantly prolonged the average life span of the mice and showed a significant reduction in proteinuria. Histopathological investigations also revealed that pathological conditions such as renal arteritis, granuloma or arthritis of the knee joints were much lighter in the treated group than in the untreated group. Furthermore, the lymphocyte phenotypes in thymus, lymphnode, and spleen were partially normalized and became similar to those found in young control animals by the treatment with 22-oxa-1 alpha,25(OH)2D3. These results suggest that this compound inhibits the development of lupus nephritis in MRL/l mice and may be therapeutically effective on the mice.

Animals↗
PubMed1989

Regulatory activities of 2 beta-(3-hydroxypropoxy)-1 alpha, 25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism.

Regulatory activities of 2 beta-(3-hydroxypropoxy)-1 alpha, 25-dihydroxyvitamin D3 [ED-71], a novel synthetic vitamin D3 derivative, on calcium metabolism were investigated. The compound behaved similar to 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3] in the ex vivo intestinal calcium transport using rat everted gut sac and the in vivo bone mobilization using vitamin D-deficient rats. By means of Raisz's assay method, 45Ca releasing activity of ED-71 was not greater than that of 1,25(OH)2D3. The time course curve of ED-71 in plasma made a mild round shape compared with that of 1,25(OH)2D3 and the former's plasma concentration remained increased longer than the latter's. The therapeutic effect of ED-71 for the animal models with osteoporosis seemed to be better than that of 1,25(OH)2D3. The results suggest that ED-71 may be a promising drug for therapy of osteoporosis.

Animals↗
PubMed1989

Purification and characterization of NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine binding protein in rat kidney.

The NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine(T3)-binding protein (CTBP) has been purified over 30,000-fold from rat kidney by using charcoal extraction, Mono Q-Sepharose, Blue Sepharose CL-6B, and Sephacryl S-200 column chromatography. Purified CTBP had a sedimentation coefficient of 4.7 S, Stokes radius of 32.5A, and calculated molecular weight of 58,000. The apparently homogeneous protein consisted of a single polypeptide chain with Mr of 58,000 as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Scatchard analysis of T3 binding showed that NADPH increases maximal binding capacity without changes in the affinity constant (Ka = 2.43 X 10(9) M-1). Double reciprocal analysis of NADPH and binding capacity gave maximal binding capacity of 16,400 pmol/mg of CTBP, Mr = 58,000. The order of affinity of iodothyronine analogues to purified CTBP was as follows: L-T3 = D-T3 greater than triiodothyroacetic acid greater than L-thyroxine. [125I]T3 bound to purified CTBP spontaneously dissociated from CTBP at 20 degrees C (t 1/2 = 22 min) in the absence of NADPH, whereas the dissociation was not observed in the presence of NADPH. The optimal pH for T3 binding was 7.2-7.5 Na+, K+, Ca2+, and Mg2+ (0-200 mM) did not influence T3 binding to CTBP. The purified CTBP did not bind to DNA and was not adsorbed to concanavalin A-Sepharose.

Animals↗
PubMed1989

Evidence for the presence of two active forms of cytosolic 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) in rat kidney. Specialized functions of two CTBPs in intracellular T3 translocation.

Cytosolic NADPH-dependent 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) purified from rat kidney was further characterized in its T3 binding and its interaction with nuclei. Pretreatment of the CTBP with NADP induced dithiothreitol (DTT)-dependent T3 binding. The DTT-dependent T3 binding was increased by NADP in a concentration-dependent manner, and the maximal binding was obtained by 0.1 microM NADP. Higher concentrations of NADP (more than 0.1 microM), however, reduced T3 binding. NAD also induced DTT-dependent T3 binding, but was very low compared to that induced by NADP. NADPH and NADH did not produce DTT-dependent T3 binding. This NADP-activated, DTT-dependent T3 binding was characterized as follows: Ka for T3 binding was 1.8 x 10(9) M-1, and the maximal binding capacity was 15,000 pmol/mg of protein in the CTBP activated by 0.1 microM NADP. The molecular weight of the CTBP was 58,000 (4.7 S). A complex of [125I]T3 and CTBP (NADP.DTT.CTBP.[125I]T3), which was made from the CTBP pretreated with NADP and DTT, did not bind to DNA. However, the complex bound to the nuclei prepared from rat kidney. Treatment of the nuclei with 0.38 M KCl and with DNase I did not lead to loss of the binding activity for the complex. Treatment of nuclei with 0.5 M NaCl led to the loss of the activity for binding the complex. A complex of [125I]T3 and NADPH-activated CTBP did not bind these nuclear preparations. These results suggested that the active form of CTBP is present in two different forms: one is NADPH-activated, which plays a role as a reservoir for cytoplasmic T3, and the other is NADP-activated, which plays a role as a T3 carrier protein that transfers T3 from cytoplasm to nucleus.

Animals↗
PubMed1989

Differences in nuclear thyroid hormone receptors among species.

Hepatic nuclear thyroid hormone receptors from rat, dog, chicken, and rainbow trout were compared. Receptor affinities for 3,5,3'-triiodo-L-thyronine (T3) were similar in preparations from rat, dog, and chicken, using isolated nuclei and nuclear extracts. Rainbow trout nuclear receptor showed a lower affinity for T3. Almost half of the receptors were released into the medium with rat and chicken nuclei, and 79.7 +/- 1.1% of the receptors were released with rainbow trout nuclei, when isolated nuclei were incubated with T3 at 22 degrees for 2 hr. The affinity constant of rat liver receptor for calf thymus DNA-cellulose at 0.17 M KCl, pH 7.4, was 3.98 +/- 1.47 x 10(5) M-1, when determined using DNA-cellulose columns. The number of salt bridges involved in DNA binding of the rat receptor was 5.73 +/- 0.38. When receptor-DNA interactions were compared among species, significant differences were found, but the receptors from dog and rainbow trout liver were similar. Sephacryl S-200 column chromatography showed that chicken receptor had a Stokes radius significantly smaller than that of rat receptor. Partial proteolysis of T3-receptor complex using trypsin alpha-chymotrypsin, elastase, and papain produced distinct T3-binding fragments in different species. Our data provide evidence that nuclear thyroid hormone receptors from different species have significant structural dissimilarities.

Animals↗
PubMed1989

Epidemiological observation of coxsackieviruses group B in sewage.

Different types of coxsackieviruses group B were isolated from the sewage consecutively annually from January 1982 to March 1987: type 3 in 1982, type 4 in 1983, type 2, 4 and 5 in 1984, type 3 in 1985, and type 4 in 1986 were found. These viruses caused large epidemics among children aged 1 to 4 and proximities. Herald waves for the epidemics were observed six times during this period, and the viruses were detected in a brief period of isolation. With respect to the periodicity of these viruses, the cycles for types 3 and 4 were 2 to 3 years, and longer cycles seemed to be exhibited by types 1, 2, and 5. The onset and termination of the epidemics will only be grasped by surveys throughout the year. HEp-2 cells exhibited the best sensitivity to the viruses.

Adolescent↗