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Y Nishii

Publications and source records attributed to Y Nishii.

At least 91 records · Page 5Linked to original sources
PubMed1989

The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion.

1,25-Dihydroxyvitamin D (1,25-(OH)2D3) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH)2D3 results in hypercalcemia. An analogue of 1,25-(OH)2D3 with little or no calcemic activity, 22-oxacalcitriol (OCT), was recently developed. We confirmed this lack of calcemic activity by acute and chronic administration to normal rats. A single intraperitoneal injection of vehicle (propylene glycol), OCT, or 1,25-(OH)2D3 (1.0 micrograms/rat) increased calcium by 0.32, 0.30, and 1.40 mg/dl, respectively. When rats were given daily injections of vehicle or 0.5 micrograms of either 1,25-(OH)2D3 or OCT for 4 d, calcium did not change in the rats receiving vehicle or OCT, but increased from 8.4 to 11.4 mg/dl in the rats treated with 1,25-(OH)2D3. In primary cultures of bovine parathyroid cells, 10 nM OCT was as active as 10 nM 1,25-(OH)2D3, suppressing PTH release by 33%. This suppression is due, at least in part, to blocking of transcription of the PTH gene. Using a probe prepared by random prime labeling of an Msp I fragment of plasmid PTHm122, we found that a single 40-ng dose of OCT or 1,25-(OH)2D3 depressed PTH mRNA levels by 70-80% by 48 h when compared with vehicle. Thus, OCT is a very effective suppressor of PTH secretion with virtually no calcemic activity. This analogue may be a valuable tool for the treatment of secondary hyperparathyroidism.

Animals↗
PubMed1989

A synthetic analogue of vitamin D3, 22-oxa-1 alpha,25-dihydroxyvitamin D3, is a potent modulator of in vivo immunoregulating activity without inducing hypercalcemia in mice.

The in vivo immunoregulating activity and the hypercalcemic action of 4 synthetic analogues of vitamin D3 with an oxygen atom in the side chain were compared with those of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] in mice. Oral administration of these vitamin D3 compounds augmented the primary immune response, induced by immunization with a suboptimal number of sheep erythrocytes, without inducing hypercalcemia. The order of the in vivo potency to induce the immune response was 22-oxa-1 alpha,25(OH)2D3 greater than 1 alpha,25(OH)2D3 not equal to 20-oxa-1 alpha,25(OH)2D3 not equal to 22-oxa-1 alpha(OH)D3 greater than 1 alpha(OH)D3 not equal to 20-oxa-1 alpha(OH)D3. 22-Oxa-1 alpha,25(OH)2D3 was about 50 times more potent than 1 alpha,25(OH)2D3 in inducing the in vivo primary immune response, but the former was only 1/100 as active as the latter in inducing hypercalcemia. These results suggest that the immunoregulating activity of vitamin D compounds can be separated structurally from their hypercalcemic action in vivo.

Animals↗
PubMed1989

Resistance to 1,25-dihydroxyvitamin D3 of cultured psoriatic epidermal keratinocytes isolated from involved and uninvolved skin.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], a hormonally active form of vitamin D3, has been reported to stimulate epidermal differentiation and to be an effective treatment of psoriatic lesions. We studied the responsiveness of psoriatic epidermal keratinocytes to 1,25-(OH)2D3 in explant-outgrowth cultures of involved and uninvolved skin from six patients with psoriasis. A feeder layer was required for outgrowth of psoriatic epidermal keratinocytes of involved skin, but not for that of cells of uninvolved skin. The growth of normal epidermal keratinocytes was inhibited by 1,25-(OH)2D3, and the number of DNA-synthesizing cells, determined in autoradiographs, was reduced to about 15% of that in control cultures by 1 nmol/L 1,25-(OH)2D3 (0.4 ng/mL). Epidermal keratinocytes isolated from both involved and uninvolved skin of patients with psoriasis were resistant, and 100-fold more 1,25-(OH)2D3 was required to inhibit their DNA synthesis. These results afford new insight into the etiology and therapy of psoriasis.

Adult↗
PubMed1989

Evaluation of mitochondrial function by measuring the heat production in state 3 and state 4 respiration.

Using a microcalorimetric method, we have measured the heat production in states 3 and 4 respiration of a mitochondrial preparation from rat heart ventricle. Adenosine triphosphate production in state 3 respiration was also determined for the same preparation after heat production was measured. In Tris-buffered solution with pyruvate and malate used as substrates, the total heat production in states 3 and 4 respiration for a 10-min reaction period were about 709 and 207 mJ/mg of mitochondrial protein, respectively. 2,4-Dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation, increased the heat production in both states 3 and 4 respiration. On the other hand, antimycin A1, an inhibitor of the electron transport system, decreased the heat production in both states. When ventricle mitochondrial dysfunction was induced by the in vivo administration of a high dose of isoproterenol, heat production was increased in state 4 respiration. These results indicate that the calorimetric method can be used to evaluate the mitochondrial function.

Animals↗
PubMed1989

Possible role of histones in the organization of rat liver thyroid hormone receptors in chromatin.

The effects of histone subfractions on rat liver thyroid hormone receptor-DNA interaction were examined using an in-vitro DNA-cellulose binding assay. H1 histones bound to DNA showed reversible and potent inhibition of receptor-DNA binding without affecting receptor hormone binding. Poly-lysine, bovine serum albumin, ovalbumin and cytochrome c did not alter receptor-DNA binding. H1 histone subfractions (calf thymus lysine-rich histone (CTL)-1, CTL-2 and CTL-3) showed potent inhibition of receptor-DNA binding indistinguishable from each other. The quantity of H1 histone subfractions bound to DNA was the same. Although each subfraction has different functional properties, inhibition of receptor-DNA binding was a common feature of all the H1 histone subfractions, which is important for the non-random distribution of the receptor in chromatin. Binding of the receptor to core histones was investigated; it was found to bind to core histones more potently than to other proteins (H1 histone, ovalbumin and cytochrome c). Among core histone subfractions, H4 histone bound to the receptor most potently and is the candidate to be one of the acceptor sites of the receptor in chromatin.

Animals↗
PubMed1989

Changes in cytosolic 3,5,3'-tri-iodo-L-thyronine (T3) binding activity during administration of L-thyroxine to thyroidectomized rats: cytosolic T3-binding protein and its activator act as intracellular regulators for nuclear T3 binding.

Changes in the amount of cytosolic 3,5,3'-tri-iodo-L-thyronine (T3)-binding protein (CTBP) and its activator during administration of L-thyroxine (T4) to thyroidectomized rats were investigated. Thyroidectomy decreased the amount of CTBP in the kidney, whereas the activator was not significantly modified by thyroidectomy. The activator was increased by administration of T4 to thyroidectomized rats. The amount of CTBP was also increased by administration of T4. The activator increased the maximal binding capacity (MBC) without changes in the affinity constant for T3 binding in CTBP. A T4-induced increase in MBC in cytosol inhibited nuclear T3 binding in vitro by competition of T3 binding between CTBP and the nuclear receptor. These results suggest that thyroid hormone increases the capacity for cytosolic T3 binding through increasing the amount of CTBP and its activator, and that these increases play a role in regulating the amount of T3 that binds to its nuclear receptor.

Animals↗
PubMed1989

Inter- and intracellular luminal formation in porcine thyroid tissues cultured in a collagen substrate.

Porcine thyroid epithelial cells, isolated and cultured on a type I collagen substrate, formed a monolayered sheet. When the apical surface of the monolayer was further covered with the same collagen substrate, the epithelial cells migrated and formed intercellular follicular lumen-like structures. In addition, a true intracellular follicular lumen sometimes appeared, especially in cells of the monolayer region. It was proved by serial sections that the intracellular follicular lumina, 1-5 microns in diameter, lined by rather long microvilli and stained for PAS, had no openings to the extracellular space. The intracellular lumina are presumed to fuse with each other to form an intercellular follicular lumen, or fuse with the performed intercellular follicular lumen. Auto-radiographic studies using 125I revealed that iodination of thyroglobulin takes place in the peripheral region of both intracellular and intercellular follicular lumina.

Animals↗
PubMed1989

Protein-binding properties of 22-oxa-1 alpha,25-dihydroxyvitamin D3, a synthetic analogue of 1 alpha,25-dihydroxyvitamin D3.

Protein binding properties of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1,25-D3), a synthetic analogue of 1 alpha,25-dihydroxyvitamin D3 (1,25-D3), were compared with those of vitamin D3 derivatives. The order of binding affinity to the chick embryonic intestinal receptor was 1,25-D3 greater than 22-oxa-1,25-D3 greater than 25-hydroxyvitamin D3 (25-D3) greater than 24R, 25-dihydroxyvitamin D3 (24, 25-D3) greater than vitamin D3 (D3), while that to the rat plasma vitamin D-binding protein (DBP) was 25-D3 greater than 24,25-D3 greater than D3 greater than 1,25-D3 greater than 22-oxa-1,25-D3. The binding potencies of 22-oxa-1,25-D3 to the receptor and DBP were about 1/8 and 1/600 of the respective values of 1,25-D3. When the distribution of the tritiated compounds in human plasma components was examined by an in vitro polyacrylamide gel electrophoretic method, [3H]-22-oxa-1,25-D3 was found to bind only to the lipoproteins including chyromicron. These results suggest that the replacement of a carbon atom into an oxygen atom in the side chain structure of 1,25-D3 results significant decrease in the binding affinity to DBP and that 22-oxa-1,25-D3 is transported as a complex-form not with DBP but with lipoprotein to the target tissues.

Animals↗
PubMed1989

Comparison of the inhibitions of proliferation of normal and psoriatic fibroblasts by 1 alpha,25-dihydroxyvitamin D3 and synthetic analogues of vitamin D3 with an oxygen atom in their side chain.

The inhibitory effects of 1 alpha,25-(OH)2D3 and synthetic oxa-derivatives of vitamin D3 on growth of normal and psoriatic fibroblasts in culture were compared. Proliferation of normal fibroblasts was strongly inhibited by these new compounds in the following order: 22-oxa-1 alpha,25-(OH)2D3 greater than 22-oxa-1 alpha-(OH)D3 greater than 1 alpha,25-(OH)2D3 greater than 20-oxa-1 alpha,25-(OH)2D3. 22-Oxa-1 alpha,25-(OH)2D3 was about 10-times more inhibitory than 1 alpha,25-(OH)2D3. Proliferation of psoriatic fibroblasts was not inhibited by 1 alpha,25-(OH)2D3 at concentrations of up to 10(-6) M, but was suppressed by 10(-8)-10(-6) M 22-oxa-1 alpha,25-(OH)2D3 and 10(-6) M 22-oxa-1 alpha-(OH)D3. These results suggest that oxa-derivatives of vitamin D3, especially 22-oxa-1 alpha,25-(OH)2D3, should be useful in further studies on the cause and treatment of psoriasis.

Calcitriol↗
PubMed1988

Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats.

The effect of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] on 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism was examined in rats fed on a low-calcium diet. These rats exhibit hypocalcaemia, high urinary cyclic AMP excretion, a markedly elevated serum 1,25(OH)2D concentration and low serum concentrations of both 24,25(OH)2D and 25(OH)D. When the rats are treated orally with 1, 5 or 10 micrograms of 24,25(OH)2D3/100 g every day, there is a dramatic decrease in serum 1,25(OH)2D concentration in a dose-dependent manner concomitant with an increase in serum 24,25(OH)2D concentration. Serum calcium concentration and urinary cyclic AMP excretion are not significantly affected by the 24,25(OH)2D3 treatment, which suggests that parathyroid function is not affected by the 24,25(OH)2D3 treatment. The 25(OH)D3 1 alpha-hydroxylase activity measured in kidney homogenates is markedly elevated in rats on a low-calcium diet but is not affected by any doses of 24,25(OH)2D3. In contrast, recovery of intravenously injected [3H]1,25(OH)2D3 in the serum is decreased in 24,25(OH)2D3-treated rats. Furthermore, when [3H]1,25(OH)2D3 is incubated in vitro with kidney or intestinal homogenates of 24,25(OH)2D3-treated rats there is a decrease in the recovery of radioactivity in the total lipid extract as well as in the 1,25(OH)2D3 fraction along with an increase in the recovery of radioactivity in the water-soluble phase. These results are consistent with the possibility that 24,25(OH)2D3 has an effect on 1,25(OH)2D3 metabolism, namely that of enhancing the degradation of 1,25(OH)2D3. However, because a considerable proportion of the injected 24,25(OH)2D3 is expected to be converted into 1,24,25(OH)3D3 by renal 1 alpha-hydroxylase in 24,25(OH)2D3-treated rats, at least a part of the decrease in serum 1,25(OH)2D concentration may be due to a competitive inhibition by 24,25(OH)2D3 of the synthesis of 1,25(OH)2D3 from 25(OH)D3. Thus the physiological importance of the role of 24,25(OH)2D3 in regulating the serum 1,25(OH)2D concentration as well as the mechanism and metabolic pathway of degradation of 1,25(OH)2D3 remain to be clarified.

24,25-Dihydroxyvitamin D 3↗
PubMed1988

Differential effects of 1 alpha,25-dihydroxycholecalciferol and 24R,25-dihydroxycholecalciferol on the proliferation and the differentiated phenotype of rabbit costal chondrocytes in culture.

1 alpha,25-Dihydroxycholecalciferol [1,25-(OH)2D3] stimulated the proliferation and DNA synthesis of rabbit costal growth cartilage cells in the logarithmic growth phase in culture. The stimulatory effects of 1,25-(OH)2D3 were observable at a concentration of 10(-10) M and maximal at a concentration of 10(-8) M. On the other hand, 1,25-(OH)2D3 inhibited their expression of the cartilage phenotype, as judged morphologically, histochemically, and biochemically by a decrease in glycosaminoglycan (GAG) synthesis. The inhibition of GAG synthesis was also dose dependent and observable at a concentration of 10(-10) M. 1,25-(OH)2D3 also stimulated the proliferation of resting cartilage cells and inhibited their GAG synthesis, but its effects on these cells were less than those on growth cartilage cells, suggesting that 1,25-(OH)2D3 acts more specifically on growth cartilage cells than on resting cartilage cells. 1,25-(OH)2D3 had no effect on either DNA synthesis or GAG synthesis of growth cartilage cells in confluent cultures. 24R,25-Dihydroxycholecalciferol [24,25-(OH)2D3] had no effect on proliferation, DNA synthesis, or GAG synthesis of growth cartilage cells in the logarithmic growth phase. However, 24,25-(OH)2D3 had no effect on DNA synthesis of these cells in confluent cultures, but stimulated their expression of the cartilage phenotype. The stimulatory effect was dose dependent and maximal at 10(-7) M. Since chondrocytes express their differentiated phenotype as they become confluent in culture, these results suggest that 1,25-(OH)2D3 stimulates the growth of rapidly proliferating chondrocytes with a poorly differentiated phenotype and suppresses their expression of the cartilage phenotype, while 24,25-(OH)2D3 stimulates expression of the differentiated phenotype of highly differentiated chondrocytes.

24,25-Dihydroxyvitamin D 3↗
PubMed1988

Effect of thyroid hormone on the protein inhibitors for Ca2+-dependent proteinase in brain: evidence for the induction by thyroidectomy of irreversible changes in immature rats.

The effects of thyroid hormone on the levels of protein inhibitors for Ca2+-dependent proteinase were studied in rat brain. Four different inhibitory proteins (I, II, III, and IV) were isolated from immature (7-day-old) rat brain. The molecular weights of these inhibitory proteins, which were estimated by gel-exclusion chromatography on Sephacryl S-200 column, were approximately 280,000 (I), 70,000 (II), 50,000 (III), and 35,000 (IV). All of these inhibitory proteins were decreased by thyroidectomy. Four-day T4 administration (100 micrograms/kg daily) to thyroidectomized-immature animals restored proteins I, II, and IV. However, protein III was not recovered with the same treatment of the rats. In mature rats (40-day-old), four different inhibitory proteins were identified in the brain. The molecular weights were identical to those obtained in immature rat brain. As observed in immature rats, all of these inhibitory proteins were decreased by thyroidectomy. In contrast to the results obtained in immature animals, however, inhibitory protein III, as well as I, II, and IV, was restored by T4 administration (100 micrograms/kg daily) to thyroidectomized mature rats. The results suggested that thyroid hormone increases protein inhibitors for Ca2+-dependent proteinase in brain, and that irreversible decrease in one of the inhibitors is induced by thyroid hormone deficiency in immature animals. The phenomenon may be related to the neonatal hypothyroidism-induced irreversible damage to the central nervous system in patients with cretinism.

Aging↗
PubMed1988

Selective alterations of insulin actions by glucagon in isolated rat epididymal adipocytes.

Previously we demonstrated that glucagon inhibits high affinity insulin binding without influence on low affinity binding in rat adipocytes in vitro. In this study we investigated the effects of glucagon on insulin actions in adipocytes in vitro. Glucagon modified neither glucose oxidation nor lipogenesis stimulated by insulin. The antilipolytic action of insulin was decreased by preincubation of the cells with glucagon. Glucose transport enhanced by insulin was diminished by preincubation of the cells with glucagon. The decrease in antilipolysis was a lowering of the maximal response to insulin, whereas the decrease in glucose transport was a lowering of the sensitivity to insulin. These results suggested that glucagon does not necessarily inhibit all of the insulin actions, and that the mechanism of insulin stimulation of glucose transport, which is supposed to be mediated by glucagon-sensitive insulin receptor, is different from those of insulin-induced antilipolysis, glucose oxidation, and lipogenesis.

3-O-Methylglucose↗
PubMed1988

Conformational transition of thyroid hormone receptor upon hormone binding: demonstration by aqueous two-phase partitioning.

An aqueous two-phase partitioning study of partially purified nuclear thyroid hormone receptor from rat liver was performed. Stability of 3,5,3'-tri-iodo-L-thyronine (T3)-receptor complex and T3-binding activity in the presence of dextran or polyethylene glycol were assessed in order to determine the amount of occupied or unoccupied receptors in each phase. Partition coefficients were calculated as the ratio of receptor concentration in the upper polyethylene glycol-rich phase H2O and that in the lower dextran-rich phase H2O. The partition coefficient was a sensitive function of the salt at pH above 6.1 and below 5.1. The salt had no effect on the partition coefficient at pH around 5.6. These results suggest that the isoelectric point of the thyroid hormone receptor is about 5.6, confirming previous determinations using isoelectric focusing. The partition coefficient of the receptor decreased upon T3 binding, regardless of the salt composition. In contrast, the partition coefficient of thyroxine-binding globulin increased upon T3 binding. Free T3 preferentially partitioned into the upper polyethylene glycol-rich phase and gave a partition coefficient higher than 1.0. These results strongly suggest that the decrease in the partition coefficient of the receptor upon hormone binding reflects conformational changes or changes in electrostatic properties of the receptor upon hormone binding. Such an alteration may be involved in biological activation of the receptor upon hormone binding.

Animals↗
PubMed1988

The uptake and long-term storage of India ink particles and latex beads by fibroblasts in the dermis and subcutis of mice, with special regard to the non-inflammatory defense reaction by fibroblasts.

The fate of India ink particles and polystyrene latex beads injected into the dermis and subcutis of the skin of the auricle and back in mice was observed with the naked eye, light microscopy and electron microscopy. The tattoo patterns made by injected ink particles remained essentially unchanged for life as observed with the naked eye. India ink particles and latex beads were endocytosed by fibroblasts as well as macrophages in the dermis and subcutis. Numerous ink particles or small latex beads (0.22 micron in diameter) were packed into vacuoles 0.1-10.0 micron in diameter which occupied a large volume of the cytoplasm of the cell body and processes of fibroblasts, whereas numerous particles and larger beads (0.22 and 2.0 micron) were taken up into the cell body of macrophages in the vicinity. Most fibroblasts, characterized by long cell processes and well developed rough endoplasmic reticulum, are easily distinguished from macrophages, the latter being round or oval in shape, and having many lysosomes and numerous irregularly shaped microvillous projections. It is believed that fibroblasts taking up and storing the ink particles or latex beads move poorly and are almost fixed in the connective tissue: the tattoos therefore do not change markedly. It is emphasized that the uptake and long-term storage of ink particles and latex beads by the dermal and subcutaneous fibroblasts represent a specific non-inflammatory defense mechanism that protects the living body, without immune reactions, against injuries and invasions by non-toxic foreign agencies. The histiocyte, a term proposed by KIYONO (1914) for a fixed macrophage on the basis of his studies using vital dye staining, is considered to include, in addition to true macrophages, fibroblasts showing endocytotic activities for small foreign bodies such as acid dyes, ink particles, and latex beads.

Animals↗
PubMed1988

Partial purification and properties of neutral PTHase from the cytosolic fraction of rat renal cortex.

A possible new enzyme, a cytosolic neutral PTH-degrading enzyme previously described by us, was purified by ammonium sulfate fractionation, Sephadex G-200 column chromatography and DEAE cellulose column chromatography from the 100,000 x g supernatant of rat kidney. Three active peaks (designated P-I, P-II and P-III) were obtained through a DEAE cellulose chromatographic column. These three activity peaks were interchangeable on rechromatography. Further characterization of the major P-II fraction was attempted. When PTH was used as the substrate, this enzyme preparation (P-II) was inhibited by Ca2+, ATP and glutathione (GSH), but not by trypsin inhibitor, PMSF, E-64, leupeptin, chymostatin or pepstatin. This enzyme preparation could hardly hydrolyze several synthetic analogs containing MCA but not Leu-MCA and Z-Phe-Arg-MCA. When Z-Phe-Arg-MCA was used as the substrate, this enzyme preparation was activated by ATP and GSH, while no activation was induced when PTH was used. These results indicate that the neutral PTH-degrading enzyme seems to represent a new PTHase capable of specifically splitting PTH at certain locations.

Animals↗
PubMed1987

Synthetic analogues of vitamin D3 with an oxygen atom in the side chain skeleton. A trial of the development of vitamin D compounds which exhibit potent differentiation-inducing activity without inducing hypercalcemia.

Four analogues of vitamin D3 with an oxygen atom in the side chain skeleton were synthesized to determine whether their differentiation-inducing activity could be separated structurally from their activity to induce hypercalcemia. The order of the in vitro potency to reduce nitroblue tetrazolium in human myeloid leukemia cells (HL-60) was 22-oxa-1 alpha, 25-(OH)2D3 greater than 1 alpha, 25-(OH)2D3 greater than 20-oxa-1 alpha, 25-(OH)2D3 not equal to 22-oxa-1 alpha-(OH)D3 greater than 1 alpha-(OH)D3 greater than 20-oxa-1 alpha-(OH)D3. 22-Oxa-1 alpha, 25-(OH)2D3 was also about 10-times more potent than 1 alpha, 25-(OH)2D3 in suppressing proliferation and inducing differentiation of mouse myelomonocytic leukemia cells (WEHI-3), but the former was much weaker than the latter in inducing the release of 45Ca from prelabeled fetal mouse calvaria. These results suggest that the differentiation-inducing activity of vitamin D compounds can be separated structurally from their activity to induce hypercalcemia.

Animals↗