Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-four surgically menopausal women were randomly allocated to one of two transdermally-administered estrogen replacement therapies (ERT): Group A was administered Estradiol (E2) TTS 0.05 mg/day for 6 months and 0.025 mg/day for the following six months and group B, E2 TTS 0.10 mg/day for the first 6 months and 0.05 mg/day for the following 6 months. For both groups, the treatment regimen was based upon the twice-weekly application of transdermal patches to the lower abdomen for three weeks a month. Serum E2, alkaline phosphatase (AP), osteocalcin (BGP) and urinary hydroxyproline (OHP) excretion levels were measured before the operation, at the beginning of ERT and after 6 and 12 months of treatment. Bone mineral density (BMD) in the distal regions of the forearms was measured by single photon absorptiometry at the start of the study and after 6 and 12 months. In Group A, both mean cortical and trabecular BMD had increased by, respectively, 1.53% and 2.17% after 6 months of therapy; after the second 6 months a significant decrease was observed in both parameters (2.40% and 3.62%, respectively). In Group B, mean cortical and trabecular BMD increased by 1.50% and 2.10%, respectively (significant increase in trabecular bone) after the first 6 months of treatment; after the following 6 months, these values persisted (+0.15 and -0.03%, respectively). Mean AP, OHP and BGP serum levels rose after the operation. In Group A, AP and OHP showed a significant decrease after the first 6 months (-34.90% and -30.90%), followed by an increase at the last evaluation of 22.50% and 35.50%, that reached statistical significance only for OHP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone metabolism changes after transdermal estradiol dose reduction during estrogen replacement therapy: a 1-year prospective study. 796 46

The steady-state mRNA levels of different osteogenic markers and their modulation by 17 beta-estradiol in the murine osteogenic cell line MN7 during proliferation and differentiation in vitro were examined. mRNA of collagen type I, osteopontin, bone morphogenetic protein 2, plasminogen activator inhibitor 1, alkaline phosphatase, and osteocalcin were isolated from MN7 cultures grown for 7, 11, 14, and 17 days. Northern blot analysis revealed steady-state transcript levels depending on MN7 cell density. The order of appearance of Col I, OP, ALP, and OC resembled the pattern of gene expression observed during osteoblast maturation in vitro. Furthermore, PAI-1 steady-state transcript levels peaked during subconfluence (day 11) but BMP-2 RNA levels reached their maximum after the culture had become confluent. 17 beta-Estradiol showed a dose-dependent stimulation of the different osteoblast-related transcripts present in a subconfluent MN7 culture at the time of analysis. Furthermore, the effects of 17 beta-estradiol (17 beta E2) at different time points of MN7 growth varied according to cell density. 17 beta E2 added to subconfluent MN7 cultures modulated the transcript level in a negative way, but RNA levels of the investigated osteogenic markers in confluent cultures were stimulated with 100 nM 17 beta-estradiol. No effect of 17 beta-estradiol on proliferation was detected. The present studies have revealed differential osteoblast gene expression related to MN7 cell proliferation and differentiation in vitro and emphasize the importance of 17 beta E2 in the regulation of growth of this preosteoblastic cell line in vitro.
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PMID:Characterization of the stromal osteogenic cell line MN7: mRNA steady-state level of selected osteogenic markers depends on cell density and is influenced by 17 beta-estradiol. 814 Sep 31

We present evidence that 17 beta-estradiol (17 beta-E2) regulates 1,25(OH)2D3-induced alkaline phosphatase synthesis and osteocalcin secretion by the human osteosarcoma cell line MG-63. When cells were pre-treated with 17 beta-E2 for 48 h prior to treatment with 1,25(OH)2D3 (50 nM) for another 48 h, alkaline phosphatase activity increased by 40% (P < 0.025) with 2 nM 17 beta-E2 and plateaued at levels of 20 and 200 nM 17 beta-E2. Under the same experimental conditions, osteocalcin secretion was enhanced by 37% (P < 0.005) with 2 nM E2. However, 17 beta-E2 had no effect on basal alkaline phosphatase or on osteocalcin secretion. Moreover, simultaneous addition of 17 beta-E2 and 1,25(OH)2D3 to cells did not result in any additional effect over 1,25(OH)2D3 treatment alone. Tamoxifen (10 nM) inhibited 17 beta-E2-induced activities in 1,25(OH)2D3-treated cells while not affecting control cells. Dexamethasone pretreatment (100 nM, 48 h) also stimulated alkaline phosphatase activity in MG-63 cells. Moreover, dexamethasone pretreatment followed by treatment with 17 beta-E2 and 1,25(OH)2D3 gave an additive effect for alkaline phosphatase activity. 17 alpha-Estradiol (17 alpha-E2), a less active form of estrogen, failed to modify, at low concentrations, control or 1,25(OH)2D3-induced alkaline phosphatase synthesis and osteocalcin secretion. In fact, a 100-1000-fold higher concentration of 17 alpha-E2 was necessary to reproduce the effects of 17 beta-E2 on osteocalcin secretion. The addition of insulin-like growth factor I (IGF-I) for 24 h (1-50 ng/ml) to MG-63 cells did not modify 1,25(OH)2D3-induced osteocalcin release from these cells. However, longer incubations with 50 ng/ml IGF-I did reproduce some of the effects observed with 17 beta-E2. Thus, the effects of 17 beta-E2 are probably not related to IGF-I production in MG-63 cells since under these conditions the addition of IGF-I alone should have produced a response at shorter incubation times and in the presence of lower concentrations of IGF-I. Since 17 beta-E2 pretreatment was necessary to observe any effects on 1,25(OH)2D3-induced activities, we hypothesized that 17 beta-E2 regulated 1,25(OH)2D3 receptors in MG-63 cells. When cells were treated with 100 nM 17 beta-E2 for 48 h, the binding affinity was unchanged: 37.3 +/- 1.9 versus 35.1 +/- 0.4 pM for cells whether treated or not with 17 beta-E2, respectively. In contrast, a significant increase in binding capacity (Bmax) was noted (15 +/- 3.5%; P < 0.025).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of 17 beta-estradiol on the human osteosarcoma cell line MG-63. 818 30

Forty-eight Angus x Hereford steers (initial BW = 336 +/- 8.3 kg) were used in a 56-d study to evaluate growth and endocrine responses to continuous or discontinuous grazing of high-endophyte-infected Kentucky-31 (K; > 57% infestation rate) or low-endophyte-infected Johnstone tall fescue (J; < 1% infestation rate) and implantation with 0 or 24 mg/steer of estradiol-17 beta (E2; Compudose). Steers were allotted by weight to eight 3-ha paddocks (four paddocks of each fescue variety) with six steers per paddock. Two paddocks of each variety were grazed continuously (KK and JJ), whereas steers on the remaining four paddocks were rotated every 14 d from K to J (KJ) or from J to K (JK). Three steers in each paddock were implanted with E2 on d 0. The study extended from May 25, 1988 to July 20, 1988 with steers exposed to potential heat-stress conditions for 52 d of the 56-d study. Body weights were obtained on d 0, 28, and 56, and blood samples were taken on d 28 and 56. Overall ADG, serum prolactin, and serum alkaline phosphatase activity were greater (P < .05) in JJ than in KK steers. Rotation from K to J did not increase overall ADG, prolactin, insulin-like growth factor I (IGF-I), or alkaline phosphatase activity compared with the continuously grazed KK, whereas JK steers had lower (P < .10) ADG, prolactin, and alkaline phosphatase activity than JJ steers. Estradiol-17 beta increased (P < .10) IGF-I in JJ, KJ, and JK steers but not in KK steers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth and endocrine responses of cattle to implantation of estradiol-17 beta during continuous or discontinuous grazing of high- and low-endophyte-infected tall fescue. 846 63

17 beta-Estradiol (E2) induces cathepsin D mRNA levels and intracellular levels of immunoreactive protein in MCF-7 human breast cancer cells. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alone does not affect cathepsin D gene expression in this cell line; however, in cells cotreated with TCDD and E2, TCDD inhibited E2-induced cathepsin D mRNA levels, the rate of gene transcription, and levels of immunoreactive protein. The inhibitory responses were observed within 30 to 120 min after the cells were treated with TCDD. TCDD also inhibited E2-induced secreted alkaline phosphatase activity in aryl hydrocarbon (Ah)-responsive MCF-7 and wild-type mouse Hepa 1c1c7 cells cotransfected with the human estrogen receptor (hER) and the pBC12/S1/pac plasmid, which contains the 5' promoter region (-296/+57) of the cathepsin D gene and an alkaline phosphatase reporter gene. The E2-responsive ER/Sp1 sequence (-199 to -165) in the cathepsin D 5' region contains an imperfect GTGCGTG (-175/-181) xenobiotic responsive element (XRE); the role of this sequence in Ah responsiveness was investigated in gel electrophoretic mobility shift assays and with plasmid constructs containing a wild-type ER/Sp1 oligonucleotide or a mutant ER/Sp1-"XRE" oligonucleotide containing two C-->A mutations in the XRE sequence (antisense strand). In plasmid constructs which contained a chloramphenicol acetyltransferase reporter gene and the wild-type ER/Sp1 promoter sequence, E2-induced chloramphenicol acetyltransferase activity and mRNA levels were inhibited by TCDD whereas no inhibition was observed with the mutant ER/Sp1-"XRE" plasmids. Electrophoretic mobility shift assays showed that the nuclear or transformed cytosolic Ah receptor complex blocked formation of the ER-Sp1 complex with the wild-type but not the ER/Sp1 mutant oligonucleotide. Moreover, incubation of the wild-type bromodeoxyuridine-substituted ER/Sp1 oligonucleotide with the nuclear Ah receptor complex gave a specifically bound cross-linked 200-kDa band. These data demonstrate that Ah receptor-mediated inhibition of E2-induced cathepsin D gene expression is due to disruption of the ER-Sp1 complex by targeted interaction with an overlapping XRE.
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PMID:Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. 852 36

The effect of short-term estradiol treatment, administered from the time of ovariectomy, on increased bone turnover and subsequent bone loss was studied in the rat. Adult female Sprague-Dawley rats were ovariectomized and administered daily subcutaneous (s.c.) injections of 17 beta-estradiol at 8 micrograms/ kg per day (Low) and 20 micrograms/kg per day (High) or vehicle alone (Veh). Femoral trabecular bone volume (BV/TV) and trabecular number (Tb.N) in the distal femur were transiently increased at 6 days postoperation in a dose-dependent manner following estradiol administration [mean +/- SEM: BV/TV (%), day 0, 6.6 +/- 0.2; day 6, Veh 7.8 +/- 0.4, Low 10.2 +/- 2.2, High 12.8 +/- 1.7 (p < 0.05); Tb.N (/mm), day 0, 2.30 +/- 0.24; day 6, Veh 2.89 +/- 0.33, Low 3.4 +/- 0.7, High 4.39 +/- 0.34 (p < 0.05)]. Estradiol prevented the ovariectomy-induced decrease in BV/TV and Tb.N between 9 and 15 days observed in Veh rats. Both serum alkaline phosphatase and urine hydroxyproline excretion were maintained at preoperative levels or lower from day 6 postoperation with high dose estradiol. Serum osteocalcin, however, rose above preoperative levels with estradiol at days 6 and 9, but returned to these values on days 15 and 21 postoperation. These results suggest that estradiol, administered from the time of ovariectomy, immediately suppressed markers associated with osteoblast proliferation/matrix synthesis and bone resorption. Mineralization does not appear to be so rapidly suppressed by estradiol with relatively high levels immediately following administration, resulting in a transient increase in trabecular bone volume and trabecular number.
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PMID:Estradiol treatment transiently increases trabecular bone volume in ovariectomized rats. 892 43

We examined the effects of the synthetic glucocorticoid dexamethasone (Dex) and of the sex steroids progesterone (Prog) and testosterone (Testo) on proliferation and differentiation of progenitors for osteoblasts, adipocytes, and macrophages in cell populations derived from lumbar vertebrae of adult male and female rats. To assay for these progenitors, we used a previously described colony assay, where progenitors are identified by the appearance of colonies of the differentiated phenotype in long term cultures of cell populations containing these progenitors. In cell populations derived from both males and females, Dex (10(-9)-10(-6) mol/L) induced a similar dose-dependent increase in the number of osteoblast colonies (bone nodules), colonies of alkaline phosphatase (AP)-positive cells, adipocyte colonies and macrophage colonies (ED2-positive cells). Prog (10(-8)-10(-5) mol/L), on the other hand, increased bone nodule formation in female-derived populations but not in male-derived populations. Maximal stimulation was seen at 10(-5) mol/L. 17 beta-Estradiol (E2) enhanced the Prog-induced increase in the number of bone nodules in a dose-related fashion. Maximal stimulation was seen at 10(-8) mol/L E2. E2 (10(-9)-10(-6) mol/L) had no effect on Dex-induced bone nodule formation, indicating that the effect is specific for Prog-induced stimulation of bone nodule formation. Prog also caused a dose-dependent increase in the number of colonies of AP-positive cells. Interestingly, the effect of Prog on the number of AP-positive colonies was the same in populations derived from both sexes. Prog-induced stimulation of adipocyte and macrophage development in female-derived populations was significantly greater than that in male-derived populations. Testo (10(-9)-10(-5) mol/L) had no effect on any of the parameters evaluated in populations derived from either males or females. These observations demonstrate that the effect of Prog on proliferation and differentiation of progenitors for osteoblasts, adipocytes, and macrophages in cell populations derived from lumbar vertebrae of adult male or female rats is sex-dependent and is seen either only (bone nodule formation) or more pronounced (adipocyte and macrophage development) in female-derived populations.
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PMID:Progesterone stimulates proliferation and differentiation of osteoprogenitor cells in bone cell populations derived from adult female but not from adult male rats. 898 43

In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites. Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
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PMID:Formation of catechol estrogen glutathione conjugates and gamma-glutamyl transpeptidase-dependent nephrotoxicity of 17beta-estradiol in the golden Syrian hamster. 906 57

The anabolic effect of 17beta-estradiol in osteoblastic MC3T3-E1 cells was investigated. The cells were cultured for 3 days in the medium containing either vehicle or 17beta-estradiol (10(-11)-10(-9) M). 17beta-Estradiol significantly increased alkaline phosphatase activity and protein concentration in the cells. The steroid (10(-9) M) also significantly elevated the cell numbers and the cellular DNA content. The anabolic effect by 17beta-estradiol was blocked by the presence of dipicolinate (10(-3) M), a chelator of zinc ion, suggesting a role of cellular zinc in osteoblastic cell function. The presence of zinc sulfate (10(-5) M) or beta-alanyl-L-histidinato zinc (AHZ) (10(-5) M) significantly enhanced the 17beta-estradiol (10(-10) or 10(-9) M)-induced increase of alkaline phosphatase activity and protein concentration in the cells; the effect of AHZ was greater than that of zinc sulfate. The enhancement by zinc compounds was not based on the augmentation of osteoblastic cell numbers. The co-addition of cycloheximide (10(-6) M), an inhibitor of protein synthesis, completely blocked the zinc compound (10(-5) M)-induced enhancement of 17beta-estradiol's (10(-9) M) effect to increase alkaline phosphatase activity and protein concentration in the cells. Moreover, the anabolic effect of 17beta-estradiol together with or without zinc compounds was abolished by the presence of staurosporine (10(-8) M), an inhibitor of protein kinase C, or of okadaic acid (10(-7) M), an inhibitor of protein phosphatase. The present study demonstrates that the anabolic effect of 17beta-estradiol is enhanced by zinc-chelating dipeptide in osteoblastic MC3T3-E1 cells, and that the enhancing effect may involve protein synthesis and protein kinase activity.
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PMID:Zinc enhancement of 17beta-estradiol's anabolic effect in osteoblastic MC3T3-E1 cells. 916 27

Lack of consistent information concerning the pathophysiology of corticosteroid-related bone loss may be due to coexisting independent factors that influence bone mineral density (BMD). For example, the disease being treated may increase bone turnover and cause bone loss, and its severity may influence the dose of corticosteroids chosen. Similarly, disease remission due to the treatment or disease progression despite treatment may influence bone turnover and the rate of bone loss. The hormonal changes purportedly responsible for reduced bone formation or increased bone resorption may be the result of the disease, not the corticosteroids. To determine the pathophysiology of corticosteroid-related bone loss, we conducted a controlled, prospective study in men with no systemic illness treated with corticosteroids to reduce antisperm antibodies. We measured BMD using dual x-ray absorptiometry and circulating biochemical and hormonal determinants of bone turnover in 9 men before and during prednisolone treatment and in 10 age-matched controls. The results were expressed as the mean +/- SEM. There were no differences in BMD between the two groups at baseline. The patients received 50 mg prednisolone daily for 3.7 +/- 0.6 months (range, 1-6). BMD decreased by 4.6 +/- 0.8% at the lumbar spine (P = 0.0007), by 2.6 +/- 0.6% at the trochanter (P = 0.004), and by 4.8 +/- 1.9% at the Ward's triangle (P < 0.04). The decrease in lumbar spine BMD correlated with the cumulative dose of corticosteroids (r = -0.49; P = 0.03). Serum osteocalcin and skeletal alkaline phosphatase decreased by 28.5 +/- 15.5% (P = 0.08) and 24.2 +/- 8.6% (P < 0.03), respectively. The decrease in lumbar spine BMD correlated with the decrease in osteocalcin (r = -0.48; P < 0.02). Serum testosterone and sex hormone-binding globulin decreased by 28.6 +/- 4.4% (P < 0.003) and 28.5 +/- 8.3% (P < 0.007), respectively. The testosterone/sex hormone-binding globulin ratio did not change. The decrease in total testosterone correlated with the decrease in osteocalcin (r = -0.40; P = 0.05). There were no detectable changes in urinary C-telopeptide, serum PTH, or serum calcium. Estradiol decreased by 23.5 +/- 11.4% (P < 0.003). Corticosteroid therapy results in rapid bone loss, probably due to reduced bone formation. Neither increased bone resorption nor secondary hyperparathyroidism appears to contribute to the rapid bone loss. Whether the reduction in bone formation may be partly mediated by changes in sex steroids remains unclear.
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PMID:Corticosteroid-induced bone loss in men. 950 31


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