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)

The aims of this study performed in ewes were: (1) to confirm in this animal model the effects on bone of ovariectomy (OVX) alone or associated with Lentaron (L), a potent peripheral aromatase inhibitor, used to amplify the effects of OVX and (2) to evaluate the effects of a new selective estrogen receptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old ewes were divided into five groups: sham (n = 7); OVX (n = 8); OVX + L (n = 8); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], serum osteocalcin [OC], and bone alkaline phosphatase [BAP]) were measured each month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX induced a significant increase in biochemical markers. This effect was the highest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, eroded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bone markers, which returned to sham levels as well as histomorphometry both in cortical and in cancellous bone. Cancellous osteoid thickness decreased by 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were increased by MDL and tended to return to the sham values. The effects of OVX on bone turnover were different on cortical and cancellous bone. These effects on cortical bone were reflected by changes in biochemical markers. MDL markedly reduces bone turnover and increases BMD suggesting that this new agent may prevent postmenopausal bone loss.
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PMID:Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study. 1114 94

Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of levormeloxifene.
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PMID:Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy. 1115 42

A 64-year postmenopausal woman had noticed a left breast lump 5 months before presentation and was admitted due to increasing tumor size. Physical examination showed a well demarcated, movable mass 5 cm in diameter in the upper outer quadrant of the left breast. The lesion was not painful. She had no past history of malignancy or chest wall irradiation. She had no family history of malignancy. Mammography revealed an irregular tumorous lesion with coarse calcifications in the left breast. Intracystic papillary cancer was suspected by ultrasonography. Aspiration breast cytology yielded insufficient material for diagnosis. Laboratory findings were all within the normal limits including alkaline phosphatase and three tumor markers (CEA, CA 15-3, ST-439). An excisional biopsy of the left breast tumor was performed. Histopathological examination revealed malignant phyllodes tumor with osteosarcomatous features and negative tumor margins. Positive vimentin and negative cytokeratin staining was confirmed by immunohistochemistry, suggesting that the tumor did not originate from epithelial cells of the breast. The estrogen receptor (ER) status of the tumor was negative but progesterone receptor (PgR) was weakly positive. Positive p53 nuclear immunoreaction but negative c-erbB-2 overexpression by immunohistochemical staining was observed in this tumor. There was no evidence of generalized disease. She has been well 6 months after surgery without adjuvant therapy.
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PMID:A case of malignant phyllodes tumor of the breast with osteosarcomatous features. 1118 Jul 71

We have developed a universally applicable system for conditional gene expression in embryonic stem (ES) cells that relies on tamoxifen-dependent Cre recombinase-loxP site-mediated recombination and bicistronic gene-trap expression vectors that allow transgene expression from endogenous cellular promoters. Two vectors were introduced into the genome of recipient ES cells, successively: (i) a bicistronic gene-trap vector encoding the beta-galactosidase/neo(R) fusion protein and the Cre-ER(T2) (Cre recombinase fused to a mutated ligand-binding domain of the human estrogen receptor) and (ii) a bicistronic gene-trap vector encoding the hygro(R) protein and the human alkaline phosphatase (hAP), the expression of which is prevented by tandemly repeated stop-of-transcription sequences flanked by loxP sites. In selected clones, hAP expression was shown to be regulated accurately by 4'hydroxy-tamoxifen. Strict hormone-dependent expression of hAP was achieved (i) in vitro in undifferentiated ES cells and embryoid bodies, (ii) in vivo in virtually all the tissues of the 10-day-old chimeric fetus (after injection of 4'hydroxy-tamoxifen to foster mothers), and (iii) ex vivo in primary embryonic fibroblasts isolated from chimeric fetuses. Therefore, this approach can be applied to drive conditional expression of virtually any transgene in a large variety of cell types, both in vitro and in vivo.
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PMID:An efficient system for conditional gene expression in embryonic stem cells and in their in vitro and in vivo differentiated derivatives. 1122 62

Nuclear receptors for 17 beta-estradiol (E(2)) are present in growth plate chondrocytes from both male and female rats and regulation of chondrocytes through these receptors has been studied for many years; however, recent studies indicate that an alternative pathway involving a membrane receptor may also be involved in the cell response. E(2) was found to directly affect the fluidity of chondrocyte membranes derived from female, but not male, rats. In addition, E(2) activates protein kinase C (PKC) in a nongenomic manner in female cells, and chelerythrine, a specific inhibitor of PKC, inhibits E(2)-dependent alkaline phosphatase activity and proteoglycan sulfation in these cells, indicating PKC is involved in the signal transduction mechanism. The aims of the present study were: (1) to examine the effect of a cell membrane-impermeable 17 beta-estradiol-bovine serum albumin conjugate (E(2)-BSA) on chondrocyte proliferation, differentiation, and matrix synthesis; (2) to determine the pathway that mediates the membrane effect of E(2)-BSA on PKC; and (3) to compare the action of E(2)-BSA to that of E(2). Confluent, fourth passage resting zone (RC) and growth zone (GC) chondrocytes from female rat costochondral cartilage were treated with 10(-9) to 10(-7) M E(2) or E(2)-BSA and changes in alkaline phosphatase specific activity, proteoglycan sulfation, and [(3)H]-thymidine incorporation measured. To examine the pathway of PKC activation, chondrocyte cultures were treated with E(2)-BSA in the presence or absence of GDP beta S (inhibitor of G-proteins), GTP gamma S (activator of G-proteins), U73122 or D609 (inhibitors of phospholipase C [PLC]), wortmannin (inhibitor of phospholipase D [PLD]) or LY294002 (inhibitor of phosphatidylinositol 3-kinase). E(2)-BSA mimicked the effects of E(2) on alkaline phosphatase specific activity and proteoglycan sulfation, causing dose-dependent increases in both RC and GC cell cultures. Both forms of estradiol inhibited [(3)H]-thymidine incorporation, and the effect was dose-dependent. E(2)-BSA caused time-dependent increases in PKC in RC and GC cells; effects were observed within three minutes in RC cells and within one minute in GC cells. Response to E(2) was more robust in RC cells, whereas in GC cells, E(2) and E(2)-BSA caused a comparable increase in PKC. GDP beta S inhibited the activation of PKC in E(2)-BSA-stimulated RC and GC cells. GTP gamma S increased PKC in E(2)-BSA-stimulated GC cells, but had no effect in E(2)-BSA-stimulated RC cells. The phosphatidylinositol-specific PLC inhibitor U73122 blocked E(2)-BSA-stimulated PKC activity in both RC and GC cells, whereas the phosphatidylcholine-specific PLC inhibitor D609 had no effect. Neither the PLD inhibitor wortmannin nor the phosphatidylinositol 3-kinase inhibitor LY294022 had any effect on E(2)-BSA-stimulated PKC activity in either RC or GC cells. The classical estrogen receptor antagonist ICI 182780 was unable to block the stimulatory effect of E(2)-BSA on PKC. Moreover, the classical receptor agonist diethylstilbestrol (DES) had no effect on PKC, nor did it alter the stimulatory effect of E(2)-BSA. The specificity of the membrane response to E(2) was also demonstrated by showing that the membrane receptor for 1 alpha,25-(OH)(2)D(3) was not involved. These data indicate that the rapid nongenomic effect of E(2)-BSA on PKC activity in RC and GC cells is dependent on G-protein-coupled PLC and support the hypothesis that many of the effects of E(2) involve membrane-associated mechanisms independent of classical estrogen receptors. (c) 2001 Wiley-Liss, Inc.
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PMID:17 beta-estradiol-BSA conjugates and 17 beta-estradiol regulate growth plate chondrocytes by common membrane associated mechanisms involving PKC dependent and independent signal transduction. 1125 24

To investigate the bioactivities of soybean, which act on bone metabolism, we studied the effect of a soybean ethanol extract on the activity of osteoblast MC3T3-E1 cells. Soy extract (0.01-0.1 g/l) dose-dependently increased survival (P<0.05) and DNA synthesis (P<0.05) of MC3T3-E1 cells. In addition, soy extract (0.05 g/l) increased alkaline phosphatase activity (P<0.05) and collagen synthesis (P<0.05) of MC3T3-E1 cells. Moreover, the anti-estrogen tamoxifen eliminated the stimulation of MC3T3-E1 cells on the proliferation, ALP activity and collagen synthesis by soy extract, indicating that the main action of the soy extract on osteoblastic MC3T3-E1 cells is similar to that of estrogen effects. Treatment with soy extract prevented apoptosis, as assessed by a one-step sandwich immunoassay and DNA gel electrophoresis studies. This effect may be associated with the activation of the estrogen receptor, since we observed soy extract-mediated survival against apoptosis was blocked by the estrogen receptor antagonist tamoxifen in cells, further supporting a receptor-mediated mechanism of cell survival. These results suggest that osteoblast function is promoted by soy extract and that the estrogen receptor is involved in the response, thereby playing an important role in bone remodeling. In conclusion, soy extract has a direct stimulatory effect on bone formation in cultured osteoblastic cell in vitro. Presumably, dietary soy products are useful in the prevention of osteoporosis.
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PMID:Soybean ethanol extract increases the function of osteoblastic MC3T3-E1 cells. 1131 61

In the mouse, ovariectomy (OVX) leads to significant reductions in cancellous bone volume while estrogen (17beta-estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent increase in bone formation would require the proliferation and differentiation of osteoblast precursors, we hypothesized that E2 regulates mesenchymal stem cells (MSCs) activity in mouse bone marrow. We therefore investigated proliferation, differentiation, apoptosis, and estrogen receptor (ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-operated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significant increase in ERalpha mRNA and protein expression as well as alkaline phosphatase (ALP) activity and proliferation rate. In contrast, E2 treatment resulted in a decrease in ERbeta mRNA and protein expression as well as apoptosis in both OVX and sham mice. E2 up-regulated the mRNA expression of osteogenic genes for ALP, collagen I, TGF-beta1, BMP-2, and cbfa1 in MSCs. In a comparison of the relative mRNA expression and protein levels for two ER isoforms, ERalpha was the predominant form expressed in MSCs obtained from both OVX and sham-operated mice. Cumulatively, these results indicate that estrogen in vitro directly augments the proliferation and differentiation, ERalpha expression, osteogenic gene expression and, inhibits apoptosis and ERbeta expression in MSCs obtained from OVX and sham-operated mice. Co-expression of ERalpha, but not ERbeta, and osteogenic differentiation markers might indicate that ERalpha function as an activator and ERbeta function as a repressor in the osteogenic differentiation in MSCs. These results suggest that mouse MSCs are anabolic targets of estrogen action, via ERalpha activation. J. Cell. Biochem. Suppl. 36: 144-155, 2001.
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PMID:Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice. 1145 79

Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.
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PMID:Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys. 1147 85

Trans-3,4',5-trihydroxystilbene (resveratrol), a polyphenolic compound found in the human diet, was reported recently to serve as an estrogen agonist with cultured MCF-7 cells transfected with estrogen response element-luciferase reporter plasmids. As currently shown, treatment of cultured human endometrial adenocarcinoma (Ishikawa) cells with resveratrol (concentrations as high as 10 microM) did not significantly increase the levels of an estrogen-inducible marker enzyme, alkaline phosphatase. To the contrary, when alkaline phosphatase was induced by treatment with 1 nM of 17beta-estradiol (E(2)), resveratrol exhibited a dose-dependent decrease in activity (IC(50) = 2.3 microM). Furthermore, when Ishikawa cells were treated with resveratrol as a single agent, estrogen-inducible progesterone receptor (PR) was not enhanced, and PR expression induced by treatment with E(2) was inhibited by resveratrol in a dose-dependent fashion at both the mRNA and protein levels. In addition, resveratrol mediated suppression of a functional activity of PR as demonstrated by down-regulation of alpha(1)-integrin expression induced by E(2) plus progesterone. With transient transfection experiments conducted with Ishikawa cells, antiestrogenic effects were confirmed by dose-dependent inhibition of E(2)-induced estrogen response element-luciferase transcriptional activity. Because resveratrol antagonized estrogenic effects in Ishikawa cells, competitive binding analyses were performed to examine the potential of displacing [(3)H]E(2) from human estrogen receptor (ER). Resveratrol showed no discernable activity with ER-alpha, but with ER-beta, E(2) was displaced with an IC(50) of 125 microM. However, mRNA and protein expression of ER-alpha but not ER-beta were suppressed by resveratrol in Ishikawa cells, in the concentration range of 5-15 microM. In addition, in the presence or absence of E(2), resveratrol inhibited Ishikawa cell proliferation in a time-dependent manner with cells accumulating in the S phase of the cycle < or =48 h. This effect was reversible. Analysis of some critical cell cycle proteins revealed a specific increase in expression of cyclins A and E but a decrease in cyclin-dependent kinase 2. These data suggest resveratrol exerts an antiproliferative effect in Ishikawa cells, and the effect may be mediated by both estrogen-dependent and -independent mechanisms.
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PMID:Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells. 1150 64

The plasma membrane form of the estrogen receptor-alpha (mER-alpha) is involved in rapid estrogen-induced prolactin release from GH(3)/B6 rat pituitary tumor cells and can be detected immunocytochemically using several estrogen receptor-alpha (ER-alpha) antibodies. We recently described staining of fixed cells via a biotin-avidin-alkaline phosphatase sandwich assay. From this protocol, we have developed a rapid, quantifiable 96-well plate immunoassay for mER-alpha, using a different alkaline phosphatase substrate, para-nitrophenylphosphate, which generates a soluble yellow product, para-nitrophenol. We also permeabilized cells with detergent during fixation to measure intracellular ER-alpha (iER-alpha) with the same assay and then compared intracellular versus membrane ER-alpha levels in two GH(3)/B6 cell subclones originally selected for high and absent mER-alpha expression by immunocytochemistry. While the F10 subclone expresses plentiful amounts of the mER-alpha, the D9 subclone has undetectable levels of mER-alpha using this assay. In addition, there is a seven-fold difference in iER-alpha expression between the high (F10) and no (D9) mER-alpha expressing subclones. In the high mER-alpha expressing cell line, the mER-alpha totals approximately one third of total cellular ER-alpha. Neither membrane or intracellular forms of ER-beta were detected with this assay. The pNp assay allows convenient and quantitative comparison of multiple parameters of mER-alpha and iER-alpha regulation and should be applicable to other antigens that are expressed on the cell surface as well as intracellularly.
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PMID:A comparison of membrane vs. intracellular estrogen receptor-alpha in GH(3)/B6 pituitary tumor cells using a quantitative plate immunoassay. 1152 34


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