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 stem bark of Erythrina lysistemon, one of the traditionally used "women remedies", has been assessed for its estrogenic activity. The ethyl-acetate extract of the stem bark of E. lysistemon showed estrogenic activities in vitro either in a yeast-based estrogen receptor assay or on the estrogen-dependent stimulation of alkaline phosphatase activity in the human endometrial carcinoma cell line Ishikawa. The estrogenic activity was investigated in vivo in young ovariectomized Wistar female rats after a 7-day treatment. The estrogenicity was evaluated through the proliferative status of target sex organs such as uterus and vagina. The results obtained showed that oral administration of 200 mg/kg BW/d of E. lysistemon extract in comparison to untreated ovariectomized rats significantly increased the vaginal epithelial height by 47.23% (from 8.71+/-0.47 to 12.34+/-1.31 microm); and induced a weak increase of uterine epithelial height by 6.76% (from 5.42+/-0.52 to 5.84+/-0.91 microm). Both were not as pronounced as those elicited in the positive control of 100 microg/kg BW/d of ethinylestradiol given orally. Overall our results suggest that the extract of E. lysistemon contains secondary metabolites endowed with estrogenic activity.
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PMID:Estrogenic effects of the ethyl-acetate extract of the stem bark of Erythrina lysistemon Hutch (Fabaceae). 1648 90

The purpose of this study was to investigate the in vitro effects of resveratrol (RSVL) and cyclosporin A (CsA) on proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cell (BMSC) cultures. Application of RSVL (10(-8) -10(-6) mol l(-1)) resulted in a dose-dependent increase in [3H]-thymidine incorporation, alkaline phosphatase (ALP) activity and calcium deposition of BMSCs cultures, which was accompanied with the increase of NO production and cGMP content. Concurrent treatment with the estrogen receptor antagonist ICI182,780 (10(-7) mol l(-1)) or the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (6 x 10(-3) mol l(-1)) abolished the RSVL (10(-6) mol l(-1))-induced increase in NO production and cGMP content and eliminated the RSVL-induced increase in proliferation and osteoblastic differentiation of BMSCs. In contrast, CsA (10(-6) -10(-5) mol l(-1)) dose-dependently decreased [3H]-thymidine incorporation, ALP activity and calcium deposition of BMSCs cultures, which was accompanied with the reduction of NO production in the conditioned media. Concurrent treatment with RSVL (10(-6) mol l(-1)) significantly reversed the CsA (3 x 10(-6) mol l(-1))-mediated decrease in NO production and restored the proliferation and differentiation potential of BMSCs. Our data suggest that (1) the NO/cGMP pathway may play an important role in both RSVL-induced and CsA-inhibited proliferation and osteoblastic differentiation of mouse BMSCs, and (2) RSVL may act through an ER/NO/cGMP pathway to reverse the inhibitory effect of CsA on BMSC cultures. Taken together, the data suggest that RSVL may prevent osteoporosis induced by CsA.
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PMID:Resveratrol prevents CsA inhibition of proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cells through an ER/NO/cGMP pathway. 1652 94

The glycoprotein Wnt-7a participates in a signaling pathway that transmits information among uterine cell types. Disruption of this pathway by the transplacentally acting carcinogen diethylstilbestrol (DES) is associated with morphological abnormalities of the female reproductive tract (FRT). This raises the question whether estrogens in the diet might also interfere with this pathway. Therefore, this study investigated the influence of the steroid hormone 17beta-estradiol (E2), the mycotoxin zearalenone (ZEN), the soy phytoestrogen genistein (GEN), and DES on the expression of Wnt-7a in an endometrial adenocarcinoma cell line (Ishikawa cells) by reverse transcription/competitive PCR. In addition, the enzymatic activity of alkaline phosphatase (ALP) was determined, which is estrogen receptor (ER)-dependently regulated in Ishikawa cells. After treatment of Ishikawa cells with E2, ZEN, GEN, and DES, a decrease in the gene expression of Wnt-7a was observed. Maximum effect (50% reduction) was observed after treatment with concentrations that induced maximum expression of the ALP. Experiments in the presence of the ER antagonist (ICI 182,780) suggested that the ER is involved in the regulation of Wnt-7a in Ishikawa cells. In conclusion, interference with the expression of Wnt genes in the FRT might be a novel mechanism by which estrogens disrupt the function of the FRT.
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PMID:Estrogens modulate the gene expression of Wnt-7a in cultured endometrial adenocarcinoma cells. 1653 52

Tibolone is a synthetic steroid which undergoes tissue selective metabolism into several metabolites having estrogenic, progestogenic or androgenic activities. The effects of 3 alpha-hydroxy tibolone (Org 4094), 3 beta-hydroxy tibolone (Org 30126) and their sulfated metabolites were investigated on human fetal osteoblasts (hFOB). Tibolone had no effect on selected osteoblast marker proteins in estrogen-receptor negative hFOB cells. In contrast, 3 alpha-hydroxy and 3beta-hydroxy tibolone resulted in dose-dependent increases in alkaline phosphatase activity in estrogen receptor (ER) alpha-positive hFOB cells. The maximum increase for both metabolites was comparable to the effects of an optimal dose of 17beta-estradiol, and occurred at 10 muM. At 20 muM, both metabolites increased mRNA levels for alkaline phosphatase and type 1 collagen and protein levels for osteocalcin. Sulfated metabolites of tibolone also increased alkaline phosphatase activity. The estrogen receptor antagonist ICI 182, 780 inhibited stimulation of alkaline phosphatase activity by sulfated and non-sulfated tibolone metabolites, but was more potent on the former. Taken together, these results suggest that stable transfection of ER alpha into hFOB cells confers regulation by 3 alpha-hydroxy and 3beta-hydroxy tibolone metabolites of osteoblast metabolism.
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PMID:Effects of stable transfection of human fetal osteoblast cells with estrogen receptor-alpha on regulation of gene expression by tibolone. 1670 83

The benzothiophene selective estrogen receptor modulators (SERMs), raloxifene and arzoxifene, in the clinic or clinical trials for treatment of breast cancer and postmenopausal symptoms, are highly susceptible to oxidative metabolism and formation of electrophilic metabolites. 4'F-DMA, fluoro-substituted desmethyl arzoxifene (DMA), showed attenuated oxidation to quinoids in incubation with rat hepatocytes as well as in rat and human liver microsomes. Incubations of 4'F-DMA with hepatocytes yielded only one glucuronide conjugate and no GSH conjugates, whereas DMA underwent greater metabolism giving two glucuronide conjugates, one sulfate conjugate, and two GSH conjugates. Phase I and phase II metabolism were further evaluated in human small intestine microsomes and in human intestinal Caco-2 cells. In comparison to DMA, 4'F-DMA formed significantly less glucuronide and sulfate conjugates. The formation of quinoids was further explored in hepatocytes in which DMA was observed to give concentration- and time-dependent depletion of GSH accompanied by damage to DNA, which showed inverse dependence on GSH; in contrast, GSH depletion and DNA damage were almost completely abrogated in incubations with 4'F-DMA. 4'F-DMA shows ligand binding affinity to estrogen receptor (ER)alpha and ERbeta with similarity to both raloxifene and to DMA. ER-mediated biological activity was measured with the ERE-luciferase reporter system in transfected MCF-7 cells and Ishikawa cells, and in MCF-7 cells, proliferation was measured. In all systems, 4'F-DMA exhibited anitestrogenic activity of comparable potency to raloxifene but did not manifest estrogenic properties, mirroring previous results on inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells. These results suggest that 4'F-DMA might be an improved benzothiophene SERM with similar antiestrogenic activity to raloxifene but improved metabolic stability and attenuated toxicity, showing that simple chemical modification can abrogate oxidative bioactivation to potentially toxic metabolites without loss of activity.
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PMID:Chemical modification modulates estrogenic activity, oxidative reactivity, and metabolic stability in 4'F-DMA, a new benzothiophene selective estrogen receptor modulator. 1678 Mar 56

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2-4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.
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PMID:Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women. 1681 26

We aimed to produce an estrogen-responsive reporter plasmid that would permit monitoring of estrogen receptor function in the uterus in vivo. The plasmid pBL-tk-CAT(+)ERE was induced by estrogen in bovine endometrial stromal cells. When the CAT gene was replaced by the secreted alkaline phosphatase SeAP, the resulting construct pBL-tk-SeAP(+)ERE remained estrogen responsive. However when the tk promoter was replaced by the cytomegalovirus (cmv) promoter, the resulting plasmid (pBL-cmv-SeAP(+)ERE) was not estrogen responsive. Inhibition of ERE function was not due to an effect in trans or due to lack of estrogen receptor. It was not due to an interaction between the cmv promoter and the SeAP gene. cmv promoter function was dependent on NF-kappaB, and mutagenesis in the NF-kappaB sites reduced basal reporter expression without imparting responsiveness to estrogen. A mutation in the TATA box also failed to impart estrogen responsiveness. Modeling of DNA accessibility indicated the ERE was inserted at a site accessible to transcription factors. We conclude that the cmv promoter inhibits ERE function in cis when the two sequences are located in the same construct, and that this effect does not involve an interaction between cmv and reporter gene, NF-kappaB sites or the TATA box, or DNA inaccessibility.
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PMID:Interactions between the cytomegalovirus promoter and the estrogen response element: implications for design of estrogen-responsive reporter plasmids. 1687 Jul 13

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Ialpha1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)(n)] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)(n) >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05-0.55]. A low number of repeats [(TA)(n) <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77-20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)(n) repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).
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PMID:Influence of genetic polymorphisms on bone disease of preterm infants. 1698 90

Flavonoids, which have been detected in a variety of foods, have been repeatedly reported to affect bone metabolism. However, the effects of flavonoids on osteoblastogenesis remain a matter of some controversy. In this study, the effects of quercetin on the differentiation and proliferation of human adipose tissue-derived stromal cells (hADSC) were determined. Quercetin was found to increase osteogenic differentiation in a dose-dependent manner. Other flavonoids, chrysin and kaempferol, were also shown to increase the osteogenic differentiation of hADSC, but this stimulatory effect was weaker than that associated with quercetin. Quercetin pretreatment administered prior to the induction of differentiation also exerted stimulatory effects on the osteogenic differentiation of hADSC. RT-PCR and real time PCR analysis showed that quercetin treatment induced an increase in the expression of osteopontin, BMP2, alkaline phosphatase and Runx2. Quercetin inhibited the proliferation of hADSC, but did not affect their survival. The pretreatment of quercetin increased ERK phosphorylation during osteogenic differentiation, although it did not increase ERK activity in control culture condition. ICI182780, an specific estrogen receptor antagonist, failed to inhibit the effects of quercetin on osteogenic differentiation. Quercetin-pretreated hADSC showed better bone regenerating ability in skull defect model of nude mice than naive cells. Our findings indicate that quercetin enhances osteogenic differentiation via an independent mechanism from estrogen receptor (ER) activation, and prove useful for in vivo bone engineering, using human mesencymal stem cells (hMSC).
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PMID:Quercetin, a flavonoid, inhibits proliferation and increases osteogenic differentiation in human adipose stromal cells. 1699 34

Several data implicate the immune system in bone lost after estrogen deficiency, however, some of the effects on the immune system of estrogen deficiency or of estrogen receptor (ER) modulation are not well established. In this study, the effect of ER agonists on the immune system in ovariectomized mice is analyzed. Mice were ovariectomized and were administered 17beta-estradiol (E2), raloxifene (RAL) or genistein (GEN). The effect of a 4-week treatment on bone turnover and on several parameters that reflect the status of the immune system was studied. Results show that ovariectomy provoked both uterine atrophy and thymic hypertrophy. Although RAL corrected thymic hypertrophy, only E2 corrected both. Ovariectomized mice showed increased levels of serum calcium and cathepsin K gene expression and decreased levels of serum alkaline phosphatase (ALP) activity, which suggests that there is a persistent alteration in bone metabolism. Moreover, ovariectomy increased B-cells and CD25+ cells, and decreased the percentages of T-cells and Cbfa1 gene expression in bone marrow (BM). All ER agonists corrected, although to different degrees, changes induced by the ovariectomy. Furthermore, results showed that it is essential to adjust ER agonist doses to avoid immunosuppression, since all ER agonists decreased BM T-cell levels.
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PMID:Estrogen receptor agonists and immune system in ovariectomized mice. 1716 2


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