Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cronolone (9 alpha-fluoro-11 beta-hydroxy-17 alpha-acetoxypregn-4-ene-3,20-dione) is widely employed to regulate breeding activity in the ewe, but its biological activity in the uterus of this and most other species has not been studied. In this study several in vivo uterus-related activities of cronolone have been examined in the sheep, mouse and rabbit. In some experiments the corresponding activities of medroxyprogesterone acetate (6 alpha-methyl-17 alpha-acetoxypregn-4-ene-3,20-dione, MAP) were also examined. Cronolone maintained pregnancy in ovariectomized ewes but not in ovariectomized mice and rabbits; it terminated pregnancy in some mice and in all rabbits that were receiving daily progesterone treatment. Cronolone could not sensitize the mouse uterus for the induction of the decidual-cell reaction or block the induction of such sensitivity by progesterone, but did support limited growth of the oil-stimulated horn after sensitization with progesterone. Cronolone induced uteroglobin secretion by rabbit endometrium. It was concluded that, whereas MAP is a potent progestogen in the sheep, mouse and rabbit, cronolone is a progestogen in the sheep and rabbit only. In the mouse and especially the rabbit, cronolone has other, non-progestational activities, which block pregnancy.
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PMID:Some biological activities of cronolone and medroxyprogesterone acetate in the uterus of the sheep, mouse and rabbit. 247 75

Various aspects of the binding of the synthetic progesteongens, cronolone (9 alpha-fluoro-11 beta-hydroxy-17 alpha-acetoxypregn-4-ene-3,20-dione) and medroxyprogesterone acetate (6 alpha-methyl-17 alpha-acetoxypregn-4-ene-3,20-dione, MAP) to uterine cytosol progesterone receptors of the sheep, rabbit and mouse were studied, in an attempt to explain interesting species differences in the biological activity of these steroids. For the sheep, data for binding-site concentration, relative binding affinity (RBA), dissociation constant (Kd) and rates of association and dissociation indicate specific binding of cronolone to the progesterone receptor and these would seem to explain in part the high progestational activity of cronolone in this species. By contrast, with the mouse, there was only a low level of specific binding of cronolone and this appears to explain its inability to maintain pregnancy in this species. Results for the binding activity of cronolone in rabbit uterus were similar to those for the sheep and thus inability of cronolone to maintain pregnancy in the rabbit is not explained by a failure to bind the progesterone receptor. Species differences in binding to the progesterone receptor were also seen with MAP where the RBA, with respect to progesterone, was high in the sheep and rabbit and lower in the mouse. The results, however, do not relate directly to the progestational activity of MAP in these species. Overall, the data indicate that species differences in the binding activity of steroid receptors constitute one factor that causes species-dependent variation in biological responses to progestogens.
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PMID:In vitro binding of progesterone, cronolone and medroxyprogesterone acetate to uterine progesterone receptors of sheep, rabbit and mouse. 247 58

Endothelins (ETs) were initially thought to be primarily involved in the control of cardiovascular activity, but the presence of ETs and their receptors in a wide variety of other tissues has suggested a much broader range of functions. Specific receptors for ETs are found in nonvascular tissues including neuronal, neuroendocrine, and endocrine cells. In addition, immunoreactive ETs are present in the brain, pituitary, and peripheral endocrine tissues. However, the ET levels in hypothalamo-hypophysial portal and peripheral blood are low, suggesting that the ET system participates in neuroendocrine regulation through paracrine and/or autocrine mechanisms. Both ETA and ETB receptors are expressed in the hypothalamus, adrenal, parathyroid glands, pancreas, ovary, uterus, placenta, and prostate, while only ETA receptors are expressed in GT1 neurons, anterior pituitary cells, alpha T3-1 immortalized gonadotropes, parathyroid-derived cells, thyrocytes, testicular Leydig and Sertoli cells, normal and neoplastic ovarian granulosa cells, chondrocytes, and other cell types. Activation of ET receptors elicits the sequence of cellular events typical of Ca(2+)-mobilizing receptors, with prominent increases in phosphoinositide hydrolysis and elevations of [Ca2+]i that occur in oscillatory and nonoscillatory modes depending on the cell type. ET-induced activation of the phosphoinositide/Ca(2+)- mobilizing pathway in neuronal and endocrine cells is associated with rapid stimulation of secretory responses, including release of gonadotropin-releasing hormone, oxytocin, vasopressin, substance P, atrial natriuretic peptides, gonadotropins, thyrotropin, growth hormone, parathyroid hormone, aldosterone, and catecholamines. On the other hand, ET has inhibitory actions on prolactin, progesterone, and renin release. In addition to stimulating phospholipase C-dependent pathways, ETs also activate phospholipase D-and MAP-kinase-dependent pathways in some of their target cells, as well as expression of early response genes and increased mitogenic activity. In many neuroendocrine cells, ET induces rapid and marked desensitization of its signaling system, in association with extensive internalization of ET receptors and reduced signaling and secretory responses. These findings raise the possibility that ETs participate in the control of secretory responses in the hypothalamo-pituitary system and peripheral endocrine cells, as well as in long-term aspects of regulation in certain neuroendocrine cells.
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PMID:Expression and signal transduction pathways of endothelin receptors in neuroendocrine cells. 881 99

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
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PMID:EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. 1041 81

Three experiments were conducted to determine: (1) the direction of uterine contractions in Days 32 and 52 postpartum ewes (Experiment 1); (2) the effect of PGF(2alpha) on direction of uterine contractions (Experiment 2); and (3) the effect of PGF(2alpha) on fertility rates in Day 32 postpartum ewes (Experiment 3). In Experiment 1, non-lambing (>90 days postpartum) and lambing ewes (day of lambing=Day 0) received medroxyprogesterone acetate (MAP) vaginal sponges for 8 days and 500 IU of eCG at sponge withdrawal (Days 30 or 50 postpartum). At the time of eCG injection, ewes were divided into the following groups: (1) non-lambing (control; n=29); (2) Day 32 postpartum dry (n=15) and lactating (n=16); and (3) Day 52 postpartum dry (n=14) and lactating (n=16). At estrus or 60h post-eCG, the uterus was exteriorized through a mid-ventral incision, and the origin and direction of uterine contractions were recorded for 10min. In Experiment 2, ewes received MAP sponges on Day 16 postpartum followed by 500 IU of eCG on day of sponge removal (Day 30). At estrus, the ewes were divided into the following treatments: (1) two injections of saline 4h apart (n=10) and (2) 12.5mg of PGF(2alpha) followed by another 12.5mg 4h later (n=7). After the second injection, ewes were laparotomized and uterine contractions were counted. In Experiment 3, estrus was induced in postpartum ewes, and ewes were mated to two rams, then received the same two treatments as described in Experiment 2 (ram+saline; n=32 and ram+PGF(2alpha); n=28). Two days following mating, ewes were laparotomized and the oviducts flushed for recovery of ova. In Experiment 1, lactational status had no effect, therefore, the data were pooled. Control ewes had a greater percentage (p<0.05) of uterine contractions (69%) moving towards the oviducts than did Day 32 (8%) or Day 52 (43%) ewes. In Experiment 2, PGF(2alpha) treatment increased the proportion of contractions (p<0.05) moving toward the oviducts (controls 16%, PGF(2alpha) 42%). Number of PGF(2alpha)-treated ewes (Experiment 3) with fertilized ova were not significantly different from the control ewes (5/32 versus 2/28; respectively). In conclusion, it can be said that the direction of uterine contractions moving toward the oviducts increased as the postpartum interval progressed or if they received PGF(2alpha) injection. PGF(2alpha) treatment did not improve fertility rates in Day 32 postpartum ewes.
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PMID:Uterine contraction patterns and fertility in early postpartum ewes. 1092 78

The follow-up of women after ART is for the most part related, over the short and long term, to the follow-up of the child born through ART. What is important to know is the possible repercussions of treatment on women's health over the short and long term. To date, no study has proven that menopause comes on earlier after ART treatments. Similarly, none of the international studies has demonstrated a significant increase in breast, ovary, uterus, or colon cancer related to ovulation-inducing treatment. However, for reasons of safety, vigilance is required. Large-scale follow-up of this nature essentially involves crossing registries (cancers, ART), but must respect the desires of women not to be indefinitely reminded of their past infertility. In addition, a study is reported on pursuing the parental project in a cohort of 1200 women who delivered at least one child conceived through MAP more than 3 years before.
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PMID:[Post-ART follow-up for women]. 1878 70