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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue-type plasminogen activator (tPA) is secreted by rat granulosa cells in response to treatment with activators of protein kinase A (follitropin, FSH), protein kinase C (gonadotropin-releasing hormone, GnRH) and tyrosine kinase (epidermal growth factor, EGF). Because steroid hormones have been shown to enhance the gonadotropin stimulation of ovarian differentiation, we investigated the effects of steroid hormones, alone or together with various kinase activators, on tPA activities and mRNA levels in cultured rat granulosa cells. Treatment of cells with dexamethasone (DEX; a glucocorticoid agonist) or R1881 (an androgen agonist) caused an increase in tPA secretion and mRNA levels. In addition, the stimulation of tPA activity and mRNA levels by FSH (50 ng/ml) was synergistically enhanced by cotreatment with DEX or R1881 in a time-dependent manner with 2.8- and 1.6-fold increase at 9 h after incubation as compared to cells treated with FSH alone. In contrast, treatment with diethylstilbestrol had no effect on tPA levels. Furthermore, tPA activity and mRNA levels induced by GnRH and EGF were also increased by cotreatment with DEX or R1881 as compared with cells treated with GnRH or EGF alone. Likewise, the stimulation of tPA mRNA levels by dibutyryl cAMP, a protein kinase A activator, and phorbol myristate acetate (PMA), a protein kinase C activator, was enhanced by cotreatment with DEX or R1881. These results demonstrate that glucocorticoid and androgen enhance tPA secretion and mRNA levels stimulated by FSH, GnRH and EGF in granulosa cells. The rat granulosa cells provide a useful model for studying the mechanism of regulation of tPA gene expression by steroid hormones.
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PMID:Synergistic effect of glucocorticoids and androgens on the hormonal induction of tissue plasminogen activator activity and messenger ribonucleic acid levels in granulosa cells. 210 7

We studied the effects of LHRH and its analogs on plasminogen activator production and progesterone and estradiol secretion by granulosa cells isolated from adult rat Graafian follicles. LHRH and its agonist ([des- -Gly10,D-Trp6,Pro9-NHEt]LHRH) stimulated small but significant increases in plasminogen activator production. This stimulatory action of LHRH was blocked by the addition of the specific antagonist ([D- pGlu1,D-Phe2,D-Trp3,6]LHRH). In contrast, LHRH treatment had no significant effect on basal steroid production by granulosa cells of Graafian follicles cultured for 2-6 days. However, LHRH decreased the FSH-stimulated steroidogenesis. This inhibitory effect of LHRH on steroidogenesis was abolished by concomitant addition of the LHRH antagonist. The results show that LHRH has a stimulatory effect on plasminogen activator production and a suppressive action on steroidogenesis in granulosa cells isolated from Graafian follicles of adult rats.
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PMID:LHRH stimulates plasminogen activator and inhibits steroid production by granulosa cells of adult rat Graafian follicles. 308 86

The main emphasis of this paper is on the changes in function of granulosa cells as they undergo cytodifferentiation in follicles developing from the preantral to the antral stage, and on the hormones present in the milieu of gonadotrophins and steroids which are essential for these events to proceed normally. We found that FSH alone could induce aromatase activity in cultures of immature granulosa cells and that this effect could be duplicated by dibutyryl cyclic AMP. Incubation of cell sonicates under optimal conditions indicated that FSH acted on granulosa cells to increase the cellular concentration of active aromatase. Prior treatment with androgens augmented the FSH effect. Progesterone synthesis is another differentiated function which can be induced in culture by FSH alone and augmented in the presence of androgens. In assessing the enzymes involved in progesterone synthesis we found that cholesterol side-chain cleavage activity had similar hormonal requirements whereas 3 beta-hydroxysteroid dehydrogenase activity was stimulated by FSH alone. FSH also stimulates cyclic AMP binding activity in cultured granulosa cells during cytodifferentiation. These proteins represent another class of intracellular proteins, quite distinct from the steroidogenic enzymes, which increase as the granulosa cells mature. The ability of FSH to induce the appearance of LH and prolactin receptors, and stimulate the secretion of plasminogen activator and proteoglycans is reviewed. It is concluded that the appearance of steroidogenic enzymes and other intracellular proteins, cell-surface and secreted proteins as well as morphological maturation of granulosa cells require the presence of FSH. In the "turning-on" of some of these differentiated functions androgens play a permissive role. Having established events which occur during normal development of the follicle, we considered ways by which this overall process could be interrupted and fertility controlled. Here we describe the ways by which prolactin and LHRH interfere with the normal process of granulosa cell cytodifferentiation.
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PMID:Hormonal interactions in the control of granulosa cell differentiation. 631 Feb 32

We studied the effects of LHRH and a potent agonist on plasminogen activator production by granulosa cells obtained from immature rats. Both LHRH and the agonist produced a dose-related increase in plasminogen activator production. Concomitant addition of LHRH or its agonist together with FSH to the granulosa cell cultures enhanced the stimulatory effects of FSH on plasminogen activator production. These in vitro findings suggest that LHRH exerts a direct stimulatory effect on plasminogen activator secretion by rat granulosa cells which may explain the acute stimulating effects of LHRH and its agonist on ovulation in hypophysectomized rats.
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PMID:Luteinizing hormone releasing hormone stimulates plasminogen activator production by rat granulosa cells. 640 19

The abilities of LHRH and a potent LHRH agonist ([D-Ser-(But),6, des-Gly-NH210]LHRH ethylamide) inhibit FSH responses by rat granulosa cells and Sertoli cells in vitro have been compared. Granulosa cells isolated from 22- or 25-day-old diethylstilbestrol-primed rats and cultured under defined conditions for 48 h with NIH-FSH-S13 (300 ng/ml) or cholera toxin (0.1 microgram/ml) showed increased aromatase activity, as determined by the release of 3H2O from [1 beta-3H]testosterone. LHRH (10(-7) M) or th agonist (10(-8) M) added simultaneously with FSH or cholera toxin inhibited the effects on the release of 3H2O without influencing the protein content of the cell cultures. A smaller stimulation of 3H2O production occurred with (Bu)2cAMP (1.0 mM) plus 3-isobutyl-l-methylxanthine (0.1 mM), and this was partially suppressed in the presence of LHRH or the agonist. Parallel studies with Sertoli cells from 15- or 20-day-old rats demonstrated that culture under appropriate conditions with FSH, cholera toxin, or (Bu)2cAMP (0.5 mM) for 24 h caused an increase in cellular aromatase activity and enhanced secretion into the medium of plasminogen activator. However, no inhibition by LHRH (10(-7) or 10(-9) M) or the agonist (10(-6) or 10(-8) M) occurred when the peptides were added either simultaneously or 24 h before the stimulatory agent. Similarly, Sertoli cells from 11-day-old rats treated daily with LHRH agonist for 5 days in culture, showed no inhibition of aromatase activity after a 4-h stimulation with FSH or (Bu)2cAMP. FSH dose-response curves (0-300 ng/ml) for aromatase activity were shown to be similar after 5 days of culture with or without 10(-8) M LHRH agonist, indicating that the LHRH did not cause a shift in the sensitivity to FSH. The lack of inhibition was seen in Sertoli cell cultures maintained at 37 or 32 C. The enzyme digestion method used to isolated Sertoli cells was not responsible for the lack of effects of LHRH, since cell cultures prepared without the aid of proteolytic enzymes showed similar FSH stimulation of aromatase activity in the presence or absence of 10(-8) M agonist. Further, there was no evidence of degradation of the LHRH agonist when incubated with Sertoli cell cultures. From these studies, we conclude that 1) granulosa cells and Sertoli cells from immature rats differ in their responses to LHRH, and 2) the immature Sertoli cell is an unlikely target for a direct inhibiting influence of LHRH on spermatogenesis.
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PMID:Differential effects of luteinizing hormone-releasing hormone on follicle-stimulating hormone-dependent responses in rat granulosa cells and Sertoli cells in vitro. 678 Mar 24

Testicular LHRH-peptidase and testicular urokinase-type plasminogen activator are Sertoli cell-secreted proteases which display similar molecular properties. However, there is relatively little information regarding the substrate specificity and potential cross-reactivity of these enzymes. Testicular extracts were prepared from homogenates of whole rat testes and assessed by LHRH-peptidase assay, and by radial caseinolysis assays for plasminogen activator and plasmin-like activity. Following partial purification of the protease activities in testicular extracts by gel filtration and ion-exchange chromatography, it was confirmed that testicular LHRH-peptidase and plasminogen activator are clearly separable. There was no detectable plasmin-like activity in the testicular extracts; however, the extracts were found to contain an inhibitor, or inhibitors, of both plasminogen activator and plasmin activity. In addition to LHRH and Gly6-substituted LHRH analogues, the partially purified LHRH-peptidase degraded both angiotensins I and II, but not the gonadotrophin-releasing-hormone-associated peptide derived from the LHRH precursor molecule. These properties of the LHRH-peptidase provide further evidence that it is a testis-specific prolyl endopeptidase, involved in regulating and/or limiting peptide activity in the testis.
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PMID:Comparison of LHRH-peptidase and plasminogen activator activity in rat testis extracts. 962 84

Reversible stereoselective complexes were spontaneously obtained from mixing acetonitrile solutions of enatiomeric d-poly(lactic acid) (d-PLA), l-poly(lactic acid) (l-PLA), and leuprolide, a l-configured nonapeptide LHRH analogue. The complex spontaneously aggregated and precipitated in high yields (>90%) from acetonitrile solution, forming uniform, porous microparticles. The stereocomplex microparticles showed a continuous release of the interlocked peptide for a period of one to three months under physiological conditions. Various factors, including method of complex formation, molecular weight of PLA, leuprolide:polymer and d-PLA:l-PLA complex ratios, and additives, influenced the release pattern of leuprolide from the stereocomplexes. Continuous release of leuprolide for over 100 days was observed for certain stereocomplex compositions. In vivo evaluation of the leuprolide loaded stereocomplexes in rats by monitoring testosterone levels in the blood of rats after subcutaneous injection showed low testosterone levels for over 42 days.
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PMID:Heterostereocomplexes prepared from d-PLA and l-PLA and leuprolide. II. Release of leuprolide. 1295

Reversible hetero-stereoselective complexes were obtained by mixing acetonitrile solutions of enantiomeric D-poly(lactic acid) (d-PLA) and leuprolide, an L-configured nonapeptide LHRH analogue. The complex spontaneously aggregated and precipitated in high yields (95%) from acetonitrile solutions, forming uniform, porous microparticles with a mean unweighed particle size of 1.7 microm. The complexation of L-configured peptide occurred only with D-PLA, and not with L-PLA or racemic D,L-PLA. Various factors affecting the release pattern of leuprolide from the hetero-stereocomplexes were investigated. Complexes with D-PLA of low molecular weight (< 10,000 Da) displayed lower release rates of leuprolide than high molecular weight D-PLA (> 50,000 Da). Changing the leuprolide: D-PLA ratio from 1:50 to 1:10 (w/w) in the stereocomplex, resulted in a faster release of leuprolide. Similarly, the release rate of leuprolide was twice as fast when adding poly(ethylene glycol) to the acetonitrile complexation solution. Leuprolide was released from most of the formulations in a first order pattern, with only a small burst release during the first 24 h. Addition of water to the complexation solution significantly increased the initial release of the peptide. Low testosterone levels for over 25 days were observed in an in vivo release study of leuprolide from a hetero-stereocomplex formulation, monitoring testosterone levels in the blood of rats after sub cutaneous injection.
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PMID:Hetero-stereocomplexes of D-poly(lactic acid) and the LHRH analogue leuprolide. Application in controlled release. 1545 19

Most surgical procedures performed by obstetrician-gynecologists are associated with pelvic adhesions that cause subsequent serious sequelae, including small bowel obstruction, infertility, chronic pelvic pain, and difficulty in postoperative treatment, including complexity during subsequent surgical procedures. This study was conducted to determine if gonadotropin-releasing hormone analogues (GnRHa) affect the expressing tissue-type plasminogen activator (t-PA) and its inhibitor-1 (PAI-1) in peritoneal cells in culture. Human peritoneal Met5A cells were used to examine the effects of GnRHa leuprolide, buserelin and goserelin on the levels of t-PA and PA-1. Antigen concentrations were measured in conditioned media and cell lysates by real-time PCR and ELISA. GnRH receptor (GnRHR) mRNA was determined by RT-PCR. GnRHR mRNA was detected in Met5A cells. Exposure of Met5A cells to GnRHa induced a rapid decrease of PAI-1 level in cultured medium but not in cell lysate (protein and mRNA). These effects of GnRHa on PAI-1 were not associated with any changes in t-PA level. These results suggest that GnRHa may be an effective stimulator of local peritoneal fibrinolytic activity, as it decreases PAI-1 secretion in peritoneal Met5A cells by a mechanism linked to GnRHR.
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PMID:GnRH receptor and peritoneal plasmin activity. 2023 28

The Gonadotropin-Releasing Hormone (GnRH) exists in two isoforms, GnRH-I and GnRH-II, in most vertebrates, including humans. Both of these isoforms and their respective receptors have been found in many healthy and pathologic extra nervous system tissues, such as cells found in cancers of the reproductive systems and, in particular, in breast cancer. GnRH analogues are used as therapeutic agents in the case of sex-hormone-dependent tumours. Besides acting as suppressors of steroidogenesis, GnRH analogues seem to interfere with mitogenic signal transduction pathways, thus behaving as negative regulators of tumour growth and progression. GnRH analogues counteract the proliferating effects of both epidermal growth factor (EGF) and insulin like growth factor (IGF-I); additionally, it affects the mitogen-activated protein kinase (MAPK) cascade and modulates the activity of the urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitory (PAI) system, which is involved in the process of metastasis. In addition, GnRH analogues decrease the expression of many growth factors involved in the development of human uterine myomas (as well as endometriotic tissue), such as the vascular endothelial growth factor (VEGF), which is deeply implied in the angiogenesis of many benign and malignant tumours, including breast cancer. Angiogenesis is one of the primary processes leading to the progression and metastasis of breast cancer cells, and a key therapeutic goal in the fight against tumours is the blocking of new vessel sprouts. Given these premises, this review provides an update on the background of anti-neoplastic properties of GnRH analogues..
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PMID:The pharmacological pathways of GnRH mediating the inhibition of mammary tumours: implications in humans and domestic animals. 2221 66


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