Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the preclinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.
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PMID:Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. 179 69

The studies described here support the concept that relaxin is a product of the ovarian follicle and interacts with systemic hormones in the local regulation of the ovary. This report reviews the work indicating that relaxin is a product of the ovarian follicle and presents evidence for the biologic action of relaxin within the follicle. Production of relaxin by cells of the theca interna was given support by immunocytochemical localization work, in vitro production studies, and detection of relaxin mRNA by in situ hybridization. The relaxin content of porcine follicular fluid was shown to increase with development induced by gonadotropins. During thecal cell culture, luteinizing hormone and porcine follicular fluid increased relaxin secretion, whereas the presence of granulosa cells was without effect. A biologic action for relaxin on connective tissue remodeling was supported by an increase in follicle-stimulating hormone-stimulated plasminogen activator activity by granulosa cells. Additional work is needed to investigate the possibility of other roles for relaxin within the follicle, to identify relaxin receptors, and to explore the interaction of relaxin with endocrine and other paracrine factors in the ovary.
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PMID:Production and biologic action of relaxin within the ovarian follicle: an overview. 187 63

The purpose of this study was to adduce further evidence for a paracrine role for human decidual relaxin (Rlx) in the remodelling of collagen in the fetal membranes in the peripartal period. The binding of [125I]porcine Rlx to membrane-enriched fractions from fetal membranes as well as from dispersed cells from the fetal membranes was used to demonstrate the presence of specific Rlx receptors. Rlx added in vitro to cultured amnion/chorion cells increased the release of plasminogen activator and collagenase into the medium. Rlx had no effect on the release of beta-glucuronidase. An in vivo correlate of these in vitro results was obtained, the detection of plasminogen activator and collagenase in amniotic fluids. The active fraction of collagenase was increased in amniotic fluids collected after spontaneous rupture of the membranes. PRL, hCG, estrogen, and progesterone added in equimolar amounts to cultured amnion/chorion cells from elective cesarean sections and normal term deliveries also effected the release of plasminogen activator and collagenase. The greatest effects were found in cells from cesarean section tissue, in terms of the stimulation of plasminogen activator release by Rlx and PRL and of collagenase release by prostaglandin F2 alpha and, to a lesser extent, by Rlx, PRL, and hCG. We conclude that human fetal membranes are targets for a number of hormones, including the decidual paracrine hormones Rlx, PRL, and prostaglandin F2 alpha as well as estrogen, progesterone, and hCG. These hormones act to release or inhibit the enzymes involved in collagen breakdown before rupture of the fetal membranes.
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PMID:The human fetal membranes: a target tissue for relaxin. 300 43

Dispersed cells from human amnion and chorion were cultured with and without relaxin. The addition of this hormone caused an increased secretion of both collagenase and plasminogen activator into the culture medium over a 32 h period, but had no effect on proteoglycanase or beta-glucuronidase secretion. The increase in plasminogen activator was dose-related to the amount of relaxin added in vitro. The results show that the fetal membranes are a novel target tissue for relaxin in the human, and suggest that relaxin in vivo may cause a similar release of collagenolytic enzymes, leading to the weakening and eventual rupture of the fetal membranes.
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PMID:Relaxin stimulates collagenase and plasminogen activator secretion by dispersed human amnion and chorion cells in vitro. 630 28

The release of plasminogen activator by rat granulosa cells in vitro has been shown to be dependent on the concentration of FSH, and it has thus been proposed as a good assay for this hormone. However, it has been recently claimed that relaxin was also able to trigger the release of plasminogen activator by the same cells. In order to check the specificity of the assay, we studied the behavior of a large number of hormones and we found that it was strictly specific for FSH activity.
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PMID:The release of plasminogen activator by rat granulosa cells is highly specific for FSH activity. 640 24

Granulosa cells isolated from the ovaries of pregnant mare serum gonadotropin (PMSG)-treated immature rats were cultured with relaxin or FSH. Both hormones increased the secretion of plasminogen activator into the culture medium. Relaxin caused a dose-related rise in plasminogen activator but did not increase cAMP or progesterone levels in the medium of freshly harvested granulosa cells, although they were responsive to FSH. This ability of relaxin to stimulate plasminogen activator synthesis without progesterone or cAMP rises indicates that the pathways of post-receptor events leading to stimulation of plasminogen activator differ markedly from those of the gonadotropins. Relaxin is thus a fully characterized peptide hormone produced by the ovary with a well-defined action upon the granulosa cell and may have an intraovarian role in the events leading to ovulation.
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PMID:Relaxin stimulates plasminogen activator secretion by rat granulosa cells in vitro. 681 Dec 60

Manipulation of one ovary in prepubertal gilts treated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) results in cysts on the manipulated ovary and corpora lutea (CL) on the non-manipulated (control) ovary. Because tissue-type plasminogen activator (tPA) might play a role in follicular rupture and because relaxin might increase tPA production, concentrations of tPA and relaxin in manipulated and control follicles were measured at different stages of development. Prepubertal gilts were treated with 1000 IU PMSG followed by 750 IU hCG at 72 hr later. Follicles on one ovary in each gilt were manipulated at laparotomy 48 hr after PMSG administration. Gilts were ovariectomized at 72, 90, 108, 114, 144, and 216 hr after PMSG. Concentrations of tPA and relaxin were determined for follicular fluid from follicles dissected free of ovarian stroma and snap frozen in liquid nitrogen and media from follicles cultured for 48 hr. Relaxin did not differ between treatment groups (manipulated and control) at any time (P > 0.05); whereas, tPA was greater in control follicles at 114 hr after PMSG than in manipulated follicles (P < 0.01). The effect of pyrilamine, a histamine-1 receptor antagonist, on tPA concentrations was determined in manipulated and control follicles collected at 3, 12, 24, 42, and 66 hr after manipulation. Concentrations of tPA were similar in control and manipulated follicles for gilts treated with pyrilamine, but again control follicles had greater (P < 0.05) tPA concentrations at 114 hr after PMSG. Thus, tPA seems to be involved in ovulation, and blockage of ovulation and subsequent cyst formation results from inadequate tPA activity in manipulated follicles.
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PMID:Concentrations of tissue-type plasminogen activator and relaxin in normal and induced-cystic follicles of gilts. 960 98

Changes in plasminogen activator are associated with the reproductive tissue remodelling that occurs during growth. Given the trophic effects of relaxin on the pig uterus and cervix, the present study was designed to examine the impact of relaxin on urokinase and tissue-type plasminogen activator (uPA and tPA) protein and activity in the uterus and cervix of prepubertal pigs. After relaxin administration in vivo to induce growth of the immature uterus and cervix, plasminogen activator activity was measured in uterine flushes and uterine and cervical tissue using a chromogenic substrate assay. Immunoreactive uPA and tPA protein in uterine flushes and uterine and cervical tissue was detected by western blotting. Urokinase plasminogen activator activity was significantly higher (P < 0.05) in uterine flushes from relaxin-treated animals than in controls. However, there was no change in uterine flush tPA activity or protein in response to in vivo relaxin treatment. There was no evidence for acid-labile inhibitors of plasminogen activator in uterine flushes of any of the animals. Cell-associated uterine tissue uPA and tPA activity, as well as protein, were similar in relaxin-treated and control prepubertal pigs. In the cervix, cell-associated tPA activity decreased significantly (P < 0.05) in relaxin-treated animals, while cervical uPA activity was unchanged. These results support the view that at least one means by which relaxin promotes pig uterine growth is by increasing uterine secretion of uPA. In addition, these studies suggest that relaxin administration in vivo to prepubertal gilts has tissue-specific effects with respect to plasminogen activator.
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PMID:Regulation of urokinase- and tissue-type plasminogen activator by relaxin in the uterus and cervix of the prepubertal gilt. 987 63