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1.
PLoS Genet ; 9(1): e1003271, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23382703

RESUMEN

The mechanisms that guide motile sperm through the female reproductive tract to oocytes are not well understood. We have shown that Caenorhabditis elegans oocytes synthesize sperm guiding F-series prostaglandins from polyunsaturated fatty acid (PUFA) precursors provided in yolk lipoprotein complexes. Here we use genetics and electrospray ionization tandem mass spectrometry to partially delineate F-series prostaglandin metabolism pathways. We show that omega-6 and omega-3 PUFAs, including arachidonic and eicosapentaenoic acids, are converted into more than 10 structurally related F-series prostaglandins, which function collectively and largely redundantly to promote sperm guidance. Disruption of omega-3 PUFA synthesis triggers compensatory up-regulation of prostaglandins derived from omega-6 PUFAs. C. elegans F-series prostaglandin synthesis involves biochemical mechanisms distinct from those in mammalian cyclooxygenase-dependent pathways, yet PGF(2α) stereoisomers are still synthesized. A comparison of F-series prostaglandins in C. elegans and mouse tissues reveals shared features. Finally, we show that a conserved cytochrome P450 enzyme, whose human homolog is implicated in Bietti's Crystalline Dystrophy, negatively regulates prostaglandin synthesis. These results support the model that multiple cyclooxygenase-independent prostaglandins function together to promote sperm motility important for fertilization. This cyclooxygenase-independent pathway for F-series synthesis may be conserved.


Asunto(s)
Caenorhabditis elegans , Oocitos , Prostaglandinas F , Reproducción , Espermatozoides , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/metabolismo , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Ácidos Grasos Omega-3/química , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/química , Ácidos Grasos Omega-6/metabolismo , Femenino , Humanos , Masculino , Ratones , Oocitos/metabolismo , Oocitos/fisiología , Prostaglandinas F/biosíntesis , Prostaglandinas F/química , Reproducción/genética , Reproducción/fisiología , Motilidad Espermática/genética , Espermatozoides/metabolismo , Espermatozoides/fisiología
2.
Gen Comp Endocrinol ; 177(2): 256-62, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22543191

RESUMEN

Prostaglandin levels in different tissues and cyclooxygenase (COX-2) gene expression were compared between wild and cultured Senegalese sole (Solea senegalensis) broodstock in which a significantly different fatty acid profile, particularly lower tissue levels of arachidonic acid (ARA, 20:4n-6) and higher levels of eicosapentaenoic acid (EPA, 20:5n-3) in the cultured fish compared to wild had already been described. This is the first report of the COX-2 mRNA expression in Senegalese sole. Cyclooxygenase (COX-2) mRNA expression and prostaglandin (2- and 3-series) levels were determined in tissues from 32 broodstock fish, 16 (8 males and 8 females) from each origin wild and cultured (G1). Transcripts of COX-2 were highly expressed in gills, sperm-duct (s-duct), testis, oviduct and spleen compared to liver, kidney and muscle. Differences in COX-2 transcripts expression were found in response to the origin of the fish and expression was significantly higher in s-duct and gills from wild fish compared to cultured. Wild fish showed significantly higher levels of total 2-series PGs and lower levels of 3-series compared to cultured fish. The significance of the lower COX-2 expression and lower PG 2-series production in some of the tissues of cultured fish was discussed in relation to the previously described differences in fatty acid profile (lower tissue levels of ARA and higher levels of EPA and EPA/ARA ratio in cultured fish) and the reproductive failure to spawn viable eggs from G1 cultured Senegalese sole compared to successful spawning from captive wild broodstock.


Asunto(s)
Ciclooxigenasa 2/genética , Peces Planos/genética , Peces Planos/metabolismo , Prostaglandinas/biosíntesis , Alprostadil/análogos & derivados , Alprostadil/metabolismo , Animales , Animales Salvajes , Acuicultura , Ciclooxigenasa 2/metabolismo , Dinoprostona/biosíntesis , Femenino , Masculino , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis
3.
Science ; 215(4538): 1396-8, 1982 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-6278592

RESUMEN

The concentration of oxytocin receptors increased in the myometrium of pregnant women and reached maximum levels in early labor. Concentrations of oxytocin receptors were also high in the decidua and reached a maximum at parturition. In vitro, prostaglandin production by the decidua, but not by the myometrium, was increased by the addition of oxytocin. Oxytocin may therefore stimulate uterine contractions by acting both directly on the myometrium and indirectly on decidual prostaglandin production. Oxytocin receptors are probably crucial for the onset of human labor, and the stimulus for the increase in uterine prostaglandins may be oxytocin originating from the fetus.


Asunto(s)
Trabajo de Parto , Oxitocina/fisiología , Receptores de Superficie Celular/fisiología , Útero/fisiología , Decidua/fisiología , Femenino , Humanos , Miometrio/fisiología , Embarazo , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis
4.
Science ; 190(4217): 894-6, 1975 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-1188369

RESUMEN

The arteriovenous difference in the concentration of prostaglandin F2alpha (PGF2alpha) across the brain of the anestrous sheep was measured before and during the induction of luteinizing hormone secretion with 17 beta-estradiol. The results indicate that (i) the brain in vivo is a significant source of PGF2alpha, (ii) the release of PGF2alpha from the brain occurs in pulses with a circhoral rhythm, and (iii) the process through which estrogen exerts its negative and positive feedback effects on luteinizing hormone secretion may involve amplitude modulation of PGF2alpha output from the brain.


Asunto(s)
Encéfalo/metabolismo , Estradiol/farmacología , Hormona Luteinizante/metabolismo , Prostaglandinas F/biosíntesis , Animales , Encéfalo/efectos de los fármacos , Femenino , Prostaglandinas F/sangre , Ovinos , Factores de Tiempo
5.
C R Biol ; 342(5-6): 186-191, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31495738

RESUMEN

The aim of our study was to understand the role of transcription factor p53 in the control of healthy human ovarian cell functions. Ovarian granulosa cells were transfected with a cDNA construct encoding p53. The intracellular accumulation of p53, of the apoptosis marker bax, and of the proliferation marker PCNA, as well as the release of progesterone (P4), insulin-like growth factor I (IGF-I), oxytocin (OT), and prostaglandin F (PGF) and E2 (PGE) were evaluated by quantitative immunocytochemistry and RIA/IRMA. Transfection with the p53 cDNA construct resulted in the accumulation of p53 and bax, in a reduced level of released PCNA and PGF, and in an increased PGE output. No changes in P4, IGF-I, and OT secretion were found. These observations are the first demonstration of the involvement of p53 in the control of healthy human ovarian cell functions, namely, in the downregulation of proliferation, in the upregulation of apoptosis, and in the alteration of PGF and PGE release, but not of P4, IGF-I, or OT.


Asunto(s)
Ovario/fisiología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiología , Electroforesis en Gel de Poliacrilamida , Femenino , Proteínas Fluorescentes Verdes/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Ovario/metabolismo , Oxitocina/biosíntesis , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Prostaglandinas F/biosíntesis , Proteína X Asociada a bcl-2/biosíntesis
6.
J Clin Invest ; 70(4): 798-805, 1982 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-6811614

RESUMEN

Glandular epithelium and stromal cells of human endometrium were separated and maintained in monolayer culture. At the time the cells became confluent, cell suspensions were prepared and incubated with [14C]arachidonic acid. Radiolabeled prostaglandin E2 and, to a lesser extent, prostaglandin F2 alpha and metabolites of these prostaglandins, were formed principally in stromal cells. There was considerably less prostaglandin formation in endometrial glands either after maintenance in monolayer culture or in freshly separated glands. In stromal cells of endometrium prostaglandin formation was linear with time of incubation for 2.5 min and with [14C]arachidonic acid concentrations up to 8 microM. When stromal cells and epithelial cells were combined, all prostaglandin formation could be accounted for by that produced in stromal cells. Little or no prostaglandin formation was detected in stromal cells from human adipose tissue or in fibroblasts from human genital or abdominal skin or human fallopian tube.


Asunto(s)
Endometrio/metabolismo , Prostaglandinas/biosíntesis , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Células Cultivadas , Dinoprost , Dinoprostona , Epitelio/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Cinética , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis
7.
J Clin Invest ; 77(1): 202-11, 1986 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-3080473

RESUMEN

Human umbilical arteries converted arachidonic acid to three hydroxyeicosatetraenoic acids (HETEs) as well as prostaglandins. The mono-HETEs have been identified by reverse-phase high pressure liquid chromatography and gas chromatography-mass spectroscopy as 15-HETE and 11-HETE. 15-HETE in arterial segments appears to be derived mainly via the 15-lipoxygenase pathway, whereas 11-HETE, and the presumed di-HETE(s) were products of cyclooxygenase. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, stimulated prostanoid production with a concomitant inhibition of 15-HETE formation. These results suggested that 15-HETE may function as an endogenous regulator of prostacyclin. In human umbilical arterial microsomes, 15-HETE was found to inhibit 6-keto-prostaglandin F1 alpha and total prostanoid production in a concentration-dependent manner (median inhibition constant [IC50] of 52 +/- 3 and 63 +/- 4 microM respectively). The relative distribution of prostaglandins, however, remained unaffected, indicating that the site of action was cyclooxygenase. Kinetic analysis revealed that 15-HETE was a competitive inhibitor of the enzyme. Although no changes in maximum velocity occurred, the apparent Km was significantly different (9.3 +/- 6.9 microM [1 SD] for control vs. 37.6 +/- 17.7 microM for the 15-HETE-treated enzyme). Furthermore, the inhibitory effect of 15-HETE on prostacyclin production was confirmed using cultured bovine endothelial cells. In this cell system, not only did 15-HETE inhibit endogenous prostacyclin production, but also the conversion of exogenous [1-14C]arachidonic acid to prostacyclin (IC50 of 40 +/- 17 microM). No effect on arachidonic acid release was noted. To investigate whether our in vitro finding that 15-HETE inhibited prostacyclin production could be relevant to the in vivo situation, our final studies were performed on vasculature obtained from the diabetic milieu. We found that the production of 15-HETE was significantly increased in vasculature obtained from the infant of the diabetic mother (1.14 +/- 0.26 pmol/mg) when compared to control neonates (0.77 +/- 0.22; P less than 0.01). A concomitant decrease in prostacyclin production was seen (51.6 +/- 12.6 pmol/mg in infants of diabetic mothers vs. 71 +/- 22.3 in controls). Moreover, an inverse correlation between these two eicosanoids was also noted. Our results suggest a potential in vivo regulatory role for 15-HETE on prostacyclin production.


Asunto(s)
Inhibidores de la Ciclooxigenasa , Ácidos Hidroxieicosatetraenoicos/farmacología , Músculo Liso Vascular/enzimología , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Calcimicina/farmacología , Bovinos , Diabetes Mellitus/metabolismo , Endotelio/enzimología , Endotelio/metabolismo , Femenino , Humanos , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Recién Nacido , Músculo Liso Vascular/metabolismo , Prostaglandinas F/antagonistas & inhibidores , Prostaglandinas F/biosíntesis , Arterias Umbilicales
8.
J Clin Invest ; 75(2): 404-12, 1985 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-3156147

RESUMEN

Abnormalities in glomerular function have been observed frequently in the early stages of both clinical and experimental diabetes mellitus. Because prostaglandins (PGs) are present in the glomerulus and have profound effects on glomerular hemodynamics, and because abnormalities of PG metabolism have been noted in other tissues from diabetics, we studied PG biosynthesis in glomeruli obtained from rats in the early stages of experimental diabetes mellitus. Streptozotocin, 60 mg/kg, was administered intravenously to male Sprague-Dawley rats. Control rats received an equal volume of the vehicle. Glomeruli were isolated 9-23 d later. Production of eicosanoids was determined by two methods: by direct radioimmunoassay after incubation of glomeruli under basal conditions and in the presence of arachidonic acid (C20:4), 30 microM, and by radiometric high-performance liquid chromatography (HPLC) after incubation of glomeruli with [14C]C20:4. When assessed by radioimmunoassay, mean basal production of both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) was twofold greater in the diabetic animals whereas production of thromboxane B2 (TXB2) was not significantly greater than control. In response to C20:4, both PGE2 and PGF2 alpha were also greater in the diabetic animals, but these differences were not statistically significant. The increased rate of basal PG production did not appear to be related directly to the severity of the diabetic state as reflected by the degree of hyperglycemia at the time of sacrifice. In fact, the rates of glomerular PG production in the individual diabetic animals correlated inversely with the plasma glucose concentration. The increased rate of PG synthesis did not appear to be due to a nonspecific effect of streptozotocin inasmuch as glomerular PG production was not increased significantly in streptozotocin-treated rats which were made euglycemic by insulin therapy. Furthermore, addition of streptozotocin, 1-10 mM, to the incubation media had no effect on PGE2 production by normal glomeruli. PGE2 production by normal glomeruli was also not influenced by varying the glucose concentration in the incubation media over a range of 1-40 mM. When metabolism of [14C]C20:4 was evaluated by high-performance liquid chromatography conversion to labeled PGE2, PGF2 alpha, TXB2, and hydroxyheptadecatrienoic acid by diabetic glomeruli was two- to threefold greater compared with that in control glomeruli, whereas no significant difference in conversion to 12- and 15-hydroxyeicosatetraenoic acid occurred. These findings indicate that glomerular cyclooxygenase but not lipoxygenase activity was increased in the diabetic animals. A concomitant increase in glomerular phospholipase activity may also have been present to account for the more pronounced differences in PG production noted in the absence of exogenous unlabeled C20:4. These abnormalities in PG biosynthesis by diabetic glomeruli may contribute to the altered glomerular hemodynamics in this pathophysiologic setting.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Glomérulos Renales/metabolismo , Prostaglandinas/biosíntesis , Animales , Dinoprost , Dinoprostona , Técnicas In Vitro , Glomérulos Renales/efectos de los fármacos , Masculino , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Ratas , Ratas Endogámicas , Estreptozocina/toxicidad , Tromboxano B2/biosíntesis
9.
J Clin Invest ; 67(5): 1292-6, 1981 May.
Artículo en Inglés | MEDLINE | ID: mdl-7014633

RESUMEN

Bovine aortic endothelial and smooth muscle cells in culture were incubated with arachidonic acid or prostaglandin H2. The amount of prostacyclin nd thromboxane A2 synthesized ws then determined by specific radioimmunoassay for 6-keto-prostaglandin F1 alpha and thromboxane B2. Although smooth muscle cells produced only 6-keto-prostaglandin F1 alpha and thromboxane B2 in a ratio of 5:1 to 10:1. The same ratio of these metabolites of arachidonic acid ws also found when prostaglandin production from endogenous arachidonic acid was stimulated in endothelial cells by the ionophore A23187. Cyclooxygenase inhibitors inhibited the production of both metabolites equally, whereas thromboxane synthetase inhibitors selectively inhibited the production of thromboxane B2. Cells in culture were also incubated with [1-14C]arachidonic acid and the extracted products were identified by two-dimensional thin-layer chromatography. 6-Keto-prostaglandin F1 alpha was the only metabolite produced by smooth muscle cells, but endothelial cells synthesized 6-keto prostaglandin F1 alpha, thromboxane B2, prostaglandin E2, and prostaglandin F2 alpha.


Asunto(s)
Endotelio/metabolismo , Epoprostenol/biosíntesis , Prostaglandinas/biosíntesis , Tromboxanos/biosíntesis , Animales , Aorta/metabolismo , Ácidos Araquidónicos/metabolismo , Bovinos , Células Cultivadas , Prostaglandinas F/biosíntesis , Tromboxano B2/biosíntesis , Tromboxano-A Sintasa/metabolismo
10.
J Clin Invest ; 64(5): 1277-87, 1979 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-500811

RESUMEN

Prostaglandins have been postulated to participate in the regulation of salt excretion during acute volume expansion. The present papillary and cortical micropuncture studies were designed to examine the effect of prostaglandin synthesis inhibitors on segmental chloride transport during hydropenia (with and without meclofenamate) and 10% volume expansion (with and without both meclofenamate and indomethacin). Both inhibitors significantly decreased the urinary excretion rate of prostaglandins E(2) and F(2alpha). Clearance studies on the intact right kidney demonstrated no effect of either agent on glomerular filtration rate, but a significant reduction in chloride excretion during hydropenia and volume expansion was observed. To assess the specific site(s) of enhanced chloride reabsorption, absolute and fractional chloride delivery was measured in the late proximal tubule, thin descending limb of Henle, and the early and late distal tubules. In addition, the fraction of filtered chloride remaining at the base and tip of the papillary collecting duct was compared to that fraction remaining at the superficial late distal tubule. During hydropenia, meclofenamate had no effect on fractional chloride delivery out of the superficial late distal tubule or the juxtamedullary thin descending limb of Henle, but significantly reduced the fraction of chloride delivered to the base of the papillary collecting duct. During volume expansion, neither meclofenamate nor indomethacin had an effect on absolute chloride delivery out of the proximal tubule or the thin descending limb of Henle. However, absolute chloride delivery to the early distal tubule was significantly reduced, and was associated with a decrease in fractional chloride reabsorption in this segment. Furthermore, the fraction of chloride delivered to the base of the collecting duct was significantly reduced. Fractional reabsorption along the terminal 1 mm of the collecting duct was not altered by either meclofenamate or indomethacin. These results suggest that inhibitors of prostaglandin synthesis result in an increase in chloride reabsorption in the superficial loop of Henle, and in segments between the superficial late distal tubule and the base of the collecting duct. The results are consistent with the view that prostaglandins inhibit chloride transport in the thick ascending limb of Henle, and/or the cortical and outer medullary collecting tubule.


Asunto(s)
Corteza Renal/metabolismo , Médula Renal/metabolismo , Nefronas/metabolismo , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , Cloruro de Sodio/metabolismo , Animales , Transporte Biológico , Tasa de Filtración Glomerular , Indometacina/farmacología , Ácido Meclofenámico/farmacología , Antagonistas de Prostaglandina/farmacología , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Punciones/métodos , Ratas , Cloruro de Sodio/orina
11.
J Clin Invest ; 75(6): 1852-7, 1985 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3891787

RESUMEN

In this investigation, we sought to resolve the apparent paradox that is posed by the fact that there is a simultaneous increase in the production of prostaglandin and cortisol in women during labor. A paradox obtains, since in most tissues, cortisol acts to inhibit prostaglandin formation. Using previously characterized model systems for the in vitro study of arachidonic acid metabolism in amnion, decidua, and myometrium, we found that prostaglandin production by amnion and endometrial stromal cells in monolayer culture was not decreased by glucocorticosteroid treatment. On the other hand, prostaglandin production by myometrial smooth muscle cells in culture was inhibited by greater than 90% in response to dexamethasone (10(-7) M) treatment. Importantly, the major prostaglandin produced by myometrium, as well as myometrial smooth muscle cells in culture, is prostacyclin, a prostaglandin that acts to cause uterine quiescence. We suggest that the immunity of amnion and decidua to the action of glucocorticosteroids may allow for the accelerated production of prostaglandins E2 and F2 alpha, which act to cause myometrial contractions; simultaneously, glucocorticosteroid produced in large quantities in women in labor may lead to decreased production of prostacyclin by myometrium, thereby reducing uterine quiescence. In this coordinated manner, the uterine contractions that culminate in delivery of the fetus may proceed uninterrupted in the face of increased cortisol production.


Asunto(s)
Glucocorticoides/farmacología , Hidrocortisona/metabolismo , Trabajo de Parto , Prostaglandinas/biosíntesis , Amnios/efectos de los fármacos , Células Cultivadas , Dinoprost , Dinoprostona , Endometrio/efectos de los fármacos , Epoprostenol/biosíntesis , Femenino , Humanos , Miometrio/efectos de los fármacos , Embarazo , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis
12.
J Clin Invest ; 72(2): 455-65, 1983 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6409932

RESUMEN

To address the hypothesis that metabolites of arachidonic acid are important regulators of prostaglandin (PG) synthesis in intact vascular tissue, we studied arachidonate metabolism in rabbit aortas in response to a continuous infusion of arachidonic acid, 10 micrograms/ml. Prostacyclin (PGI2; measured as 6-keto-PGF1 alpha) production rate accelerated during the first 2 min, reached peak velocity at 2 min, and then progressively decelerated. The velocity profile of PGI2 production was similar to that previously reported for cyclooxygenase holoenzyme assayed in vitro, and was consistent with progressive inactivation of the enzymes leading to PGI2 synthesis. We determined the specific inhibition of cyclooxygenase and prostacyclin synthetase by measuring PGI2 and PGE2 production rates and by infusing cyclic endoperoxides. Our results indicate preferential inactivation of cyclooxygenase during arachidonate metabolism, most likely due to cyclooxygenase-derived oxidative intermediates. This was a dose-dependent response and resulted in a progressive decrease in the 6-keto-PGF1 alpha/PGE2 ratio. Exogenously added 15-hydroperoxy eicosatetraenoic acid, on the other hand, actually stimulated cyclooxygenase activity at low doses, while markedly inhibiting prostacyclin synthetase. This finding, along with the accelerating nature of arachidonate metabolism, is consistent with the concept of "peroxide tone" as a mediator of cyclooxygenase activity in this system. These results demonstrate that arachidonate metabolites regulate PG synthesis in intact blood vessels. The progressive enzymatic inhibition intrinsic to arachidonate metabolism may be a model for similar changes occurring in states of enhanced lipid peroxidation. These metabolic alterations might greatly influence the numerous vascular functions known to involve arachidonic acid metabolism.


Asunto(s)
Aorta Torácica/metabolismo , Ácidos Araquidónicos/farmacología , Sistema Enzimático del Citocromo P-450 , Oxidorreductasas Intramoleculares , Leucotrienos , Prostaglandinas/biosíntesis , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Calcimicina/farmacología , Dinoprostona , Relación Dosis-Respuesta a Droga , Epoprostenol/biosíntesis , Epoprostenol/metabolismo , Femenino , Peróxidos Lipídicos/farmacología , Masculino , Perfusión , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandinas E/análisis , Prostaglandinas E/biosíntesis , Prostaglandinas F/análisis , Prostaglandinas F/biosíntesis , Conejos
13.
J Clin Invest ; 77(1): 252-9, 1986 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-3455932

RESUMEN

To determine whether the amount of cyclooxygenase metabolites correlates with the development of lupus nephritis, intrarenal eicosanoid production was measured in autoimmune mice. Disease progression was related to the renal biosynthesis of prostaglandin (PGE2), prostacyclin (6 keto PGF1 alpha), and thromboxane (TXB2) using the MRL-lpr and NZB X NZW F1 hybrid mouse strains with predictably progressive forms of renal disease that mimic the human illness. Mice were evaluated for renal disease by measuring urinary protein excretion and renal immunopathological conditions and these features were related to renal eicosanoid production. These studies show that: (a) intrarenal synthesis of TXB2 increased incrementally in MRL-lpr and NZB X NZW F1 hybrid mice as renal function deteriorated and renal pathologic events progressed; (b) there were no consistent increases in the levels of two other cyclooxygenase metabolites, PGE2 or 6 keto PGF1 alpha; (c) increased TXB2 production occurred in the renal medulla, cortex, and within enriched preparations of cortical glomeruli; (d) when renal disease was prevented by pharmacologic doses of PGE2, intrarenal TXB2 did not increase; (e) administration of a dose of ibuprofen (9 mg/kg), a cyclooxygenase inhibitor capable of reducing 90% of platelet TXB2 without affecting intrarenal levels, did not retard the progression of renal damage. Taken together, these data indicate that the intrarenal level of TXB2 rises in relation to the severity of murine lupus nephritis. Furthermore, because of the potential deleterious effects of TXA2, enhanced production of this eicosanoid may be an important mediator of renal injury.


Asunto(s)
Glomerulonefritis/metabolismo , Riñón/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Tromboxano B2/biosíntesis , Animales , Dinoprostona , Femenino , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/patología , Ibuprofeno/farmacología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/patología , Masculino , Ratones , Ratones Endogámicos NZB , Prostaglandinas E/antagonistas & inhibidores , Prostaglandinas E/biosíntesis , Prostaglandinas E/uso terapéutico , Prostaglandinas F/biosíntesis , Proteinuria/metabolismo , Especificidad de la Especie , Tromboxano B2/antagonistas & inhibidores
14.
J Clin Invest ; 81(2): 487-98, 1988 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-3276731

RESUMEN

There is much interest in defining the signals that initiate abnormal proliferation of cells in a variety of states characterized by the presence of mononuclear phagocytes. Since IL-1 is a major secretory product of activated human monocytes we examined whether this cytokine can stimulate the growth of human vascular smooth muscle cells (SMC). Neither recombinant IL-1 (rIL-1) alpha (less than or equal to 5.0 ng/ml) nor beta (less than or equal to 100 ng/ml) stimulated SMC growth during 2-d incubations under usual conditions. IL-1 did stimulate SMC to produce prostanoids such as PGE1 or PGE2 that can inhibit SMC proliferation. When prostaglandin synthesis was inhibited by indomethacin or aspirin both rIL-1 alpha and beta (greater than or equal to 1 ng/ml) markedly increased SMC growth. In longer-term experiments (7-28 d) rIL-1 stimulated the growth of SMC even in the absence of cyclooxygenase inhibitors. The addition of exogenous PGE1 or PGE2 (but not PGF1 alpha, PGF2 alpha, PGI2) to indomethacin-treated SMC blocked their mitogenic response to rIL-1. Antibody to IL-1 (but not to platelet-derived growth factor [PDGF]) abolished the mitogenic response of SMC to rIL-1. Exposure of SMC to rIL-1 or PDGF caused rapid (maximal at 1 h) and transient (baseline by 3 h) expression of the c-fos proto-oncogene, determined by Northern analysis. We conclude that IL-1 is a potent mitogen for human SMC. Endogenous prostanoid production simultaneously induced by IL-1 appears to antagonize this growth-promoting effect in the short term (2 d) but not during more prolonged exposures. IL-1 produced by activated monocytes at sites of tissue inflammation or injury may thus mediate both positive and negative effects on SMC proliferation that are temporally distinct.


Asunto(s)
Interleucina-1/farmacología , Mitógenos , Músculo Liso Vascular/citología , Prostaglandinas/metabolismo , 6-Cetoprostaglandina F1 alfa/biosíntesis , Aspirina/farmacología , División Celular/efectos de los fármacos , Células Cultivadas , Dinoprost , Dinoprostona , Inhibidores de Crecimiento/metabolismo , Técnicas Inmunológicas , Indometacina/farmacología , Músculo Liso Vascular/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Proteínas Recombinantes/farmacología
15.
J Clin Invest ; 60(1): 215-23, 1977 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-874085

RESUMEN

Rabbit renomedullary interstitial cells were isolated and grown in tissue culture. These cells synthesize 0.8 ng of prostaglandin E2 (PGE2) per microgram cellular protein per hour in monolayer tissue culture; prostaglandins A2 and F2alpha (PGA2 and PGF2alpha) biosynthesis was 10 and 5% of PGE2 biosynthesis, respectively. Arachidonic acid markedly stimulated the production of PGE2 and PGF2alpha, with conversion rates of 0.24 and 0.02%/h, respectively. Angiotensin II, hyperosmolality, bradykinin, and arginine vasopressin each stimulated PGE2 biosynthesis; maximum stimulation was 20, 3.7, 3.6, and 3.2 times basal production, respectively. PGE2 biosynthesis by the renomedullary interstitial cells was inhibited by isoproterenol, potassium, nonsteroidal anti-inflammatory agents (indomethacin, naproxen, ibuprofen, suprofen, meclofenamate, and acetylsalicylic acid), mepacrine (a phospholipase inhibitor), hydrocortisone, and cortisone. The rabbit renomedullary interstitial cell in tissue culture is a model system for the study of hormonal regulation of PGE2 biosynthesis.


Asunto(s)
Angiotensina II/farmacología , Arginina Vasopresina/farmacología , Bradiquinina/farmacología , Médula Renal/metabolismo , Riñón/metabolismo , Prostaglandinas/biosíntesis , Vasopresinas/análogos & derivados , Animales , Ácidos Araquidónicos/farmacología , División Celular , Células Cultivadas , Médula Renal/citología , Médula Renal/efectos de los fármacos , Concentración Osmolar , Potasio/farmacología , Prostaglandinas A/biosíntesis , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Conejos , Sodio/farmacología , Relación Estructura-Actividad
16.
Prostaglandins Other Lipid Mediat ; 83(4): 250-6, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17499744

RESUMEN

We investigated the mechanism by which rat luteal cells produce prostaglandin F(2 alpha) (PGF(2 alpha)) and its relevance to cell death in vitro. Treatment with progesterone (P4) of dispersed luteal cells prepared from rats on day 9 of pseudopregnancy caused dose-dependent inhibition of PGF(2 alpha) secretion. Cytokines, tumor necrosis factor alpha (TNFalpha) or interferon gamma (IFN gamma) alone had no or modest regulatory effects. Arachidonyl trifluoromethyl ketone (AACOCF(3)), a specific group IVA phospholipase A(2) inhibitor, depressed both basal and cytokine-regulated PGF(2 alpha) production. A combination of TNFalpha and IFN gamma stimulated PGF(2 alpha) synthesis and cytotoxicity (both, P<0.05). Agonistic anti-Fas antibody challenge caused a significant cytotoxic effect but without affecting PGF(2 alpha) production. The present data suggest that P4 inhibits and TNFalpha and IFN gamma cooperatively stimulate PGF(2 alpha) release by rat luteal cells. They also suggest that luteal cell death induced by TNFalpha/IFN gamma and Fas stimulation seems to occur via distinct signaling pathways involving PGF(2 alpha) production.


Asunto(s)
Células Lúteas/efectos de los fármacos , Células Lúteas/metabolismo , Prostaglandinas F/biosíntesis , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino , Ácidos Araquidónicos/farmacología , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/farmacología , Femenino , Interferón gamma/farmacología , Células Lúteas/citología , Ratas , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacología
17.
J Natl Cancer Inst ; 76(6): 1053-6, 1986 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3458943

RESUMEN

Prostaglandin production by two continuous human esophageal carcinoma cell lines HCU 18 and HCU 39 derived from poorly and moderately differentiated source tumors, respectively, was investigated. Behavior of both lines in vitro and upon sc inoculation into athymic randombred BALB/c nude mice was also assessed. Approximately half the xenografts induced by HCU 18 cells were invasive, whereas those initiated by HCU 39 cells were all well encapsulated. Although metastases were not detected in mice given injections of HCU 39 cells, metastatic tumors developed in 2 mice inoculated with HCU 18 cells. In addition, HCU 18 cells produced significantly more prostaglandin E (PGE) and prostaglandin F (PGF) than HCU 39 cells. These findings suggest a relationship between PGE and PGF production by human esophageal carcinoma cells and their invasive and metastatic potential in athymic mice.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Prostaglandinas/biosíntesis , Animales , Línea Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Trasplante de Neoplasias , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Trasplante Heterólogo
18.
Cancer Res ; 44(4): 1625-9, 1984 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-6322982

RESUMEN

The purpose of this investigation was to determine whether cells transformed by herpes simplex virus type 2 (HSV-2) can be stimulated to synthesize prostaglandins (PG). Stimulation was determined by measuring the release of PG into overlay fluids from cell monolayers prelabeled with [3H]arachidonic acid. Results showed that Ca2+ ionophore A-23187 markedly stimulated arachidonic acid release starting 30 min after treatment of HSV-2-transformed and nontransformed rat embryo fibroblast cells. However, only HSV-2-transformed cells were stimulated in production of PG. HSV-2-transformed, nontumorigenic, rat embryo fibroblast, line G, clone 2.0 cells synthesize nearly equal amounts of prostaglandin E2 (PGE2) and prostaglandin F2 alpha, while tumor (rat fibrosarcoma) cells synthesize primarily PGE2. Stimulation of PGE2 synthesis by Ca2+ ionophore A-23187 or 12-O-tetradecanoyl-phorbol-13-acetate decreased as rat fibrosarcoma cells were serially passaged in tissue culture. At low passage of parental rat fibrosarcoma cells, four distinct morphological clonal cell lines were isolated, which varied markedly in their capacity to be stimulated in PG synthesis by 12-O-tetradecanoyl-phorbol-13-acetate. There was correlation between the capacity of clone 1 cells to be stimulated in PGE2 synthesis by serum alone and capacity of the tumors produced by the clone 1 cells to metastasize to the lungs of syngeneic tumor-bearing rats. In summary, cell transformation by HSV-2 appears to be essential for stimulation of PG synthesis in cells. The capacity to be stimulated in arachidonic acid metabolism and PG synthesis may be important in the process of carcinogenesis by a putative human cancer virus.


Asunto(s)
Calcimicina/farmacología , Transformación Celular Neoplásica , Forboles/farmacología , Prostaglandinas/biosíntesis , Simplexvirus/genética , Acetato de Tetradecanoilforbol/farmacología , Animales , División Celular/efectos de los fármacos , Células Clonales , Dinoprost , Dinoprostona , Embrión de Mamíferos , Fibrosarcoma/metabolismo , Cinética , Metástasis de la Neoplasia , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Ratas
19.
Cancer Res ; 37(11): 3974-80, 1977 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-269012

RESUMEN

Data from our present studies demonstrate the capability of a 105,000 X g pellet from rat normal bone marrow, turpentine-induced hyperplastic bone marrow, and chloroma tumor to transform precursor arachidonic acid into prostaglandins. The activity of the prostaglandin synthetase systems in these tissues is inhibited by the known nonsteroid antiinflammatory drug indomethacin and by two unsaturated fatty acids previously demonstrated in other tissues. Although the overall biosynthesis of prostaglandin E2 (PGE2) was higher in the hyperplastic bone marrow than in the chloroma tumor, the PGF2alpha:PGE2 ratio was markedly higher (8-fold) in the chloroma tissue. This latter increase was probably due to the increased transformation of PGE2 into PGF2alpha by the NADPH-dependent PGE2 9-ketoreductase (an enzyme that catalyzes the transformation of PGE2 and PGF2alpha). These results indicate the greater capability of the malignant chloroma tissue to form PGF2alpha than of nonmalignant hyperplastic bone marrow. Although the role of PGF2alpha in the malignant myelogenous leukemic tumor is presently unclear, its increased formation in this tissue suggests that this substance may play a role in the hyperproliferative process.


Asunto(s)
Leucemia Experimental/metabolismo , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesis , Animales , Ácidos Araquidónicos/metabolismo , Médula Ósea/metabolismo , Ácidos Grasos Insaturados/farmacología , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Hiperplasia/metabolismo , Técnicas In Vitro , Indometacina/farmacología , Cinética , Leucemia Experimental/patología , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratas
20.
Biochim Biophys Acta ; 574(2): 351-5, 1979 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-486515

RESUMEN

Prostaglandin synthesis in human diploid fibroblasts was studied by incubating [14C]-arachidonic acid with cell homogenates. The majority of prostaglandins produced in young cells was 6-ketoprostaglandin F1 alpha. The 6-ketoprostaglandin F1 alpha-producing activity of cultures declined with in vitro aging, and was almost undetectable at the senescent stage, while total production of thromboxane B2, prostaglandin F2 alpha and prostaglandin E2-like metabolites increased with in vitro aging.


Asunto(s)
Fibroblastos/metabolismo , Prostaglandinas F/biosíntesis , Células Cultivadas , Humanos , Técnicas In Vitro , Pulmón/metabolismo , Factores de Tiempo
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