Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sequence of events within the ovary during the process of ovulation discussed in this review is schematically represented in Fig. 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events, and it appears from the available information that the effects of LH are mainly mediated via adenylate cyclase and increased cAMP levels. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated, and it appears that leukotrienes and prostaglandins, as well as plasmin, may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall, and plasmin, as well as possibly other proteolytic enzymes such as proteoglycanases, may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens. While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilation, and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH-induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
Steroids 1989 Nov
PMID:Mechanism of mammalian ovulation. 255 97

Preeclampsia is characterized by imbalances in the production rates of several arachidonic acid metabolites. There is a considerable amount of evidence to indicate that PGI2 production is decreased in preeclampsia. PGI2 is a potent vasodilator, an inhibitor of platelet aggregation, and an inhibitor of uterine contractility. Evidence is accumulating that TX production in preeclampsia is either increased or unchanged so that the ratio of TX to PGI2 favors TX. TX opposes the actions of PGI2 in that it is a potent vasoconstrictor, a stimulator of platelet aggregation, and a stimulator of uterine contractility. Therefore, an imbalance of increased TX/decreased PGI2 production can account for the major clinical symptoms of preeclampsia. There is now preliminary evidence that the placenta produces lipoxygenase, as well as cyclooxygenase compounds. The hydroxyeicosatetranoic acids (5-HETE, 12-HETE, 15-HETE) and LTB4 have been identified as placental products. The preeclamptic placenta appears to be deficient in the 5- and 12-lipoxygenase enzymes, as indicated by placental production of 5-HETE and 12-HETE. Little is known about the regulation of arachidonic acid metabolites in normal or preeclamptic pregnancies. Steroids are known to affect cyclooxygenase product production. Progesterone, for example, inhibits PGI2 production. Although circulating and urinary concentrations of progesterone do not differ between normal and preeclamptic pregnancies, there is one report that placental progesterone concentrations are higher in preeclampsia; this may partially explain the decreased placental production of PGI2. There is a considerable amount of evidence in various tissues that regulatory interactions exist between the cyclooxygenase and lipoxygenase metabolites of arachidonic acid, but the role of these interactions in preeclampsia is not known. There is still much to be learned about the etiology of preeclampsia, but it is certain that aberrations in the production of arachidonic acid metabolites play an important role. It is likely that the effective treatment of preeclampsia will come from understanding the regulation of the arachidonic acid metabolites during pregnancy, and, therefore, the ability to specifically treat the production imbalances that characterize this disorder.
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PMID:The role of arachidonic acid metabolites in preeclampsia. 303 19

Steroids and cyclooxygenase inhibitors have been advocated as adjunctive treatment for sepsis. We studied the influences of these treatments on the survival of 98 male Sprague-Dawley rats in which sepsis was induced by cecal ligation and puncture. Rats received one of four treatments: sodium chloride (NaCl); methylprednisolone, 30 mg/kg (MP); ibuprofen, 12.5 mg/kg (I); methylprednisolone, 30 mg/kg, plus ibuprofen, 12.5 mg/kg (MP + I). Cumulative survival statistics were determined daily for 14 days thereafter. Survival was not altered by either MP or I when compared to animals receiving NaCl only. However, the combination of MP + I increased mortality from day 2 through day 14. The authors conclude that (1) MP administration alone does not increase mortality in septic rats; therefore, the results do not support the contention that steroid treatment in the absence of antibiotic therapy may be detrimental; (2) the cyclooxygenase inhibitor I does not improve survival in septic rats; and (3) the combined administration of MP and I increases mortality in septic rats and the possibility that this combination might be harmful in septic patients should be considered also.
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PMID:Methylprednisolone plus ibuprofen increases mortality in septic rats. 650 29

Arachidonic acid can be metabolized to diverse products which differ widely in their biological activities. These metabolites affect basic biological mechanisms such as vascular reactivity and transport function in critical nephron segments. Metabolism of arachidonic acid is discretely localized to specific cells and differs within segments of the nephron; for example, cells of the medullary ascending limb of Henle's loop have a considerable capacity to generate cytochrome P450-dependent arachidonate metabolites but have negligible cyclooxygenase activity. Arachidonic acid metabolites participate in fluid and electrolyte homeostasis, and in the regulation of tissue blood flow, and act as modulators of vasoactive hormones, and, thereby, make important contributions to integrated renal function.
Steroids 1993 Dec
PMID:The contribution of cytochrome P450-dependent arachidonate metabolites to integrated renal function. 811 12

1,25-(OH)2D3 (1,25) exerts its effects on growth plate chondrocytes through classical vitamin D (VDR) receptor-dependent mechanisms, resulting in mineralization of the extracellular matrix. Recent studies have shown that membrane-mediated mechanisms are involved as well. 1,25 targets cells in the prehypertrophic and upper hypertrophic zones of the costochondral cartilage growth plate (GC cells), resulting in increased specific activity of alkaline phosphatase (ALP), phospholipase A2 (PLA2), and matrix metalloproteinases (MMPs). At the cellular level, 1,25 action results in rapid changes in arachidonic acid (AA) release and re-incorporation, alterations in membrane fluidity and Ca ion flux, and increased prostaglandin E1 and E2 (PGE2) production. Protein kinase C (PKC) is activated in a phospholipase C (PLC) dependent-mechanism, due in part to the increased production of diacylglycerol (DAG). In addition, AA acts directly on the cell to increase PKC specific activity. AA also provides a substrate for cyclooxygenase (COX), resulting in PGE2 production. 1,25 mediates its effects through COX-1, the constitutive enzyme, but not COX-2, the inducible enzyme. Time course studies using specific inhibitors of COX-1 show that AA stimulates PKC activity and PKC then stimulates PGE2 production. PGE2 acts as a mediator of 1,25 action on the cells, also stimulating PKC activity. The rapid effects of 1,25 on PKC are nongenomic, occurring within 3 min and reaching maximal activation by 9 min. It promotes translocation of PKC to the plasma membrane. When 1,25 is incubated directly with isolated plasma membranes, PKCalpha is stimulated although PKCzeta is also present. In contrast, when isolated matrix vesicles (MVs) are incubated with 1,25, PKCzeta is inhibited and PKCalpha is unaffected. These membrane-mediated effects are due to the presence of a specific membrane vitamin D receptor (mVDR) that is distinct from the classical cytosolic VDR. Studies using 1,25 analogs with reduced binding affinity for the classical VDR, confirm that rapid activation of PKC by 1,25 is not VDR dependent. The membrane-mediated effects of 1,25 are critical to the regulation of events in the extracellular matrix produced by the chondrocytes. MVs are extracellular organelles associated with maturation of the matrix, preparing it for mineralization. MV composition is under genomic control, involving VDR-mechanisms. In the matrix, no new gene expression or protein synthesis can occur, however. Differential distribution of PKC isoforms and their nongenomic regulation by 1,25 is one way for the chondrocyte to control events at sites distant from the cell. GC cells contain 1a-hydroxylase and produce 1,25; this production is regulated by 1,25, 24,25, and dexamethasone. 1,25 stimulates MMPs in the MVs, resulting in increased proteoglycan degradation in mineralization gels, and increased activation of latent transforming growth factor-beta 1 (TGF-beta1).
Steroids
PMID:1,25-(OH)2D3 modulates growth plate chondrocytes via membrane receptor-mediated protein kinase C by a mechanism that involves changes in phospholipid metabolism and the action of arachidonic acid and PGE2. 1032 81

The hypothesis tested in the present work is that estrone non-genomically regulates aortic nitric oxide synthase (NOS) and cyclooxygenase (COX) activities in female rats, and that such regulation depends on ovarian function. We found that physiological concentrations of estrone (E(1)) (0.1-10nM) significantly increased nitric oxide (NO) production (133 and 163% above control). The stimulatory action of E(1) on NOS activity was independent of calcium influx since the increase in NO elicited by the hormone was not affected by EGTA or verapamil. When COX activity was measured, we observed that estrone enhanced thromboxane (TXB(2)) production and prostacyclin (PGI(2)) release, but not prostaglandin (PGF(2), PGD(2), and PGE(2)) synthesis. Finally we demonstrated that the hormonal effect on NOS activity was not detected in rat aortic strips (RAS) isolated from animals deprived of ovarian activity (FR(-)) or ovariectomized rats (OVX). These results suggest that estrone exerts a direct, non-genomic action on rat aortic metabolism, which involves NOS and COX activation and depends on ovarian activity.
Steroids 2005 Apr
PMID:Novel action of estrone on vascular tissue: regulation of NOS and COX activity. 1578 80

The principal secreted estrogen, 17beta-estradiol rapidly activates signaling cascades that regulate important physiological processes including ion transport across membranes, cytosolic pH and cell proliferation. These effects have been extensively studied in the MCF-7 estrogen-responsive human breast carcinoma cell line. Here, we demonstrate that a physiological concentration of 17beta-estradiol caused a rapid, synchronous and transient increase in intracellular calcium concentration in a confluent monolayer of MCF-7 cells 2-3 min after treatment. This response was abolished when cells were pre-incubated with the phospholipase A(2) (PLA(2)) inhibitor quinacrine or with the cyclooxygenase inhibitor indomethacin. The translocation of GFP-cPLA(2)alpha to perinuclear membranes occurred 1-2 min after 17beta-estradiol treatment; this translocation was concurrent with the transient phosphorylation of cPLA(2)alpha at serine residue 505. The phosphorylation and translocation of cPLA(2) were sensitive to inhibition of the extracellular signal regulated kinase (ERK) signaling cascade and occurred simultaneously with a transient activation of ERK. The phosphorylation of cPLA(2) could be stimulated by membrane impermeable 17beta-estradiol conjugated to bovine serum albumen and was blocked by an antagonist of the classical estrogen receptor. Here we show, for the first time, that PLA(2) and the eicosanoid biosynthetic pathway are involved in the 17beta-estradiol induced rapid calcium responses of breast cancer cells.
Steroids 2006 Mar
PMID:Estrogen induces phospholipase A2 activation through ERK1/2 to mobilize intracellular calcium in MCF-7 cells. 1637 35

Previously we demonstrated that estrone non-genomically regulates rat aortic NOS and COX activity and that this effect depends on ovarian activity. The purpose of the present study was to characterize this effect and investigate the participation of phospholipase C and phophatidylinositol-3-kinase system in the intracellular transduction pathway involved in the response. Using aortic strips isolated from female fertile rats we showed that estrone stimulate nitric oxide synthase and cyclooxygenase in a short time interval (5-20 min), and that NO production was dependent in part on PGI2 production since 1 microM indomethacin significantly reduced this free radical production. Injection of 17-beta-estradiol to ovariectomized rats restored tissue capacity to rapidly increase NO production in response to "in vitro" treatment with 1 nM estrone. We also demonstrated that in aortic strips isolated from intact animals estrone elicited a rapid phospholipase C activation, inducing a biphasic increase in diacylglycerol generation (peaking at 45 s and 5 min). The presence of protein kinase C inhibitor chelerythrine did not prevent the increase of NO released in response to hormone treatment. We proved that PI3K-Akt system does not mediate NOS and COX activation. However, PLC activation was dependent on PI3K since presence of LY 294002 in the incubation medium abolished estrone-induced DAG increment. We concluded that, estrone rapid action on vascular tissue involves a cross talk between NOS and COX system, and the activation of PLC/DAG/PKC transduction pathways.
Steroids 2006 Oct
PMID:Signal transduction pathways involved in non-genomic action of estrone on vascular tissue. 1686 Aug 31

7alpha-Hydroxy-DHEA, 7beta-hydroxy-DHEA and 7beta-hydroxy-EpiA are native metabolites of dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA). Since numerous steroids are reported to interfere with inflammatory and immune processes, our objective was to test the effects of these hydroxysteroids on prostaglandin (PG) production and related enzyme gene expression. Human peripheral blood monocytes were cultured for 4 and 24 h in the presence of each of the steroids (1-100 nM), with and without addition of TNF-alpha (10 ng/mL). Levels of PGE(2), PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) were measured in the incubation medium, and cell content of cyclooxygenase (COX-2), and PGE and PGD synthases (m-PGES1, H-PGDS, L-PGDS), and peroxisome proliferator activated receptor (PPAR-gamma) was assessed by quantitative RT-PCR and Western blots. Addition of TNF-alpha resulted in elevated PG production and increased COX-2 and m-PGES1 levels. Among the three steroids tested, only 7beta-hydroxy-EpiA decreased COX-2, m-PGES1 and PPAR-gamma expression while markedly decreasing PGE(2) and increasing 15d-PGJ(2) production. These results suggest that 7beta-hydroxy-EpiA is a native trigger of cellular protection through simultaneous activation of 15d-PGJ(2) and depression of PGE(2) synthesis, and that these effects may be mediated by activation of a putative receptor, specific for 7beta-hydroxy-EpiA.
Steroids 2008 Oct
PMID:7beta-Hydroxy-epiandrosterone-mediated regulation of the prostaglandin synthesis pathway in human peripheral blood monocytes. 1855 3

The purpose of this study was to investigate the effect of progesterone (Pg) on cellular growth, migration, apoptosis, and the molecular mechanism of action displayed by the steroid. To that end, rat aortic vascular smooth muscle cell (VSMC) cultures were employed. Pg (10nM) significantly increased [(3)H]thymidine incorporation after 24h of treatment. The enhancement in DNA synthesis was blunted in the presence of an antagonist of Pg receptor (RU486 compound). The mitogenic action of the steroid was suppressed by the presence of the compounds PD98059 (MEK inhibitor), chelerythrine (PKC inhibitor), and indomethacin (cyclooxygenase antagonist) suggesting that the stimulation of DNA synthesis involves MAPK, PKC, and cyclooxygenase transduction pathways. The proliferative effect of the hormone depends on the presence of endothelial cells (EC). When muscle cells were incubated with conditioned media obtained of EC treated with Pg, the mitogenic action of the steroid declined. Wounding assays shows that 10nM Pg enhances VSMC migration and motility. The role of the steroid on programmed cell death was measured using DNA fragmentation technique. Four hours of treatment with 10nM Pg enhanced DNA laddering in a similarly extent to the apoptotic effect induced by the apoptogen hydrogen peroxide (H(2)O(2)). In summary the results presented provide evidence that Pg enhances cell proliferation, migration, and apoptosis of VSMC. The modulation of cell growth elicited by the steroid involves integration between genomic and signal transduction pathways activation.
Steroids 2010 Apr
PMID:Role of progesterone on the regulation of vascular muscle cells proliferation, migration and apoptosis. 2013 33


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