Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ab initio, quantum chemical methods have been used to study the possible modes of binding of benzoic and salicylic acids to cyclooxygenase which lead to their anti-inflammatory action. The biological data for this work were obtained from full dose response curves of the inhibitory potency of active compounds on prostaglandin production in mouse macrophages. With the help of simple regression analysis the most important reactivity indices are identified and the ionization state of the active species is discussed. From the physical significance implied by these regressions and an analysis of the electronic charge distributions of the frontier orbitals, a two-way charge transfer model is proposed. The electrostatic potentials of active and inactive congeners have been analyzed, and it is shown that an electrostatic orientation effect seems to make an important contribution to the binding of the active molecules to their receptor site. An electrostatic potential model of the binding site is proposed, and it is shown that this model is able to rationalize the source of activity or inactivity of the investigated substances.
Mol Pharmacol 1987 Mar
PMID:Electronic determinants of the anti-inflammatory action of benzoic and salicylic acids. 303 44

Rat renal mesangial cells possess morphological and functional features of smooth muscle cells in culture, such as intracellular myosin filaments, A II receptors and a contractile response to A II. Furthermore, they represent the main glomerular site of PGE2 synthesis. In the presence of A II (50 nM), their PGE2 production rate was significantly increased, this effect being potentiated by arachidonic acid (3 micrograms/ml). After a prior inhibition of arachidonic acid metabolism by cyclooxygenase inhibitors (indomethacin 1 microM or naproxen 0.02 microM) or by a cyclo- and lipoxygenase inhibitor (phenidone 670 microM), the percentage of cells contracting in response to various A II concentrations (10 pM to 10 nM) was significantly enhanced as compared to the basal conditions. On the contrary, the percentage of cells presenting a contractile response to A II in the presence of exogenous PGE2 (50 ng/ml) or of arachidonic acid (3 micrograms/ml) was significantly decreased. These modifications were not related to some changes in the A II receptor properties of the cells, i.e. the number of receptor sites and their affinity constant. The data demonstrate that the contractile response of glomerular mesangial cells is modulated by the PGE2 content of their incubation medium. Since their own PGE2 production rate is enhanced in the presence of A II, this cellular response may represent a local regulatory mechanism of their contractile properties.
Mol Cell Endocrinol 1986 Sep
PMID:Glomerular mesangial cell contractility in vitro is controlled by an angiotensin-prostaglandin balance. 309 26

A kinetic scheme of the prostacyclin-thromboxane system has been evolved on the basis of the authors experimental data and the results described elsewhere. The kinetic behavior of the model has been analysed with the aid of computer technology by varying the following parameters: phospholipase activities, free arachidonic acid exchange rates between platelets and endothelium, PGH-synthetase biosynthesis rates, velocities of arachidonic acid pathways other than the cyclooxygenase ones. It has been demonstrated that the biological system is capable of sustaining prostacyclin and thromboxane concentrations at steady fixed levels within a wide range of kinetic parameters.
Mol Biol (Mosk)
PMID:[Kinetic model of a multienzyme system of blood prostanoid synthesis. I. Mechanism of stabilization of thromboxane and prostacyclin levels]. 309 45

We have investigated the role of phospholipid-sensitive calcium-dependent protein kinase (protein kinase C) in prostaglandin F2 alpha synthesis by monolayer cultures of swine granulosa cells. In this system, specific phorbol ester derivatives known to activate protein kinase C significantly augmented the production of prostaglandin F2 alpha. Phorbol ester in conjunction with the ionophore A23187 synergistically increased prostaglandin F2 alpha production. These stimulatory actions were dose- and time-dependent, and could be abolished by the cyclooxygenase inhibitor, indomethacin, or the protein synthesis inhibitor, cycloheximide. Moreover, the rank order of potency of phorbol esters in enhancing prostaglandin F2 alpha production was concordant with that demonstrated for activation of protein kinase C in the swine ovary. In addition, a nonphorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol, also significantly enhanced prostaglandin F2 alpha biosynthesis. The synthesis of immunoassayable prostaglandin F2 alpha was confirmed by high-pressure liquid chromatographic purification of this radiolabeled metabolite of [3H]arachidonic acid. Thus, the present studies indicate that the protein kinase C effector pathway in the swine granulosa cell is functionally coupled to prostaglandin F2 alpha production.
Mol Cell Endocrinol 1987 Feb
PMID:Activation of protein kinase C is coupled to prostaglandin F2 alpha synthesis in the ovary: studies in cultured swine granulosa cells. 310 13

We investigated whether the mitogenic response induced by local mast-cell secretion in the rat mesentery was affected by suppression of phospholipase A2, lipoxygenase, or cyclooxygenase in arachidonic acid metabolism. Enzyme inhibitor was given in a single intravenous dose 5 min before intraperitoneal injection of the mast-cell secretagogue 48/80. Mepacrine, a phospholipase A2 inhibitor, suppressed the generation of both leukotrienes (SRS) and prostaglandins (PG), whereas the lipoxygenase inhibitor BW 755C reduced the generation of SRS, and the cyclooxygenase inhibitor indomethacin significantly suppressed the generation of PG. None of the enzyme inhibitors affected the basal mesenteric histamine content or histamine release in the mesentery after exposure to 48/80, and none of them affected mast-cell-mediated mitogenesis in the mesentery as judged by specific DNA activity and mitosis counting. The stimulation of DNA synthesis and mitosis initiated by secreting mast cells is apparently not mediated or modulated by synthesis of leukotrienes, prostaglandins, or other known arachidonic acid metabolites.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:On the role of arachidonic acid metabolites in mast-cell mediated mitogenesis in the rat. 614 31

Deep dermal injuries elicit discrete reaction patterns dependent on the type of injury sustained. Full thickness burn injuries produce an avascular focus of dead and dying tissue surrounded by a peripheral zone of secondary vascular dilation. In contrast, equivalent freeze injuries demonstrate vascular patency both centrally and peripherally. The basis for these differences are unknown. Because of their potent vasoactive and hematologic properties, the presence of two endogenously generated eicosanoids, thromboxane A2 (Tx A2) and prostacyclin (PGI2), were examined in this process. Implanted stainless steel mesh chambers served as an in vivo interstitial collecting reservoir permitting repeated sampling of the wound fluid without tissue disruption. Standard burn and freeze injuries were administered to the skin covering the implanted chambers. The major metabolites of these eicosanoids: 6-keto PGF1 alpha and TxB2 were measured in wound fluid during the first 24 hr following injury. Although both TxB2 and 6-keto PGF1 alpha increased significantly following either injury, treatment with indomethacin did not alter the vascular sequelae despite evident cyclooxygenase inhibition. Latex infusion of whole rats confirmed the considerable difference between these two types of injury, with or without indomethacin. Thus, little evidence was found to support the importance of either TxA2 or PGI2 in the vascular alterations which follow burn or freeze injury.
Exp Mol Pathol 1983 Jun
PMID:The role of prostacyclin and thromboxane in rat burn and freeze injuries. 634 13

Nafazatrom, an antithrombotic and antimetastatic agent containing a pyrazolone functionality, is a reducing substrate for the peroxidase activity of prostaglandin H (PGH) synthase. Nafazatrom inhibits the hydroperoxide-dependent oxidation of phenylbutazone, stimulates the reduction of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, and is oxidized by microsomal or purified enzyme preparations from ram seminal vesicles. Consonant with the effects of other peroxidase-reducing substrates, nafazatrom stimulates the oxygenation of arachidonic acid to prostaglandin endoperoxides by the cyclooxygenase component of PGH synthase. In addition, nafazatrom causes an elevation in the levels of 6-keto-prostaglandin F1 alpha, the non-enzymatic hydrolysis product of prostacyclin (PGI2) biosynthesized from arachidonic acid by ram seminal vesicle microsomes. Elevation of PGI2 biosynthetic capacity by nafazatrom occurs under conditions in which prostaglandin endoperoxide biosynthesis is maximal, suggesting that nafazatrom has a stimulatory effect on the conversion of prostaglandin endoperoxides to PGI2. Nafazatrom has no effect on the ability of ram seminal vesicle microsomes to convert PGH2 to PGI2 but protects microsomal PGI2 synthase from inactivation by 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid. Nafazatrom stimulates PGI2 biosynthesis in ram seminal vesicle microsomes by acting as a substrate for the peroxidase-catalyzed reduction of hydroperoxy fatty acids that are irreversible inactivators of PGI2 synthase. Several other compounds, including dipyridamole and triiodothyronine, exert similar effects. This may contribute to the reported ability of nafazatrom and related compounds to elevate the levels of bioassayable PGI2 in vivo and to the antithrombotic and antimetastatic activities of nafazatrom.
Mol Pharmacol 1984 Sep
PMID:Mechanism of the stimulation of prostaglandin H synthase and prostacyclin synthase by the antithrombotic and antimetastatic agent, nafazatrom. 643 40

Neutrophils isolated from the pleural cavity of rats 3 hr after the intrapleural injection of carrageenan metabolize exogenously added arachidonic acid via cyclooxygenase and lipoxygenase. In addition, these cells esterify arachidonic acid to produce diarachidonyl diglyceride. The structure of the diglyceride was determined with the use of various chemical and enzymatic digestions, gas chromatography-mass spectrometry, and 252Cf plasma-desorption mass spectrometry. The formation of this unique diglyceride is stimulated by the presence of nonsteroidal anti-inflammatory drugs. Some of the possible consequences of diarachidonyl diglyceride production are discussed.
Mol Pharmacol 1982 May
PMID:The formation of diarachidonyl diglyceride by rat neutrophils. 681 89

Previous studies have shown upregulation of lung cell interleukin-6 (IL-6) production in bleomycin-induced pulmonary fibrosis. To further elucidate the regulatory mechanisms governing this disease, the effects of bleomycin on the production of the pleiotropic cytokine, IL-6, were investigated in lung endothelial cells. Rat pulmonary artery endothelial cells were treated with bleomycin at doses previously shown to be effective in upregulating cytokine production in these cells, and the conditioned media was collected and assayed for IL-6 activity. The results show that these endothelial cells constitutively produced IL-6 and that bleomycin increased the production in a time- and dose-dependent manner. Feeding rats diets deficient in n-6 fatty acids is known to ameliorate bleomycin-induced lung fibrosis. In order to examine if fatty acids could modulate IL-6 production in vitro, cells were lipid depleted and then supplemented with 18:1n-9, 18:2n-6, or 18:3n-3 fatty acids, and the effects of bleomycin on IL-6 production reexamined. This regimen resulted in significant depletion of arachidonate in the 18:1n-9 and 18:3n-3 supplemented cells, which was associated with significantly reduced IL-6 production relative to the 18:2n-6-supplemented cells, both constitutively and when stimulated with bleomycin. Preincubation with indomethacin did not significantly inhibit the production of IL-6 by all three groups of cells, nor did supplementation with a stable prostacyclin analog increase IL-6 production. These results suggest that endothelial cell IL-6 production is not directly dependent on prostacyclin or other cyclooxygenase metabolites but may require or be upregulated by 18:2n-6 and/or metabolites derived from it.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Dec
PMID:Regulation of rat pulmonary endothelial cell interleukin-6 production by bleomycin: effects of cellular fatty acid composition. 750 28

Airway wall remodeling, including hyperplasia of airway smooth muscle, is regarded as an important contributor to airway hyperresponsiveness in asthmatic patients. The effects of the proinflammatory cytokine, tumor necrosis factor alpha (TNF alpha) on the mitogenic responses of human cultured airway smooth muscle have been investigated. Lower concentrations of TNF alpha (0.3 to 30 pM) had a small, delayed (48-h incubation), stimulatory effect on DNA synthesis that was blocked by dexamethasone (1 microM), aspirin (100 microM), or primaquine (30 microM) pretreatment, indicating that this effect was secondary to the release of cyclooxygenase products. TNF alpha (300 pM; 24- to 48-h incubation) alone had no effect on cell number or DNA or protein synthesis, but markedly reduced the stimulatory effects of thrombin (0.3 U/ml). TNF alpha (300 pM) also inhibited mitogenic responses to fetal calf serum (10%), epidermal growth factor (300 pM), and the thromboxane A2 mimetic U46619 (100 nM), indicating a nonselective effect. The inhibitory effects of TNF alpha (300 pM) were not blocked by pretreating the cells with the cyclooxygenase inhibitor aspirin (100 microM), the 5-lipoxygenase inhibitor CGS 8515 (3 microM), or the nitric oxide synthase inhibitor nitro-iminoethyl-L-ornithine (100 microM), suggesting that neither arachidonic acid metabolites nor nitric oxide were mediators of the inhibitory effect. The phospholipase A2 inhibitor primaquine (30 microM) had no effect on the inhibitory responses to TNF alpha, whereas the anti-inflammatory steroid dexamethasone (1 microM) prevented TNF alpha inhibition of mitogenic responses. Thus, concentrations of TNF alpha, within the range detected in bronchoalveolar lavage fluid from asthmatics, suppress mitogenic responses by a mechanism that is sensitive to inhibition by anti-inflammatory steroids, but does not appear to involve established targets for modulation by steroids, including arachidonic acid metabolism or induction of nitric oxide synthase.
Am J Respir Cell Mol Biol 1995 Jan
PMID:Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. 752 28


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