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At least 1,027 records · Page 57Linked to original sources
PubMed2000

Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation.

Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) isoforms. We have investigated the time-course of regulation and the role of COX-2 and iNOS in a model of experimental inflammation in mice, the air pouch injected with zymosan. This study demonstrates that there is an early acute phase (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2) produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of both iNOS and COX-2. These enzymes were detected in migrating leukocytes as well as in macrophages lining the air pouch. Administration of NS398 or indomethacin inhibited PGE2 levels and COX activity, but also nitrite levels and iNOS activity, which was accompanied by a reduction in iNOS expression. Aminoguanidine inhibited nitrite levels and iNOS activity in addition to exerting inhibitory effects on the COX pathway. Treatment of animals with dexamethasone reduced nitrite and PGE2 concentrations in air pouch exudates, as well as iNOS and COX-2 expression in migrating cells. Our results indicate that PGE2 and NO may play in vivo mutual modulatory roles in the inflammatory response caused by zymosan injection into the mouse air pouch, a suitable model to study drugs acting on those pathways.

Animals↗
PubMed2006

Novel bacterial sulfur oxygenase reductases from bioreactors treating gold-bearing concentrates.

The microbial community and sulfur oxygenase reductases of metagenomic DNA from bioreactors treating gold-bearing concentrates were studied by 16S rRNA library, real-time polymerase chain reaction (RT-PCR), conventional cultivation, and molecular cloning. Results indicated that major bacterial species were belonging to the genera Acidithiobacillus, Leptospirillum, Sulfobacillus, and Sphingomonas, accounting for 6.3, 66.7, 18.8, and 8.3%, respectively; the sole archaeal species was Ferroplasma sp. (100%). Quantitative RT-PCR revealed that the 16S rRNA gene copy numbers (per gram of concentrates) of bacteria and archaea were 4.59 x 10(9) and 6.68 x 10(5), respectively. Bacterial strains representing Acidithiobacillus, Leptospirillum, and Sulfobacillus were isolated from the bioreactors. To study sulfur oxidation in the reactors, pairs of new PCR primers were designed for the detection of sulfur oxygenase reductase (SOR) genes. Three sor-like genes, namely, sor (Fx), sor (SA), and sor (SB) were identified from metagenomic DNAs of the bioreactors. The sor (Fx) is an inactivated SOR gene and is identical to the pseudo-SOR gene of Ferroplasma acidarmanus. The sor (SA) and sor (SB) showed no significant identity to any genes in GenBank databases. The sor (SB) was cloned and expressed in Escherichia coli, and SOR activity was determined. Quantitative RT-PCR determination of the gene densities of sor (SA) and sor (SB) were 1,000 times higher than archaeal 16S rRNA gene copy numbers, indicating that these genes were mostly impossible from archaea. Furthermore, with primers specific to the sor (SB) gene, this gene was PCR-amplified from the newly isolated Acidithiobacillus sp. strain SM-1. So far as we know, this is the first time to determine SOR activity originating from bacteria and to document SOR gene in bioleaching reactors and Acidithiobacillus species.

Acidithiobacillus↗
PubMed2003

The effect of postsurgical administration of a selective cyclo-oxygenase-2 inhibitor on the healing of intrabony defects following treatment with enamel matrix proteins.

Regenerative treatment with enamel matrix proteins (EMD) has been shown to promote regeneration in intrabony periodontal defects. However, up to now various postoperative regimens such as the routine administration of nonsteroidal anti-inflammatory drugs (NSAIDs) were often used in combination with enamel matrix proteins. Therefore, it cannot be excluded that the results might have been influenced by the effect of the postoperative medication. The aim of this randomized, controlled, blinded, clinical investigation was to determine the effect of postsurgical administration of a selective cyclo-oxygenase-2 inhibitor on the healing of intrabony periodontal defects following regenerative periodontal surgery with EMD. Twenty two patients, each of whom exhibited one deep intrabony defect, were randomly treated with either EMD plus a selective cyclo-oxygenase-2 (COX-2) inhibitor (test) or with EMD alone (control). The postoperative regimen consisted of oral administration of 12.5 mg rofecoxib twice daily for 14 days. The following parameters were recorded at baseline and at 6 months by the same calibrated and blinded investigator: plaque index (Pl), gingival index (GI), bleeding on probing (BOP), pocket depth (PD), gingival recession (GR), and clinical attachment level (CAL). Power analysis to determine superiority of the anti-inflammatory treatment showed that the available sample size would yield 70% power to detect a 1 mm difference. No statistical significant differences in any of the investigated parameters between the two groups were observed at baseline. The results show that, in the test group, mean PD decreased from 8.7+/-1.4 mm to 4.7+/-2.0 mm (P<0.001) and mean CAL from 9.7+/-2.0 mm to 6.5+/-2.1 mm (P<0.001). In the control group, mean PD decreased from 8.6+/-1.6 mm to 4.7+/-1.8 mm (P<0.001) and mean CAL from 9.5+/-1.6 mm to 6.5+/-2.2 mm (P<0.001). There were no significant differences between the two groups in any of the investigated parameters. Within the limits of the present study, it can be concluded that the systemic administration of a selective COX-2 inhibitor following regenerative periodontal surgery with EMD did not result in additional clinical improvements when compared to treatment with EMD alone.

Alveolar Bone Loss↗
PubMed2006

Dissociation and unfolding of inducible nitric oxide synthase oxygenase domain identifies structural role of tetrahydrobiopterin in modulating the heme environment.

The oxygenase domain of the inducible nitric oxide synthase, Delta65 iNOSox is a dimer that binds heme, L-Arginine (L-Arg), and tetrahydrobiopterin (H(4)B) and is the site for NO synthesis. The role of H(4)B in iNOS structure-function is complex and its exact structural role is presently unknown. The present paper provides a simple mechanistic account of interaction of the cofactor tetrahydrobiopterin (H(4)B) with the bacterially expressed Delta65 iNOSox protein. Transverse urea gradient gel electrophoresis studies indicated the presence of different conformers in the cofactor-incubated and cofactor-free Delta65 iNOSox protein. Dynamic Light Scattering (DLS) studies of cofactor-incubated and cofactor-free Delta65 iNOSox protein also showed two distinct populations of two different diameter ranges. Cofactor tetrahydrobiopterin (H(4)B) shifted one population, with higher diameter, to the lower diameter ranges indicating conformational changes. The additional role played by the cofactor is to elevate the heme retaining capacity even in presence of denaturing stress. Together, these findings confirm that the H(4)B is essential in modulating the iNOS heme environment and the protein environment in the dimeric iNOS oxygenase domain.

Animals↗
PubMed1990

The steroid antagonist RU38486 is metabolized by the liver microsomal P450 mono-oxygenases.

Microsomal preparations from adult male rat liver actively oxidized RU38486 into the 11 beta-monodemethylated, 11 beta-didemethylated and 17 alpha-hydroxylated derivatives, metabolites which are known to be formed in vivo. These oxidative reactions were inhibited at different degrees by P450 chemical inhibitors. Pretreatment of the animals by P450 mono-oxygenase prototype inducers led to drastic changes in RU38486 metabolization. Methylcholanthrene treatment carried out a significant decrease while phenobarbital markedly increased the metabolic activity of the liver microsomes. Moreover, antibodies to methylcholantrene-inducible P450 forms did not affect the metabolic activity while a complete blockade-of RU38486 oxidation was observed in the presence of antibodies to phenobarbital- inducible forms. The present results demonstrate that liver P450 mono-oxygenases are engaged in different oxidative steps of RU38486 metabolism and that phenobarbital-inducible but not methylcholanthrene-inducible P450 forms are active in RU38486 degradation.

Aging↗
PubMed1984

Effects of metyrapone and norharmane on microsomal mono-oxygenase and epoxide hydrolase activities.

This study was undertaken to examine the possibility that metyrapone and norharmane stimulate epoxide hydrolase and inhibit mono-oxygenase activities by binding to a cytochrome P-450 component of a stable complex containing the two enzymes. The concentration of metyrapone and norharmane which inhibited mono-oxygenase activities of hepatic microsomes from untreated and diethylnitrosamine treated rats was lower than that required to stimulate epoxide hydrolase of the same microsomes. The ability of metyrapone and norharmane to stimulate epoxide hydrolase in these microsomes was not inhibited by the addition of carbon monoxide and reductant. Epoxide hydrolase activity was inhibited by detergents but the enzyme was still stimulated by metyrapone and norharmane under conditions of total membrane disaggregation. When microsomes were solubilized, epoxide hydrolase could be quantitatively recovered by immunoprecipitation. The immunoprecipitate contained no detectable cytochrome P-450 but was stimulated by metyrapone and norharmane. A purified epoxide hydrolase was stimulated by metyrapone but not by norharmane. The response of the enzyme to norharmane was not restored by the inclusion of cytochrome P-448. These findings suggest that metyrapone and norharmane act at separate sites on both cytochrome P-450 and epoxide hydrolase.

Alkaloids↗
PubMed1978

The inhibition of cyclo-oxygenase of rabbit platelets by aspirin is prevented by salicylic acid and by phenanthrolines.

Salicylic acid, 1,10- and 1,7-phenanthroline prevented inhibition by aspirin of platelet aggregation and of generation of thromboxane A2 due to arachidonic acid, to the ionophore A21387, to thrombin and to collagen. Dithiothreitol, another drug which prevents aggregation and formation of thromboxane A2, but only reversibly, failed to interfere with the inhibition by aspirin. Irreversible inhibition by indomethacin and by the substrate analogue 5,8,11,14-tetraynoic acid was also unaffected by salicylic acid or by 1,10-phenanthroline, which thus probably exert a specific interaction with the aspirin-binding site. Inactivation of platelet cyclo-oxygenase with arachidonic acid led to inhibition of the formation of thromboxane A2 and of aggregation due to arachidonic acid itself and to collagen, but barely affected aggregation by thrombin, even though generation of thromboxane A2 was blocked. Use of salicylic acid and of reversible inhibitors of cyclo-oxygenase may help to unravel the mechanism of inhibition due to other agents.

Animals↗
PubMed1984

Inhibition of human platelet cyclo-oxygenase activity by sulfinpyrazone and three of its metabolites.

Sulfinpyrazone and three of its major metabolites were compared in vitro for their inhibitory effect on human platelet cyclo-oxygenase activity. Sulfinpyrazone appeared to be about 15-20 times less potent than its sulfide metabolite (G25671) and 6-7 times less potent than the other two compounds, the sulfone metabolite (G31442) and p-hydroxysulfide (G33378). All four compounds were apparently competitive inhibitors of platelet cyclo-oxygenase activity. Comparison of the potency of sulfinpyrazone and its metabolites, as determined in the present study and the plasma levels previously measured in man, indicates that sulfinpyrazone and G33378 were not potent enough to be effective in man. G31442 showed inhibitory potency slightly lower than its corresponding plasma levels, whereas G25671 was effective at concentrations well below those found in human plasma. This study supports the hypothesis that sulfinpyrazone metabolites (in particular the sulfide) rather than the drug itself affect platelet function when administered therapeutically.

Arachidonic Acid↗
PubMed1985

Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate.

The ulcerogenic actions of aspirin and sodium salicylate in cat gastric antrum following intravenous injection, and their effects on the synthesis of two major cyclo-oxygenase products by antral mucosa have been determined. Near-maximal rates of gastric acid secretion were stimulated by histamine, infused i.v. for 1 h prior to bolus injection of aspirin or salicylate and throughout the subsequent 4 h. The area of lesions in the cat gastric antrum were then assessed macroscopically and the generation of both 6-oxo-PGF1 alpha and PGE2 from strips of antral mucosal tissue following 1 min vortex-incubation was determined by radioimmunoassay. The plasma and mucosal-tissue levels of both aspirin and salicylate were determined using HPLC techniques. Aspirin (0.2 mmol. kg-1 i.v.) induced substantial deep antral ulceration during the 4 h histamine infusion, whereas sodium salicylate (0.2 mmol. kg-1 i.v.) caused no significant macroscopic damage. Sodium salicylate likewise caused no significant inhibition in the ex vivo generation of either 6-oxo-PGF1 alpha or PGE2, whereas aspirin induced 92 +/- 3 and 97 +/- 1% inhibition of generation of these prostanoids respectively. The levels of total salicylate in plasma and mucosal tissue were comparable following bolus i.v. injection of aspirin or sodium salicylate. These observations support the concept that cyclo-oxygenase inhibition is an important mechanism underlying deep gastric ulceration induced by aspirin, when administered parenterally in the cat.

Animals↗
PubMed1983

Preferential utilization of endogenous arachidonate by cyclo-oxygenase in incubations of human platelets.

Thromboxane B2 (TXB2) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) formed from the endogenous and exogenous arachidonate during human platelet incubation, was evaluated by selected ion monitoring (SIM). TXB2 formed from endogenous substrate accounted for about one third of the total, whereas the great part of 12-HETE derived from exogenous arachidonate. These data indicate that under the tested conditions the pool of arachidonate that acts as substrate for cyclo-oxygenase is different from the pool that acts as substrate for lipoxygenase and that the arachidonate released from phospholipids is preferentially utilized by cyclo-oxygenase.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1992

Possible induction of fatty acid cyclo-oxygenase in lipopolysaccharide-stimulated rat Kupffer cells.

In response to stimulation with lipopolysaccharide, isolated rat Kupffer cells released increased amounts of prostaglandin E2, prostaglandin D2, 6-keto-prostaglandin F1 alpha, and thromboxane B2. There was a lag of 2-6 hours before a significant release of these metabolites into the medium was detected. Nonstimulated Kupffer cells converted exogenous arachidonic acid to prostaglandins and thromboxane B2, and a major product was prostaglandin D2. Twenty-four hours after stimulation with lipopolysaccharide, Kupffer cells produced approximately 7 times more prostaglandin E2 and 2 times more prostaglandin D2, 6-keto-prostaglandin F1 alpha; and thromboxane B2 than nonstimulated cells. Western immunoblotting of microsomal proteins prepared from the stimulated rat Kupffer cells showed a 70-kilodalton component that was immunoreactive with a polyclonal anticyclo-oxygenase antibody. The intensity of the band increased with the time of the lipopolysaccharide stimulation. These results suggest that the accelerated arachidonate metabolism in lipopolysaccharide-stimulated rat Kupffer cells might be attributed to an induction of the cyclo-oxygenase enzyme.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Platelet-activating factor-induced vasoconstriction in rat isolated, perfused hearts: contribution of cyclo-oxygenase and lipoxygenase arachidonic acid metabolites.

The mechanism of the coronary vasoconstrictor action of platelet-activating factor (PAF) has been investigated in rat isolated, perfused hearts. PAF elicited an increase in coronary perfusion pressure which was attenuated by indomethacin- or diethylcarbamazine- pretreatment, whereas FPL55712 had a marked inhibitory effect. Accompanying the coronary vasoconstrictor response to PAF was an increase in the release of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TxB2 and the appearance of biologically-active concentrations of LTB4 and LTC4 in the cardiac effluent. Indomethacin-pretreatment prevented the increase in release of the measured cyclo-oxygenase metabolites without significantly altering the generation of either LTB4 or LTC4. Diethylcarbamazine markedly inhibited the PAF-induced release of both cyclo-oxygenase and lipoxygenase products. These findings suggest a causal role for vasoconstrictor arachidonic acid metabolites in the acute cardiac effects of PAF with the quantitatively most important contribution to the vasoconstriction made by LTC4.

Animals↗
PubMedDate not supplied

Cyclo-oxygenase inhibitors in ophthalmology.

Cyclo-oxygenase inhibitors, which are formulated as ophthalmic eyedrop preparations, have recently become commercially available for use by ophthalmologists in the United States to inhibit intraoperative miosis during cataract surgery and to prevent postoperative inflammation. In addition, they are available worldwide as ocular antiinflammatory drugs and are used in the prevention and treatment of pseudophakic and aphakic cystoid macular edema. Understanding the rationale behind the use of these agents requires an understanding of the pathophysiology of the cyclo-oxygenase inhibitors. In this review recent advances in laboratory and clinical science are emphasized. The role of COIs during and following surgery is examined.

Animals↗
PubMed1982

Low-dose aspirin inhibits platelet and venous cyclo-oxygenase in man.

In a group of normal subjects we have compared rates of recovery of venous prostacyclin (PGI2) and platelet thromboxane B2 (TXB2) production after a single 300 mg dose of aspirin. Marked inhibition of both venous PGI2 synthesis and platelet TXB2 synthesis persisted for the 72 hours duration of the study. We also examined the effect of four daily doses of 40 mg aspirin on platelet and vessel wall prostaglandin biosynthesis. This produced a cumulative inhibitory effect on TXB2 production with 98.6 per cent mean inhibition at 72 hours. At this time 81-100 per cent inhibition of PGI2 was demonstrated in the four subjects studied. We conclude that the cyclo-oxygenase enzyme in human vein is sensitive to inhibition by very low doses of aspirin. No evidence was found to substantiate the view that rapid recovery of vessel wall cyclo-oxygenase activity occurs after inhibition by a single dose of aspirin.

Aspirin↗
PubMed1982

Indomethacin prevents the long-lasting inhibitory effect of aspirin on human platelet cyclo-oxygenase activity.

Aspirin and indomethacin do interact with the same site on cyclo-oxygenase. This suggestion is based on in vitro studies on ram seminal vesicles and in vivo drug interaction studies on rat platelets. The purpose of the present study was to ascertain whether the same interaction also occurred after administration of both drugs to human volunteers. Platelet aggregation induced by sodium arachidonate or by collagen, and formation of platelet MDA and TxB2 were measured before, two and 48 hours after ingestion of either indomethacin (50 mg) or aspirin (500 mg) or of both drugs (30 minutes apart). While the inhibitory effect of indomethacin on these parameters was short lasting, that of aspirin persisted for at least 48 hours. However, when both drugs were given concurrently, the long-lasting effect of aspirin was no longer detectable. Since competition at levels other than platelets was unlikely, this study indicates that indomethacin and aspirin inhibit human platelet cyclo-oxygenase by the same basic mechanism. Acetylation of the enzyme appears to be a secondary mechanism which makes the inhibitory effect of aspirin persistent.

Adult↗
PubMed1984

2-(6-carboxyhexyl)cyclopentanone hexylhydrazone: a potent inhibitor of the blood platelet cyclo-oxygenase.

Previous studies have demonstrated that 13-azaprostanoic acid (13-APA) is a potent and specific antagonist of thromboxane A2/prostaglandin H2 (TXA2/PGH2) at the platelet receptor level. In the present study we evaluated the effects of a new azaprostanoid , 2-(6- carboxyhexyl ) cyclopentanone hexylhydrazone (CPH), on human platelet function. This hydrazone was found to completely inhibit arachidonic acid (AA)-induced platelet aggregation at 1 microM CPH. On the other hand, CPH was not an effective inhibitor of PGH2-induced aggregation. Furthermore, 100 microM CPH was completely ineffective in blocking platelet aggregation stimulated by adenosine diphosphate (ADP) or the stable prostaglandin endoperoxide analog U46619 (which presumably acts at the TXA2/PGH2 receptor). Measurement of platelet thromboxane B2 (TXB2) production demonstrated tha the primary site-of-action of CPH is at the cyclo-oxygenase level. Thus, CP inhibited TXB2 formation from AA in a dose-dependent manner (0.1 microM-100 microM CPH)2. In contrast, CPH blocked TXB2 production from PGH2 only at the highest CPH concentration tested, i.e., 100 microM. These results indicate that relative to 13-APA, addition of a second nitrogen at C14 and a double bond between the 12- and 13- positions results in a loss of receptor activity but produces a high affinity for the platelet cyclo-oxygenase.

Arachidonic Acid↗
PubMed1986

The coronary vasodilator mediator released by hypoxia and isoprenaline is not affected by cyclo-oxygenase inhibition.

Donor and recipient guinea-pig hearts were perfused in series, the recipient being perfused with regassed donor effluent. Coronary perfusion pressure and force and rate of contraction were measured. Exposure of donor hearts to hypoxia (1.5 min) and to isoprenaline (5 ng) caused the appearance of vasodilator material in recipient hearts, the direct beta-adrenoceptor effects of isoprenaline carried over in the effluent being antagonized in the recipient by propranolol. Cyclo-oxygenase was inhibited by infusion of meclofenamate (60 micrograms X min-1) which consistently abolished the vasodilator responses to arachidonic acid added to the donor. The vasodilator responses of the donor to hypoxia and isoprenaline were unaffected by meclofenamate. The falls in perfusion pressure of the recipient in response to material released by these procedures were also not significantly different before (hypoxia, 11.5 +/- 2.6mm Hg; isoprenaline, 10.3 +/- 1.3mm Hg) and during the infusion (hypoxia, 10.2 +/- 4.1; isoprenaline, 11.0 +/- 1.3mm Hg). The coronary vasodilator responses to hypoxia and isoprenaline and the vasodilator material released by these procedures do not therefore appear to be due to products of arachidonic acid via cyclo-oxygenase pathways. Furthermore, since there was also no potentiation of the responses, there does not appear to be a concomitant release of a prostanoid to inhibit the major vasodilator material. Adenosine, as the likely candidate for this predominant vasodilator mediator, is discussed.

Animals↗
PubMed1981

Release of slow-reacting substance of anaphylaxis from dispersed pig lung cells: effect of cyclo-oxygenase and lipoxygenase inhibitors.

Study of the release of slow-reacting substance of anaphylaxis (SRS-A) from lung cells has been hampered by the lack of suitable animal model. Using both immunologic and pharmacologic stimuli, we have obtained histamine and SRS-A release from dispersed pig lung cells containing 6% mast cells (with a histamine content of 1.9 pg/cell). Lung cells dispersed from actively sensitized (with intratracheal Ascaris antigen) but not unsensitized pigs released both histamine (mean net release 33%) and SRS-A (mean release, 47 units/10(7) cells) when challenged with Ascaris antigen. Greater release of histamine (mean net release 52%) and of slow-reacting substance (SRS) (mean release 701 units/10(7) cells) was induced by challenge with the calcium ionophore A23187. The pharmacologic and physicochemical characteristics of the SRS together with its profile of enzymatic inactivation resembled those described for SRA-A released from human lung. Both antigen-induced and A23187-induced SRS(-A) release were enhanced by indomethacin, a cyclo-oxygenase inhibitor, but inhibited by both phenidone (IC50 35 microM) and eicosatetraenoic acid (IC50 15 microM), inhibitors of both cyclo-oxygenase and lipoxygenase, confirming that generation of SRS(-A) by either stimulus required an intact lipoxygenase pathway of arachidonic acid metabolism.

Animals↗