Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrroloquinoline quinone (PQQ) inhibited the chemiluminescence (CL) from mouse peritoneal cells initiated by zymosan, carrageenin and N-formyl-methionyl-leucyl-phenylalanine and CL generated by the xanthine-xanthine oxidase reaction and the lipid peroxidation in the rat brain homogenate. The inhibitory activity of PQQ was more potent than that of idebenone, alpha-tocopherol and ascorbic acid in all the three assay systems. In the xanthine-xanthine oxidase reaction, PQQ had no effect on the formation of uric acid at the concentration of CL inhibition. These results suggest that PQQ might have a radical scavenger-like activity. Structure-activity relationship of PQQ and its six related compounds showed that the 7- and 9-carboxyl groups of PQQ as well as the orthoquinone structure are responsible for the radical scavenger-like activity. In addition, the -NH group in the pyrrole ring of PQQ seemed to be essential for the antilipid peroxidative activity in the rat brain homogenate. When administered i.p., PQQ inhibited the development of 0.1% carrageenin-induced paw edema in rats. These results suggest that PQQ might have therapeutic effects on various diseases, of which development or exacerbation has been known to be associated with radical oxygens.
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PMID:New biological properties of pyrroloquinoline quinone and its related compounds: inhibition of chemiluminescence, lipid peroxidation and rat paw edema. 217 8

Rat pulmonary artery endothelial cells incubated with human serum that has been complement-activated by addition of cobra venom factor reveal a pronounced conversion of xanthine dehydrogenase to xanthine oxidase. This process requires the availability of the fifth component of complement (C5) but not the presence of other components (C2 and C6-C9). The phenomenon can be reproduced by addition to endothelial cells of purified human recombinant C5a but not C5a desArg or C3a. The enzyme conversion process is relatively rapid (occurring within 5-10 min), requires the presence of intact endothelial cells, and does not require protein synthesis. Similar effects on endothelial cells have been obtained with human recombinant tumor necrosis factor alpha and the chemotactic peptide N-formyl-Met-Leu-Phe. In contrast, bradykinin, recombinant human interleukin 1 beta, and phorbol ester lack this biological activity. These findings suggest novel effects of inflammatory mediators on endothelial cells.
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PMID:Mediator-induced activation of xanthine oxidase in endothelial cells. 280 79

To determine whether the effects of endotoxin on cultured lung endothelium involve proteolytic mechanisms, we incubated bovine pulmonary arterial endothelial cells with endotoxin in medium 199 + 10% fetal bovine serum (FBS) in the presence and absence of several proteinase inhibitors. Three chloromethyl ketone (CK) derivatives [N-tosyl-L-lysine (CK)-(TLCK), N-tosyl-L-phenylalanine CK(TPCK), methoxysuccinyl-Ala-Ala-Pro-Val CK(SPCK)] and a single synthetic proteinase substrate [N-alpha-p-tosyl-L-arginine methyl ester hydrochloride (TAME)] attenuated endotoxin-induced cytotoxicity (lactate dehydrogenase release) and prostacyclin production in a dose-related fashion. The most effective inhibitors of endotoxin-induced cytotoxicity were TLCK and TPCK. TLCK and TAME most effectively attenuated endotoxin-stimulated prostacyclin production. Two chemically unrelated substances, soybean trypsin inhibitor and alpha 1 proteinase inhibitor also attenuated the endotoxin response. In the absence of FBS or in the presence of 10% heat-inactivated FBS, antiproteases attenuated endotoxin-induced prostacyclin production but had less effect on cytotoxicity than with 10% FBS. We also measured the capacity of the CK inhibitors to scavenge superoxide radicals generated in a cell-free xanthine/xanthine oxidase system by measuring inhibition of cytochrome c reduction. Percent scavenging of superoxide by these inhibitors was as follows: TLCK, 62.7 +/- 5.8 (SE); TPCK, 83.9 +/- 7.7; TAME, 24.5 +/- 6.4; SPCK, 0. We conclude that certain proteinase inhibitors attenuate endotoxin-induced endothelial cytotoxicity and prostacyclin production and that direct scavenging of superoxide radicals fails to explain the protective effects of proteinase inhibition. We speculate that the effects of endotoxin on lung endothelium may involve proteolytic mechanisms even in the absence of neutrophils.
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PMID:Antiproteinases protect cultured lung endothelial cells from endotoxin injury. 284 19

Human monocytes require serum components immunoglobulin G, C3/C3b, and B/Bb to exert optimal microbicidal action against ingested microorganisms. The present study was performed to find out whether these factors act by enhancing oxygen-dependent antimicrobial mechanisms. Serum enhanced oxygen consumption and superoxide production by monocytes before phagocytosis, but did not further increase these processes in monocytes that had recently ingested bacteria. Furthermore, serum did not boost iodination during intracellular killing by monocytes. Phorbol myristate acetate, N-formyl-methyonyl-leucyl-phenylalanine, concanavalin A, and concanavalin A-Sephadex all stimulated the conversion of O2 to H2O2 by monocytes, but only concanavalin A augmented intracellular killing. Reactive oxygen intermediates generated by cell-free enzymes (xanthine oxidase or glucose oxidase) in concentrations comparable to those accumulating extracellularly during incubation of monocytes containing bacteria with phorbol myristate acetate did not promote intracellular killing. The presence of catalase during phagocytosis inhibited killing, but had no effect on killing in the postphagocytic state. Monocytes deprived of glucose for 24 h showed markedly impaired O2 consumption, O2- generation, and bacterial killing; all of these effects were rapidly reversed by restoration of glucose. It is concluded that both an intact respiratory burst and extracellular serum factors are necessary for optimal killing of intracellular Staphylococcus aureus by human monocytes. Serum does not appear to act by enhancing the respiratory burst, but rather to have a separate, synergistic role, the biochemical basis of which is unknown.
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PMID:Relationship between extracellular stimulation of intracellular killing and oxygen-dependent microbicidal systems of monocytes. 298 74

The effects on neutrophil function of the new immunomodulatory agent fanetizole mesylate were studied. Fanetizole did not affect random or stimulated migration, phagocytosis, or degranulation by normal human neutrophils. Production of superoxide in response to the chemotactic factor formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) was markedly inhibited (41.3 +/- 3.9%) by 250 microM fanetizole. This inhibition was not due to scavenging of superoxide by fanetizole, as there was no impairment of superoxide detection in a cell-free xanthine-xanthine oxidase system. Inhibition was dose dependent (no effect seen with 1 or 10 microM fanetizole) and stimulus specific (no impairment of superoxide production in response to phorbol myristate acetate). Washing the cells after fanetizole treatment partially restored their superoxide response to f-Met-Leu-Phe. Suppression of neutrophil production of toxic oxygen metabolites may partially explain the antiarthritic effect of fanetizole, and study of such selective inhibitors may be useful in probing the contribution of neutrophils to inflammatory tissue damage.
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PMID:Inhibition of neutrophil superoxide production by fanetizole. 299 53

Using the superoxide dismutase inhibitable reduction of cytochrome c assay, we studied, the effect of (-) naloxone on N-formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated superoxide (O2-) release from human neutrophils. Neutrophils were pre-incubated with the range of concentrations of (-) naloxone that is administered in models of experimental sepsis (10(-6) - 10(-4.5) M). (-) Naloxone inhibited O2- release in a dose dependent manner. 02- produced by a cell-free xanthine-xanthine oxidase system was not inhibited by (-) naloxone, indicating that (-) naloxone was not scavanging O2-. There was no difference between the effect of (-) and (+) naloxone suggesting that the inhibition of O2- was not specific for an opiate receptor. Another opiate antagonist, nalorphine, as well as the opiate agonist, morphine, also inhibited O2- release in the same concentration range. There was no difference between the effect of naloxone and morphine.
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PMID:Naloxone inhibits superoxide release from human neutrophils. 299 44

Maintenance of an acidic intralysosomal compartment may be relevant to multiple aspects of neutrophil function. The effect of lysosomal alkalinization on the neutrophil respiratory burst was studied by measuring cytochrome c reduction in response to soluble stimuli in the presence of lysosomotropic weak bases. The weak bases chloroquine, ammonium chloride, methylamine, and clindamycin all raised the intralysosomal pH and inhibited neutrophil oxidative metabolism at concentrations ranging from 0.1 to 100 mmol/L. Inhibition was dose dependent for each base and correlated significantly with the degree of lysosomal alkalinization. Concentrations that did not alkalinize the lysosome did not inhibit the respiratory burst. Inhibition by weak bases was seen when oxidative metabolism was stimulated by phorbol myristate acetate, calcium ionophore A23187, formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, or sodium fluoride. Increasing the stimulus concentration (from 5 ng/mL to 5 micrograms/mL phorbol myristate acetate and from 0.5 to 1 mumol/L A23187) diminished or abolished inhibition by weak bases. Washing the cells after incubation with bases and before stimulation substantially reversed the inhibition. None of the bases impaired detection of superoxide in a cell-free xanthine-xanthine oxidase assay. Other indexes of oxidative metabolism, including oxygen consumption and hydrogen peroxide release, were also inhibited by weak bases. Analysis of particulate NADPH oxidase activity from neutrophils stimulated in the presence of bases suggested that these cells assemble a subnormal amount of an enzyme complex with normal kinetic characteristics. Lysosomotropic weak bases alkalinized the neutrophil lysosome and produced inhibition of oxidative metabolism that was dose related, was not stimulus specific, and was largely reversed by washing the cells before stimulation. A possible explanation would be altered assembly of the enzyme complex involved in respiratory burst activation as a consequence of impaired granule/plasma membrane fusion in the presence of diminished transmembrane pH gradients.
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PMID:Inhibition of neutrophil oxidative metabolism by lysosomotropic weak bases. 300 23

Hydroxyl radicals have been generated from hydrogen peroxide and superoxide (produced with xanthine oxidase), and an iron (EDTA) catalyst, and detected with deoxyribose, or in some cases with benzoate or alpha-keto-gamma-methiolbutyric acid. Purified myeloperoxidase, and neutrophils stimulated with fMet-Leu-Phe and cytochalasin B, strongly inhibited this hydroxyl radical production in a concentration-dependent manner. Supernatants from stimulated cells also inhibited, and inhibition by cells or supernatant was prevented by azide. There was much less inhibition by myeloperoxidase-deficient neutrophils. Inhibition thus was due to myeloperoxidase released by the cells. With neutrophils stimulated with phorbol myristate acetate, which release very little myeloperoxidase, hydroxyl radical production was enhanced due to the additional superoxide produced by the cells. It is concluded that under conditions where neutrophils release myeloperoxidase as well as superoxide and hydrogen peroxide, breakdown of hydrogen peroxide by myeloperoxidase would make conditions unfavorable for hydroxyl radical production.
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PMID:Myeloperoxidase as an effective inhibitor of hydroxyl radical production. Implications for the oxidative reactions of neutrophils. 301 31

The effects of antirheumatic drugs on superoxide anion (O2-.) production by human polymorphonuclear leukocytes (PMNL) activated in vitro with phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) were investigated. Chloroquine (CLQ), auranofin (AF) and chlorotriethylphosphine gold (CTEP-G) at 10(-6) to 10(-4) M inhibited PMA and fMLP induced O2-. production in a dose dependent fashion. These drugs had no effect on O2-. production by the hypoxanthine/xanthine oxidase system, indicating that their inhibitory effects were directed at the O2-. generating mechanism and that they were not scavengers of the O2-. formed. AF and CTEP-G inhibited the specific binding of 3H fMPL to PMNL membrane receptors, whereas CLQ had no effect. Colchicine (COL) and gold sodium thiomalate (GSTM) on the other hand did not significantly affect PMA and fMLP induced O2-. production or the specific binding of the ligands to PMNL. The antirheumatic drugs had no effect on isolated neutrophil membrane protease, a chymotrypsin-like enzyme that has been implicated in the activation of NAD(P)H oxidase. However, several of the drugs inhibited the enzymatic activity of a subcellular preparation of PMNL NAD(P)H oxidase, the order of potency being GSTM greater than CLQ greater than penicillamine greater than COL greater than AF approximately equal to CTEP-G. The isolated NAD(P)H oxidase was also inhibited by the thiol compounds--thiomalic acid and dithiothreitol, suggesting that the mechanism of inhibition may involve sulfhydryl-disulfide interchange reactions.
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PMID:Interactions of antirheumatic drugs with the superoxide generation system of activated human polymorphonuclear leukocytes. 301 58

We have found that pretreatment of human neutrophils with ibuprofen (0.10-1.0 mg/ml) results in an irreversible, concentration-dependent inhibition of superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme) stimulated by the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, and to a lesser extent by serum opsonized zymosan. Inhibition of granule exocytosis and oxygen radical generation at ibuprofen concentrations less than 5 mg/ml was not due to drug cytotoxicity since release of the cytoplasmic enzyme lactate dehydrogenase was not affected by ibuprofen. In contrast to neutrophil responses mediated by C5a or FMLP, ibuprofen did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate. Ibuprofen did not function as an oxygen radical scavenger in a cell-free system in which superoxide anion was generated by the aerobic action of xanthine oxidase on hypoxanthine. Ibuprofen also inhibited in a concentration-dependent fashion both directed migration (chemotaxis) and stimulated random migration (chemokinesis) of neutrophils exposed to either FMLP or C5a. Inhibition of neutrophil adherence to plastic surfaces and bovine pulmonary artery endothelial cells was equally effective when the neutrophils were treated with ibuprofen before stimulation with FMLP or phorbol myristate acetate. The inhibitory effects of ibuprofen pretreatment of neutrophils could not be overcome by addition of prostaglandins E1 or E2 (0.3-300 nM). These results demonstrate that ibuprofen is capable of suppressing many functions thought to be important in neutrophil-mediated acute pulmonary inflammatory processes. Results of these experiments further suggest that ibuprofen may inhibit neutrophil functions by acting on cellular components separate from membrane receptors or by blockade of cyclo-oxygenase products which may be involved in these neutrophil functions.
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PMID:Inhibition of human polymorphonuclear leukocyte functions by ibuprofen. 303 52


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