Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Luteal development and demise are characterized by substantial tissue destruction and remodeling, which is associated with local production of plasminogen activation. Recently we reported involvement of tissue-type plasminogen activator (tPA) in luteolysis in rhesus monkeys. In this study, we further investigated changes in expression of both tPA and urokinase-type plasminogen activator (uPA) activity during various developmental stages of rat corpus luteum (CL) of pregnancy and their possible physiological roles in luteolysis. Rat CL or dispersed luteal cells in vitro are capable of producing both tPA and uPA, and a plasminogen activator inhibitor type-1, in a stage-dependent manner. However, only tPA activity significantly increases in late phases of CL development. Furthermore, the increase in tPA activity in the CL is well correlated with a sharp decrease in luteal progesterone production. Addition of exogenous tPA to the luteal culture considerably decreases progesterone production. In contrast, immunoneutralization of endogenously produced tPA activity by inclusion of tPA monoclonal antibody in the culture results in a significant increase in luteal progesterone production. It is therefore suggested that tPA may also be involved in suppression of rat luteal function. This hypothesis is further supported by the findings that interferon-gamma significantly inhibits luteal basal and hCG-stimulated progesterone production and also stimulates basal and hCG-induced tPA activity. On the basis of the data provided in this study and similar findings in monkeys, we conclude that endogenously produced tPA in late phase of CL development may regulate luteal regression through local autocrine or paracrine action.
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PMID:Studies on the role of plasminogen activators and plasminogen activator inhibitor type-1 in rat corpus luteum of pregnancy. 852 17

Chemical modification of proteins is a common theme in their regulation. Nitrosylation of protein sulfhydryl groups has been shown to confer nitric oxide (NO)-like biological activities and to regulate protein functions. Several other nucleophilic side chains -- including those with hydroxyls, amines, and aromatic carbons -- are also potentially susceptible to nitrosative attack. Therefore, we examined the reactivity and functional consequences of nitros(yl)ation at a variety of nucleophilic centers in biological molecules. Chemical analysis and spectroscopic studies show that nitrosation reactions are sustained at sulfur, oxygen, nitrogen, and aromatic carbon centers, with thiols being the most reactive functionality. The exemplary protein, BSA, in the presence of a 1-, 20-, 100-, or 200-fold excess of nitrosating equivalents removes 0.6 +/- 0.2, 3.2 +/- 0.4, 18 +/- 4, and 38 +/- 10, respectively, moles of NO equivalents per mole of BSA from the reaction medium; spectroscopic evidence shows the proportionate formation of a polynitrosylated protein. Analogous reaction of tissue-type plasminogen activator yields comparable NO protein stoichiometries. Disruption of protein tertiary structure by reduction results in the preferential nitrosylation of up to 20 thus-exposed thiol groups. The polynitrosylated proteins exhibit antiplatelet and vasodilator activity that increases with the degree of nitrosation, but S-nitroso derivatives show the greatest NO-related bioactivity. Studies on enzymatic activity of tissue-type plasminogen activator show that polynitrosylation may lead to attenuated function. Moreover, the reactivity of tyrosine residues in proteins raises the possibility that NO could disrupt processes regulated by phosphorylation. Polynitrosylated proteins were found in reaction mixtures containing interferon-gamma/lipopolysaccharide-stimulated macrophages and in tracheal secretions of subjects treated with NO gas, thus suggesting their physiological relevance. In conclusion, multiple sites on proteins are susceptible to attack by nitrogen oxides. Thiol groups are preferentially modified, supporting the notion that S-nitrosylation can serve to regulate protein function. Nitrosation reactions sustained at additional nucleophilic centers may have (patho)physiological significance and suggest a facile route by which abundant NO bioactivity can be delivered to a biological system, with specificity dictated by protein substrate.
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PMID:Polynitrosylated proteins: characterization, bioactivity, and functional consequences. 864 72

Smooth muscle cell (SMC) fibrinolysis is necessary for SMC migration. To determine whether the T cell lymphokines interleukin 4 (IL-4) and interferon-gamma (IFN-gamma) modulate SMC fibrinolysis and migration induced by basic fibroblast growth factor (bFGF), we examined the effects of IL-4 and IFN-gamma on human SMC tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (UPA), and plasminogen activator inhibitor 1 (PAI-1) antigen production, determined by enzyme-linked immunosorbent assays. Although IL-4 had no effects on SMC tPA, UPA, and PAI-1 production, it potentiated bFGF-induced tPA, UPA, and PAI-1 antigens. IL-4 plus bFGF resulted in a net increase in SMC fibrinolytic activity. IFN-gamma did not significantly affect bFGF induction of SMC tPA and PAI-1 antigens. However, IFN-gamma significantly decreased bFGF-mediated induction of SMC UPA antigen. IFN-gamma decreased the IL-4 plus bFGF induction of both tPA and UPA antigens. IL-4 increased and IFN-gamma abrogated bFGF induction of in vitro SMC migration through a modified micro-Boyden chamber. Therefore, IL-4 and IFN-gamma modulate bFGF-mediated induction of in vitro vascular SMC fibrinolysis and migration.
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PMID:T cell lymphokines modulate bFGF-induced smooth muscle cell fibrinolysis and migration. 912 80

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.
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PMID:Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. 995 71

All progressive renal diseases are the consequence of a process of destructive fibrosis. This review will focus on tubulointerstitial fibrosis, the pathophysiology of which will be divided into four arbitrary phases. First is the cellular activation and injury phase. The tubules are activated, the peritubular capillary endothelium facilitates migration of mononuclear cells into the interstitium where they mature into macrophages, and myofibroblasts/activated fibroblasts begin to populate the interstitium. Each of these cells releases soluble products that contribute to ongoing inflammation and ultimately fibrosis. The second phase, the fibrogenic signaling phase, is characterized by the release of soluble factors that have fibrosis-promoting effects. Several growth factors and cytokines have been implicated, with primary roles suggested for transforming growth factor-beta, connective tissue growth factor, angiotensin II and endothelin-1. Additional factors may participate including platelet-derived growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and interleukin-1, while interferon-gamma and hepatocyte growth factor may elicit antifibrotic responses. Third is the fibrogenic phase when matrix proteins, both normal and novel to the renal interstitium, begin to accumulate. During this time both increased matrix protein synthesis and impaired matrix turnover are evident. The latter is due to the renal production of protease inhibitors such as the tissue inhibitors of metalloproteinases and plasminogen activator inhibitors which inactivate the renal proteases that normally regulate matrix turnover. Fourth is the phase of renal destruction, the ultimate sequel to excessive matrix accumulation. During this time the tubules and peritubular capillaries are obliterated. The number of intact nephrons progressively declines resulting in a continuous reduction in glomerular filtration.
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PMID:Molecular basis of renal fibrosis. 1114 29

Phospholipase A(2) (PLA(2)) is a growing family of enzymes that may play a major role in inflammation. We investigated the effect of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on the gene expression of 19 different PLA(2) types (IB, IIA, IID, IIE, IIF, III, IVA, IVB, IVC, V, VIA, VIB, VIIA, VIIB, VIIIA, VIIIB, X, XII, and XIII) in human bronchoepithelial (BEAS-2B) and nasal epithelial (RPMI 2650) cells. The cells were stimulated with TNF-alpha or IFN-gamma for different lengths of time (1, 4, 18, and 48 h), and the mRNA levels of the different PLA(2) types were determined by reverse transcriptase-PCR (RT-PCR) and normalized to those of the housekeeping gene, GAPDH. In both cell lines, TNF-alpha increased the expression of PLA(2) IVA and IVC, and IFN-gamma increased the expression of PLA(2) IIA and IID. No influence on the gene expression of PLA(2)-activating protein (PLAP) was noted on cytokine stimulation. These findings indicate that TNF-alpha and IFN-gamma induce gene expression of two novel cytosolic and secretory PLA(2) types (IVC and IID, respectively) in human airway epithelial cells. The possibility that these PLA(2) types are involved in cytokine-mediated inflammation in the respiratory tract is inferred.
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PMID:Increased gene expression of novel cytosolic and secretory phospholipase A(2) types in human airway epithelial cells induced by tumor necrosis factor-alpha and IFN-gamma. 1239 16

In the present study, we compared the effect of atorvastatin (1 mg.kg(-1).day(-1)) and quinapril (0.5 mg.kg(-1).day(-1)) alone or in combination on inflammatory markers, endothelial function, intimal thickening and fibrinolytic balance in rabbits fed with either a control diet or a diet containing 1% (v/v) cholesterol for 12 weeks. Atorvastatin alone or in combination partially prevented the increase in cholesterol plasma levels observed in rabbits fed with the cholesterol-rich diet, but did not modify blood pressure levels. Quinapril administration did not alter any of these parameters in any group. Hypercholesterolaemia increased plasma levels of interleukin-1beta, interleukin-6, interferon-gamma and C-reactive protein, reduced acetylcholine-induced relaxation and produced intimal thickening. Likewise, atherosclerotic rabbits had reduced plasma tissue-type plasminogen activator activity and D-dimer levels and an increase in plasminogen-activator inhibitor-1 activity. Both drugs enhanced acetylcholine-induced relaxation, reduced intimal thickening and improved fibrinolytic balance in atherosclerotic rabbits in a similar manner. Their combination did not induce additive effects on these parameters. However, only the combination of both drugs was able to prevent the increase in inflammatory markers induced by hypercholesterolaemia. In summary, these data suggest that quinapril and atorvastatin had comparable beneficial effects on the alterations of vascular function and structure as well as fibrinolytic balance in atherosclerotic rabbits. In addition, the combination of atorvastatin and quinapril exerts a synergistic effect on inflammatory markers, which individual treatment, at the doses used, was not able to modify.
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PMID:Synergistic effect of angiotensin-converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibition on inflammatory markers in atherosclerotic rabbits. 1284 17

Aggregation of receptors for immunoglobulin G (FcgammaRs) on myeloid cells activates a series of events that are key in the inflammatory response and that can ultimately lead to targeted cell killing by antibody-directed cellular cytotoxicity. Generation of lipid-derived proinflammatory mediators is an important component of the integrated cellular response mediated by receptors for the constant region of immunoglobulins (Fc). We have demonstrated previously that, in interferon-gamma-primed U937 cells, the high affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D, sphingosine kinase, calcium transients, and protein kinase C isoforms, leading to the activation of the NADPH-oxidative burst. Here, we investigate the nature of the phospholipase that regulates arachidonic acid and eicosanoid production. Our data show that FcgammaRI couples to iPLA(2)beta for the release of arachidonic acid and the generation of leukotriene B(4) and prostaglandin E(2). Activation of iPLA(2)beta was protein kinase C-dependent; on the other hand, platelet-activating factor triggered cPLA(2)alpha by means of the mitogen-activated protein kinase pathway. These studies demonstrate that intracellular PLA(2)s can be selectively regulated by different stimuli and suggest a critical role for iPLA(2)beta in the intracellular signaling cascades initiated by FcgammaRI and its functional role in the generation of key inflammatory mediators.
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PMID:Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells. 2356 2

Airway hyperresponsiveness, airway eosinophilia and increased IgE levels in serum are the important characteristic features of asthma. We evaluated the potential of para-Bromophenacyl bromide (PBPB), a known phospholipase A(2) inhibitor, on allergen-induced airway hyperresponsiveness in a mouse model. We sensitized and challenged mice with ovalbumin (OVA) to develop airway hyperresponsiveness as assessed by airway constriction and airway hyperreactivity (AHR) to methacholine (MCh) induced by allergen. The mice were orally treated with PBPB (0.1, 1 and 10 mg/kg) during or after OVA-sensitization and OVA-challenge to evaluate its protective or reversal effect on airway constriction and AHR to MCh. Determination of OVA-induced airway constriction and AHR to MCh were performed by measuring specific airway conductance (SGaw) using non-invasive dual-chamber whole body-plethysmography. We observed that PBPB (1 mg/kg) significantly reduced OVA-induced airway constriction and AHR to MCh (p<0.01). PBPB (1 mg/kg) treatment significantly inhibited PLA(2) activity in the BAL fluid. Cytokine analysis of the BAL fluid revealed that PBPB caused an increase in interferon-gamma (IFN-gamma) (p<0.02) and a decrease in interleukin-4 (IL-4) (p<0.05) and interleukin-5 (IL-5) (p<0.05) levels. The OVA-specific serum IgE levels (p<0.01) and the BAL eosinophils (p<0.001) were also reduced significantly. Thus, PBPB is capable of modulating allergen induced cytokine levels and serum IgE levels, and alleviating allergen induced airway hyperresponsiveness and eosinophils in mice. These data suggest that PBPB could be useful in the development of novel agents for the treatment of allergen induced airway hyperresponsiveness.
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PMID:Para-Bromophenacyl bromide alleviates airway hyperresponsiveness and modulates cytokines, IgE and eosinophil levels in ovalbumin-sensitized and -challenged mice. 1545 21

The immune response induced in mice by beta-galactosidase (beta-gal) adsorbed or encapsulated on poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres was investigated. The encapsulated protein elicited higher antibody response than the protein adsorbed on the microspheres in the case of the PLA microspheres. However, the encapsulated protein elicited weaker antibody response than the adsorbed protein in the case of the PLGA (50:50) microspheres, probably because, in this case, the encapsulation process adversely affected protein immunogenicity. In the case of adsorbed beta-gal, higher antibody response was obtained with the PLA microspheres than with the PLGA (50:50) microspheres. This may be related to the lower rate of beta-gal desorption from the PLA microspheres. Based on the immunoglobulin G1/immunoglobulin G2a ratios and the stimulation indices for interferon-gamma and interleukin-4, beta-gal encapsulated or adsorbed on PLA microspheres induced a Th(1)-biased immune response whereas beta-gal encapsulated or adsorbed on PLGA (50:50) microspheres induced a Th(2)-biased immune response. The results obtained indicate that more potent immune responses are obtained when the protein is encapsulated than adsorbed on the microspheres, providing that the encapsulation process does not adversely affect protein immunogenicity. Also, the type of polymer used to prepare the microspheres, but not the method of protein association with the microspheres, may affect the type of immune response.
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PMID:Immune responses in mice of beta-galactosidase adsorbed or encapsulated in poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres. 1579 20


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