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)

Gene therapy utilizing leukocytes is an unexplored therapeutic strategy for targeting tissue-type plasminogen activator (t-PA) to fibrin and sites of inflammation. In this study, five cationic lipids were observed to enhance the adenovirus (Ad)-mediated expression of t-PA in human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner between 1000 and 15,000 lipid molecules per Ad particle (efficiency:LipofectAMINE > GenePORTER > Effectene > SuperFect > DMRIE-C). PBMCs treated with Ad/t-PA * LipofectAMINE complexes displayed elevated t-PA expression over a 4-day period and the t-PA-expressing cells facilitated the lysis of plasma clots in vitro. Functional and immunologic assays revealed that the Ad * LipofectAMINE infection protocol did not affect monocyte adhesion in vitro or elevate the expression of procoagulant activity, interleukin 8, or tumor necrosis factor alpha. The potential of this system was documented with an in vivo rat model system that involved the injection of lipopolysaccharide into the peritoneal cavity to induce an inflammatory response. Infusion of Ad/t-PA-infected rat PBMCs into the vasculature of lipopolysaccharide-treated animals was found to increase local fibrinolytic activity by 4-fold. These data provide a framework for utilizing adenovirus to transfer genes into PBMCs.
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PMID:Modulating the fibrinolytic system of peripheral blood mononuclear cells with adenovirus. 1124 35

Adipose tissue expresses a variety of genes including tumor necrosis factor alpha and type-1 plasminogen activator inhibitor (PAI-1); and these factors, produced by adipocytes, may be associated with the risk of coronary events in obesity. In this study, we characterized the production of fibrinolytic factors including tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PAI-1 in the differentiation of preadipocytes, and examined the hormonal regulation of these fibrinolytic factors in mature adipocytes. Mouse 3T3-L1 preadipocytes were employed as a model of adipocytes. Adipocyte differentiation was induced by insulin, dexamethasone, and 3-isobutyl-1-methyl xanthine (IBMX). alpha-Glycerophosphate dehydrogenase (GPDH) activity and glucose transporter 4 (GLUT4) mRNA, indices for adipocyte maturation, were induced on Day 4, and gradually increased. GPDH activity reached its maximum level on Day 14. The level of tPA, a major PA in preadipocytes, dramatically decreased with differentiation. On the other hand, that of uPA reciprocally increased. PAI-1 production was also dramatically induced concomitant with differentiation. In mature adipocytes, uPA production was dominant (25 microg/ml/24 h vs. 0.8 microg/ml/24 h for tPA). Total PA activity in the mature adipocytes was reduced by insulin or dexamethasone, but not by glucagon. Insulin, IBMX, and dexamethasone significantly decreased both uPA and tPA production, and increased PAI-1 production. Glucagon had no effect on the production of these fibrinolytic factors. Our results reveal that uPA is one of the markers for the differentiation of 3T3-L1 cells and that insulin, IBMX, and dexamethasone are potent regulators of the fibrinolytic activity in differentiated 3T3-L1 cells, reciprocally affecting PA and PAI-1 levels in them.
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PMID:Reciprocal regulation of tissue-type and urokinase-type plasminogen activators in the differentiation of murine preadipocyte line 3T3-L1 and the hormonal regulation of fibrinolytic factors in the mature adipocytes. 1157 6

Matrix metalloproteinase-9 (MMP-9) produced by tumor cells is known to be implicated in the invasion of squamous cell carcinoma (SCC). In the process of searching for agents to inhibit MMP-9 in cancer, immunosuppressive factors, dexamethasone (DEX) and interleukin-4 (IL-4) were found to inhibit protein production as well as gene expression of MMP-9 in tumor necrosis factor alpha (TNFalpha)-stimulated SCC cells. DEX and IL-4 could also suppress the expression of urokinase type plasminogen activator (uPA) to prevent the conversion from the proenzyme form of MMP-9 to its active form. Regarding their mechanisms to inhibit the expression of MMP-9 and uPA, DEX and IL-4 had no effect on the cell surface levels of TNFalpha receptors, but inhibited the activation of NF-kappaB and NF-kappaB-dependent gene expression. DEX, but not IL-4, could strongly augment the TNFalpha-induced expression of IkappaBalpha in SCC cells. These results suggest that DEX and IL-4 suppress not only immunological reactions, but also tumor invasion by targeting NF-kappaB.
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PMID:The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin-4, on NF-kappaB-mediated protease production by oral cancer. 1178 Nov 45

Endothelial dysfunction with atherosclerosis is a recognized complication of uremic patients. The hypoalbuminemia of peritoneal dialysis (PD) patients can induce a hypercoagulable and atherogenic state. In this study, we investigated the role played by malnutrition-inflammation syndrome on endothelial function markers in PD patients. We measured markers of nutrition [normalized protein catabolic rate (nPCR), albumin, prealbumin, insulin-like growth factor 1 (IGF-1), transferrin, and cholesterol], markers of endothelial damage and function [tissue-type plasminogen activator (tPA), thrombomodulin (TM), von Willebrand factor (vWF), and NO3 (representing NO)], markers of a coagulable state [fibrinogen and plasminogen activator inhibitor 1 (PAI-1)], markers of inflammation [tumor necrosis factor alpha (TNF alpha) and C-reactive protein (CRP)], and other endothelial injury factors [lipoprotein(a) [Lp(a)] and homocysteine]. We also performed an endothelial stimulation test consisting of right-arm venous occlusion (VO) for 10 minutes. The patients were divided into four groups according to their clinical atherosclerotic score (CAS). We studied 45 clinically stable PD patients. At baseline, statistically significant negative linear correlations were found between albumin and age (r = -0.54, p < 0.05), albumin and vWF post-VO (r = -0.54, p < 0.05), and albumin and TM (r = -0.36, p < 0.05), which are endothelial damage markers and prothrombotic factors. A positive linear correlation was seen between albumin and NO3 post-VO (r = 0.48, p < 0.05), indicating a high vasodilatation capacity. C-Reactive protein and TNF alpha showed a positive linear correlation (r = 0.5, p < 0.01). Similarly, TNF alpha showed a positive linear correlation with cardiovascular risk markers such as fibrinogen (r = 0.79, p < 0.01), PAI-1 (r = 0.44, p < 0.05), and homocysteine (r = 0.37, p < 0.05). Creatinine clearance showed a negative linear correlation with TM (r = -0.36, p < 0.05). Patients with albumin < 4 g/dL showed a lower tPA ratio, lower NO3, and a higher CRP, TNF alpha, and Lp(a) than did patients with albumin > 4 g/dL [tPA ratio: 2.1 +/- 1.56 (n = 29) vs. 2.6 +/- 2.3 (n = 16), p < 0.05; NO3: 47 +/- 27 micrograms/mL vs. 69 +/- 33 micrograms/mL, p < 0.05; CRP: 1.8 +/- 3 mg/dL vs. 1.1 +/- 1.6 mg/dL, p < 0.05; TNF alpha: 44.4 +/- 16 pg/mL vs. 36.6 +/- 21.4 pg/mL, p < 0.05; Lp(a): 55 +/- 39 mg/dL vs. 33 +/- 21 mg/dL, p < 0.05]. Patients with a worse CAS showed higher homocysteine levels and lower albumin values. Those relationships were maintained in both periods of the study. We found no relationships between dialysis dose and endothelial function markers. In conclusion, malnutrition-inflammation syndrome may contribute to endothelial dysfunction and, consequently, to prothrombotic and proatherogenic processes in PD patients.
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PMID:Malnutrition-inflammation syndrome is associated with endothelial dysfunction in peritoneal dialysis patients. 1476 71

Uncontrolled activation of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation, yet little is known about the activation of MMPs during orthotopic liver transplantation (OLT). OLT is associated with increased fibrinolytic activity due to elevated plasmin generation. The serine-protease plasmin not only causes degradation of fibrin clots but is also thought, amongst others, to play a role in the activation of some matrix metalloproteinases. We therefore studied the evolution of MMP-2 and -9 plasma concentrations during OLT and the effect of serine-protease inhibition by aprotinin on the level and activation of these MMPs. In a group of 24 patients who participated in a randomized, double-blind, placebo-controlled study we determined serial MMP-2 and MMP-9 plasma levels during transplantation using ELISA (total MMP), activity assays (activatable MMP) and zymography. In addition, the MMP-inhibitors TIMP-1 and TIMP-2 were assessed by ELISA. The putative regulating factors tumor necrosis factor alpha (TNF-alpha) and tissue-type plasminogen activator (t-PA) were assessed as well. Patients were administered high-dose aprotinin, regular-dose aprotinin or placebo during surgery. Plasma TIMP-1, TIMP-2 and MMP-2 level gradually decreased during transplantation. Approximately two-thirds of total MMP-2 appeared to be in its activatable proMMP form. No release of MMP-2 from the graft could be detected. In contrast, plasma levels of MMP-9 increased sharply during the anhepatic and postreperfusion periods. Peak MMP-9 levels of about eight times above baseline were found at 30 minutes after reperfusion. Most MMP-9 appeared to be in its active/inhibitor-complexed form. No significant differences were observed between the three treatment groups. However, in patients with more severe ischemia/reperfusion (I/R) injury the MMP-9 concentration, particularly of the active/inhibitor-complexed form, remained high at 120 minutes postreperfusion compared to patients with no or mild I/R injury. The decrease in plasma levels of MMP-2, TIMP-1 and TIMP-2 during OLT occurred irrespective of the severity of the I/R injury. There was a significant correlation between MMP-9 and t-PA levels, but not with TNF-alpha. In conclusion, OLT is associated with a sharp increase of MMP-9 during the anhepatic and postreperfusion periods, which coincided with the changes in t-PA. MMP-2, TIMP-1 and TIMP-2 gradually decreased during OLT. The composition of these MMPs was not altered by the use of aprotinin, suggesting that serine-protease/plasmin-independent pathways are responsible for MMP regulation during OLT. In addition, only MMP-9 seems to be involved in I/R injury during human liver transplantation.
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PMID:Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation. The effect of aprotinin and the relation to ischemia/reperfusion injury. 1498 26

Phospholipase A(2) IIA (PLA(2)IIA), which plays a crucial role in arachidonic acid metabolism and in inflammation, is upregulated under various pathological conditions, including in the gallbladder and gallbladder bile from patients with multiple cholesterol gallstones, in the liver and kidney of rats with cirrhosis, as well as in the colonic tissue of animals treated with a chemical carcinogen. The administration of ursodeoxycholic acid (UDCA) partially attenuated the PLA(2)IIA expression level in these different models. The aim of this study was to investigate the modulatory effect of UDCA on the PLA(2)IIA expression level at the cellular level. The HepG2 cells were selected to investigate the direct inhibitory effect of UDCA on PLA(2)IIA expression level. The proinflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) -induced PLA(2)IIA expression in HepG2 cells was partially inhibited by the presence of UDCA in a dose-dependent fashion. The effect of UDCA on proinflammatory cytokines-induced PLA(2)IIA expression occurred at the transcriptional level. In addition, among the bile acids tested, this inhibitory effect was UDCA-specific. In conclusion, this study supports the possible alteration of arachidonic acid metabolism and PLA(2)IIA expression level, in particular, as the protective action of UDCA in patients with chronic liver disease.
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PMID:Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells. 1579 50

The aim of the present study was to examine the effects of Avena Rhealba (AR) oatmeal extract on the metabolism of arachidonic acid (AA) and eicosanoids as well as on the expression of cytosolic phospholipase A(2 )(cPLA(2)) in the human keratinocyte cell line HaCaT. For this purpose, we examined the effects of AR on basal and A23187-triggered release of [(3)H]-AA from phospholipids and on the production of [(3)H]-labeled metabolites of the cyclooxygenase (CO) and 5-lipoxygenase (LO) pathways. AR was found to inhibit A23187-triggered [(3)H]-AA mobilization from phospholipids (p<0.05) and production of [(3)H]-labeled metabolites of CO (p<0.05) and LO (p<0.05) pathways. These results suggest AR decreases PLA(2)-dependent mobilization of AA from phospholipids. A closer examination of the effects of AR on prostaglandin 6KF1alpha (6KPGF1alpha), the stable metabolite of prostacyclin, revealed dose-dependent inhibition of this AA metabolite. AR also decreased A23187- and tumor necrosis factor alpha-induced cPLA(2) overexpression, as shown by cPLA(2) immunodetection and mRNA expression. These results demonstrate the high potential of AR in the treatment of inflammatory diseases of the skin.
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PMID:Avena Rhealba inhibits A23187-stimulated arachidonic acid mobilization, eicosanoid release, and cPLA2 expression in human keratinocytes: potential in cutaneous inflammatory disorders. 1580 94

The impact of biodegraded nano-hydroxyapatite/collagen (nHAC) composite and nano-hydroxyapatite/collagen/poly(L-lactic acid) (nHAC/PLA) scaffold composite on neutrophils reaction was evaluated in vitro. Neutrophils were separated from human peripheral blood of healthy subjects. The nHAC and nHAC/PLA materials were immersed in the D-Hanks' Balanced Salt Solution (D-HBSS) for 1 day, 7 days and 2, 4, 8 weeks (37 degrees C) as testing solution, which mixed with the neutrophils for 1 h. Both of the nHAC and nHAC/PLA materials were shown the same cell survival rate as blank control, but the lactate dehydrogenase (LDH) and tumor necrosis factor alpha (TNF-alpha) released from the neutrophils were increased significantly after the 2 weeks in nHAC sample. The possible reason relied on the high concentration of calcium due to the quick biodegradation of the nHAC material. Before 2 weeks, the LDH value of nHAC/PLA is higher than that of nHAC sample that corresponded to the initial PLA degradation in vitro. This study provided the biocompatibility test of neutrophils other than common methods, such as osteoblastic cells for biomimetic materials. Moreover, it demonstrated the calcium concentration stimulating effect for cytokine release from neutrophils.
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PMID:Human neutrophils reaction to the biodegraded nano-hydroxyapatite/collagen and nano-hydroxyapatite/collagen/poly(L-lactic acid) composites. 1634 87

Fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) in basement membranes and interstitial tissues, resulting from increased synthesis or decreased degradation of ECM or both. The plasminogen activator/plasmin system plays an important role in ECM degradation, whereas the plasminogen activator inhibitor 1 (PAI-1) is a physiologic inhibitor of plasminogen activators. PAI-1 expression is increased in the lung fibrotic diseases and in experimental fibrosis models. The deletion of the PAI-1 gene reduces, whereas the overexpression of PAI-1 enhances, the susceptibility of animals to lung fibrosis induced by different stimuli, indicating an important role of PAI-1 in the development of lung fibrosis. Many growth factors, including transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), as well as other chemicals/agents, induce PAI-1 expression in cultured cells and in vivo. Reactive oxygen and nitrogen species (ROS/RNS) have been shown to mediate the induction of PAI-1 by many of these stimuli. This review summarizes some recent findings that help us to understand the role of PAI-1 in the development of lung fibrosis and ROS/RNS in the regulation of PAI-1 expression during fibrogenesis.
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PMID:Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis. 1797 97

Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity's comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses.
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PMID:Adipose tissue: the new endocrine organ? A review article. 1905 66


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