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)

The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-beta1 (TGF-beta1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-beta1 treatment via a TGF-beta-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-beta1 action with other members of the TGF-beta family by using luciferase reporter genes. These data show that TGF-beta and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-beta may be neuroprotective.
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PMID:Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. 1042 56

Alterations of the host response by tobacco smoke adversely affect the periodontium. In this study, we examined the effects of in vitro acute smoke exposure on changes in m-RNA expression of primary peripheral mononuclear blood cells through microarray analysis. Mononuclear blood cells were isolated from four healthy non-smokers and plated in culture wells. Half of the cells were then exposed to 5 min of tobacco smoke. Fluorescent c-DNA probes were prepared from the linearly amplified m-RNAs for each sample and hybridized to cDNA microarrays representing approximately 30000 human genes. Significant increases or decreases in m-RNA gene expression between non-smoke-exposed and smoke-exposed samples were identified by permutation t-test, as implemented by the Significance Analysis of Microarrays software package. After smoke exposure, the expression of 90 genes with known function was significantly elevated and the expression of 19 genes with known function was significantly depressed. In addition, 18 upregulated and 26 downregulated transcripts were expressed sequence tags with little information available on function. Approximately 20 of the significantly elevated genes had previously been reported in the literature to be associated with periodontal pathogenesis (fold changes in parentheses). These included plasminogen activator (4.4), Heat Shock Protein (Hsp) 40 kD (2.2), thrombomodulin (4.2), cytochrome c (1.8), COX-2 (2.6), interleukin-1a (1.4), chemokine ligand 1 (3.8), cathepsin L (2.0), and calgranulin A (2.1). In addition, several significantly elevated genes not previously reported in the literature may also play a role in periodontal pathogenesis, and thus warrant further investigation. These include Diphtheria toxin receptor (heparin-binding epidermal growth factor-like growth factor) (7.8), Hsp 10 kDa (1.7), Hsp 105 kD (2.1), Hsp 70 kDa (1.6), and mitogen activated protein kinase 3 (1.5). Among the significantly depressed genes that may play a protective or destructive role in periodontal pathogenesis were interferon gamma receptor 2 (0.58) and chemokine receptor 2 (0.24). Our results may be of use in the search for the molecular mechanisms for the adverse effects of tobacco smoke on the host response.
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PMID:Alteration of gene expression profiles of peripheral mononuclear blood cells by tobacco smoke: implications for periodontal diseases. 1467 73

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
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PMID:Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice. 1636 58