UNIPROT:P00750 - FACTA Search

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)

Hyaluronan or hyaluronic acid (HA) has been used to treat osteoarthritic knees for more than 30 years. Here, we tested the hypothesis that HA with high molecular weight (MW) would have greater effects than HA with low MW on the expression of the plasminogen activator (PA)/plasmin system and gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] during early development of osteoarthritis (OA). We compared the levels of MMP-2, MMP-9, urokinase-type PA (u-PA), and PA inhibitor-1 (PAI-1) in a series of chondral, meniscal, and synovial cultures of early OA after treatment with or without three different MW HA products (Hyalgan and Artz with low MW, and Synvisc with high MW). Gelatin zymography revealed that three different HA products could decrease the secretion of MMP-2 in all tissue cultures and MMP-9 in meniscal and synovial cultures time-dependently. Enzyme-linked immunosorbent assay showed that Artz and Synvisc had significant inhibition on u-PA and PAI-1 levels after 24 h, but Hyalgan did at 96 h. Compared with Hyalgan and Artz, Synvisc provided the greatest ability to inhibit MMP-2, MMP-9, u-PA, and PAI-1 expression. Our studies clearly demonstrate that the therapeutic effects of using HA to treat early OA may be partially dependant on downregulation of the PA/plasmin system and gelatinases expression, which delay the structural progression of the disease. HA with high MW might have a greater ability than that with low MW to offer effective protection for articular cartilage.
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PMID:Effects of different molecular weight hyaluronan products on the expression of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis. 1797 44

The production of artificial epidermis using reabsorbable polymeric matrices is one of possible goals; one of most used strategies in this field is the polymer substrate functionalitation using specific growth factors, in order to accelerate and improve keratinocyte adhesion and proliferation. In this study films of poly(D,L)lactide (P(D,L)LA), have been functionalized with various concentrations of galactose (GAL, 1-5-10%, w/v) conjugated with poly-L-lysine (PLL) using 1-etil-3-(3-diaminopropil) carbodiimide (EDC) as a coupling agent. GAL is a disaccharide present in the extracellular matrix (ECM) and it is bind by Galectines, a family of cell receptors whose activation regulate the cell-matrix interaction and cell growth and apoptosis. One of these receptors, Galectin-7 (Gal-7), is selectively expressed by human keratinocytes. Spontaneously immortalized human keratinocytes (HaCaT) that express high level of Gal-7 were allowed to adhere for 4 h in serum free condition on control P(D,L)LA (PLA), and on PLA-GAL and cell proliferation; the production of matrix metalloproteinases (MMP-2, MMP-9, and MMP-28), involved in cellular migration and tissue homeostasis have been analyzed after 24 h. The presence of GAL onto the polymer surface increased both cell adhesion, spreading and proliferation along with MMP-9 and MMP-28 production, suggesting that polymer functionalization using GAL could be an useful tool for the production of an artificial epidermis.
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PMID:Functionalization of a poly(D,L)lactic acid surface with galactose to improve human keratinocyte behavior for artificial epidermis. 1808 Mar 43

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in the remodelling of connective tissues during the development and wound healing. Moreover, two MMPs, Gelatinase A (MMP-2) and Gelatinase B (MMP-9), are also present in body fluids such as blood and urine and, therefore, they can be in contact with implanted biomaterials and can be adsorbed onto their surface. In order to test this hypothesis disks of different polymers (polystyrene (PS), polyvinyl chloride (PVC), poly(D,L-lactide) (PLA), polymethyl methacrylate (PMMA) and poly(2-hydroxyethyl methacrylate) (PHEMA)) have been exposed to human plasma and adsorbed proteins have been eluted and analyzed. Using Western blot and substrate zymography analysis, we observed that both MMP-2 and MMP-9 adsorbed onto the surfaces of all the polymers, especially hydrophilic ones (PMMA and PHEMA) and PLA, in both the active and inactive forms. Furthermore, we observed that adhesion of human granulocyte neutophils to PMMA, the polymer that adsorbed the higher quantity of MMP-2 and MMP-9 compared to the others, was reduced by more that 50% by the presence of a gelatinase inhibitor. This data suggest a surprising role of these absorbed enzymes in the adhesion of neutrophil onto some polymeric biomaterials surface and, therefore, in the setting of inflammation.
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PMID:Adsorption of matrix metalloproteinases onto biomedical polymers: a new aspect in biological acceptance. 1817 51

This study aimed to characterize matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in relation to changes in left ventricle (LV) geometry and function in a porcine model with streptozotocin (STZ)-induced diabetes. In 15 Chinese Guizhou minipigs with STZ-induced diabetes (diabetic group) and 15 age-matched normal controls (control group), Doppler tissue imaging was performed at 6 months of diabetes. Serum MMP-2, -9, TIMP-1, -4 and B-type natriuretic peptide (BNP) were determined. Expression of MMPs, TIMPs, urokinase type-plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in aortic intima and LV myocardium was evaluated, with gelatinolytic activities of tissue MMP-2, -9 accessed by zymography. Left ventricle end-diastolic septum thickness (P < 0.05) and mass (P < 0.05) were increased, whereas peak systolic mitral annulus velocity (Sm, P < 0.001), LV systolic (P = 0.01) and diastolic strain (P < 0.001) were significantly decreased in diabetic group than in controls. Diabetic group showed higher expression of TIMP-1, -4 in aortic intima and LV myocardium (P < 0.01 or P < 0.05), with increased collagen content and elevated serum BNP level (P = 0.004) and lower gelatinolytic activities of tissue MMP-2, -9 (all P < 0.05). Semi-quantitative RT-PCR of those diabetic tissues revealed elevated mRNA levels of major TIMPs, uPA, uPAR and PAI-1. Reduction of serum MMP-2 and -9 levels was observed in diabetic group vs. control group (both P < 0.05). This study features elevated levels of TIMP-1, -4, uPA, uPAR and PAI-1, and decreased activities of MMP-2, -9 in aorta and myocardium in STZ-induced diabetic minipigs, indicating that MMP-TIMP dysregulation is associated with LV hypertrophy, cardiac dysfunction and increased cardiovascular fibrosis in diabetes.
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PMID:Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin-induced diabetic minipigs. 1833 30

Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
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PMID:Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. 1862 Nov 8

Prostate cancer, the most prevalent non-cutaneous cancer in men, is associated with increased age. This suggests that dietary chemopreventive measures could be effective in delaying the onset or decreasing the severity of the disease. We utilized the Lobund-Wistar rat nitrosomethylurea induced, testosterone promoted (NMU-T) model of male sex accessory gland cancer to test the potential chemopreventive effects of myo-inositol and limonene on tumor incidence and associated protease activities. Tumors were found to arise in the seminal vesicles and dorsal and anterior prostate lobes. There were also some tumors that appeared to arise in both the seminal vesicles and anterior prostate, and in some cases the tissue of origin was not clear. The distribution of tumors as to site of origin in limonene or myo-inositol treated animals did not vary from that of the starch fed control animals, and the number of animals presenting with metastases did not vary significantly between treatment groups. There was a statistically significant delay in onset of tumors in myo-inositol, but not limonene fed rats, at 10 months post-induction of carcinogenesis; however, at 12 and 15 months this was not significant. The ventral prostate and seminal vesicles expressed pro-MMP-2 and plasminogen activator (PA) activities. Based on sensitivity to amiloride, the PA activities were predominately urokinase (uPA) in the ventral prostate and a mixture of tissue-type activator (tPA) and uPA in the seminal vesicles of non-treated rats. Sex accessory gland tumors, and metastases, expressed increased levels PA and pro- and active forms of MMP-2 and -9. The PA activities of the tumors were a mixture of uPA and tPA. There was no difference in the levels of these protease activities based on the tissue of tumor origin, nor in tumor vs metastasis. These studies indicate that MMP and PA activities play a role in sex accessory gland tumor biology and that dietary supplementation with myo-inositol can delay but not ultimately prevent the development of such tumors.
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PMID:The effect of dietary supplementation with limonene or myo-inositol on the induction of neoplasia and matrix metalloproteinase and plasminogen activator activities in accessory sex organs of male Lobund-Wistar rats. 1867 99

As growth plate chondrocytes mature and hypertrophy, they reorganize their proteoglycan-rich type II collagen extracellular matrix (ECM), involving 1,25(OH)(2)D(3)-dependent regulation of matrix metalloproteinases (MMPs). Stromelysin-1 (MMP-3) and 72-kD gelatinase (MMP-2) are found in extracellular matrix vesicles (MVs) and release and activate ECM-bound latent TGF-beta1 and TGF-beta2, respectively. 1,25(OH)(2)D(3) regulates incorporation of MMP-2 and MMP-3 into MVs and release of these enzymes in the ECM. Plasma membranes (PMs) and MVs contain the 1alpha,25(OH)(2)D(3) membrane receptor ERp60 (protein disulfide isomerase A3), phospholipase A(2) (PLA(2)), PLA(2)-activating protein, the nuclear vitamin D receptor and caveolin-1. 1,25(OH)(2)D(3) secreted by chondrocytes binds MV ERp60, activating PLA(2). Resulting lysophospholipids destabilize MV membranes, releasing active MMPs. We examined 1,25(OH)(2)D(3)-dependent activation of latent TGF-beta1 stored in cartilage ECM. Interestingly, TGF-beta1 regulates 1,25(OH)(2)D(3) production. 1alpha,25(OH)(2)D(3) activates PM protein kinase C (PKC)-alpha via ERp60-dependent PLA(2)-signaling, lysophospholipid production and phospholipase C-gamma. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching MVs in PKC-zeta. Direct activation of MV MMP-3 requires ERp60 based on blocking antibodies and PKC based on inhibitor studies. However, treatment of MVs with 1,25(OH)(2)D(3) decreases MV PKC-zeta activity, suggesting more complex feedback mechanisms, potentially involving MV lipid signaling. Our observations indicate that one role of MVs is to provide MMPs at sites distant from the cells. Chondrocytes secrete 1,25(OH)(2)D(3), which acts directly on MV-membranes via ERp60, releasing MMPs. MMP-specific ECM components are hydrolyzed, resulting in release and activation of growth factors that can act back on the cells.
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PMID:1,25-Dihydroxy vitamin D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60-activated matrix vesicle matrix metalloproteinases. 1876 31

The intracellular signaling molecule mammalian target of rapamycin (mTOR) is essential for cell growth and proliferation. It is involved in mouse embryogenesis, murine trophoblast outgrowth and linked to tumor cell invasiveness. In order to assess the role of mTOR in human trophoblast invasion we analyzed the in vitro invasiveness of HTR-8/SVneo immortalized first-trimester trophoblast cells in conjunction with enzyme secretion upon mTOR inhibition and knockdown of mTOR protein expression. Additionally, we also tested the capability of mTOR to trigger signal transducer and activator of transcription (STAT)-3 by its phosphorylation status. Rapamycin inhibited mTOR kinase activity as demonstrated with a lower phosphorylation level of the mTOR substrate p70 S6 kinase (S6K). With the use of rapamycin and siRNA-mediated mTOR knockdown we could show that cell proliferation, invasion and secretion of matrix-metalloproteinases (MMP)-2 and -9, urokinase-like plasminogen activator (uPA) and its major physiological uPA inhibitor (PAI)-1 were inhibited. While tyrosine phosphorylation of STAT3 was unaffected by mTOR inhibition and knockdown, serine phosphorylation was diminished. We conclude that mTOR signaling is one major mechanism in a tightly regulated network of intracellular signal pathways including the JAK/STAT system to regulate invasion in human trophoblast cells by secretion of enzymes that remodel the extra-cellular matrix (ECM) such as MMP-2, -9, uPA and PAI-1. Dysregulation of mTOR may contribute to pregnancy-related pathologies caused through impaired trophoblast invasion.
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PMID:mTOR mediates human trophoblast invasion through regulation of matrix-remodeling enzymes and is associated with serine phosphorylation of STAT3. 1933 15

Few data are available on the involvement of brain microvascular endothelial cells (BMECs) in excitotoxic neonatal brain lesions. Therefore, we developed an original approach for investigating mouse-derived BMECs in vitro. We hypothesized that newborn and adult BMEC cultures would show age-related differences in phenotype and sensitivity to glutamate. Expression of the monocarboxylate transporter, MCT1, was higher in neonatal than in adult BMECs, whereas expression of the glucose transporter, GLUT1, was higher in adult than in neonatal BMECs that overexpressed the N-methyl-D-aspartate receptor NR1 subunit (NMDAR1) compared with adult BMECs. The ability of neonatal and adult BMECs to be activated by glutamate was confirmed through intracellular calcium ([Ca2+]i) recording. The glutamate-induced [Ca2+]i increase was blocked by the selective NMDAR antagonist, MK-801. Significant glutamate-evoked concentration-dependent release of tissue-type plasminogen activator (t-PA) and matrix metalloproteinases (MMPs) activities was found in supernatants of neonatal, but not in adult BMECs. The glutamate-mediated release of t-PA, MMP-2, and MMP-9 proteolytic activities in neonatal BMECs was blocked by MK-801. Conceivably, this protease release from neonatal BMECs may participate in neonatal brain lesions.
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PMID:Newborn- and adult-derived brain microvascular endothelial cells show age-related differences in phenotype and glutamate-evoked protease release. 1936 95

In the present study, we tested the hypothesis that angiotensin II (Ang II) has both direct (via AT1 receptors) and indirect (via sympathostimulator pathway) actions on the synthesis and activity of the enzymes involved in the extracellular matrix degradation in vivo. For this purpose, sympathectomy and blockade of the Ang II receptor AT1 were performed alone or in combination in normotensive rats. The mRNA of the plasminogen activator (t-PA) and its inhibitor (PAI-1), the mRNA, protein and activity of the matrix metalloproteinases MMP-2 and MMP-9 were examined by Q-RT-PCR, immunoblotting and zymographic methods in the left ventricle. t-PA and PAI-1 mRNA were decreased after sympathectomy and remained unchanged after AT1 receptors blockade. mRNA was increased for t-PA and decreased by similar degree for PAI-1 after double treatment. MMPs mRNA and protein levels were decreased either after sympathectomy or AT1 receptors blockade and an additive effect was acquired after double treatment. MMPs activity was decreased by similar degree in the three treated groups. Deducted interpretations from our experimental approach suggest that Ang II inhibits directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) t-PA mRNA synthesis. It seems unable to influence directly PAI-1 mRNA, but stimulates indirectly PAI-1 mRNA synthesis. Ang II stimulates directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) MMPs synthesis at both transcriptional and protein levels. The enzymatic activity of MMPs does not seem to be influenced directly by Ang II but it could be stimulated indirectly (via sympathostimulator pathway).
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PMID:Differential control of MMP and t-PA/PAI-1 expressions by sympathetic and renin-angiotensin systems in rat left ventricle. 1940 40

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