Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recent studies indicate that 1alpha,25-dihydroxyvitamin D3 (1alpha,25[OH]2D3) and 24R,25-dihydroxyvitamim D3 (24R,25[OH]2D3) differentially regulate proliferation, differentiation, and matrix synthesis of growth plate chondrocytes. To determine whether both metabolites play the same or different roles in vivo, we used the vitamin D-deficient rat as a model. Rickets was induced and then reversed by administering a single dose of ergocalciferol, 1alpha,25(OH)2D3, or 24R,25(OH)2D3 and euthanizing the animals after 4, 24, 48, or 72 h. Growth plates were either processed for histology and histomorphometry or extracted with buffered guanidine-HCl. Neutral metalloproteinase activity in the extracts was measured by use of aggrecan-containing beads, and collagenase activity was determined by use of radioactive type I collagen. The levels of tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator were also determined. The morphology of the growth plate varied as a function of treatment. While 24R,25(OH)2D3 appeared to affect cell maturation and 1alpha,25(OH)2D3 appeared to affect terminal differentiation and calcification, response to ergocalciferol was indicative of the combined responses to the individual metabolites. Enzyme activity was regulated in a differential manner. Treatment with ergocalciferol produced a rapid decline in both neutral metalloproteinase and collagenase activities that was statistically significant by 4 h. By contrast, 1alpha,25(OH)2D3 had no effect on neutral metalloproteinase activity but caused a significant decrease in both active and total collagenase activity by 4 h, while 24R,25(OH)2D3 decreased neutral metalloproteinase activity by 48 h and had no effect on collagenase activity. Ergocalciferol had no effect on TIMP levels at any time examined, whereas 1alpha,25(OH)2D3 caused an increase at 48 and 72 h and 24R,25(OH)2D3 completely blocked TIMP production at 4 and 24 h. By contrast, plasminogen activator activity by ergocalciferol was decreased at 4 h, increased by 1alpha,25(OH)2D3 at 4 and 24 h, and decreased by 24R,25(OH)2D3 at all time points examined. These in vivo results confirm our previous cell culture observations showing that growth plate chondrocytes are differentially regulated by 1alpha,25(OH)2D3 and 24R,25(OH)2D3. Moreover, they show definitively that these two vitamin D metabolites play distinct roles not only in regulating neutral metalloproteinase and collagenase activities in growth plate cartilage but in cell maturation and calcification of this tissue in vivo.
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PMID:Effect of 1alpha,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 on metalloproteinase activity and cell maturation in growth plate cartilage in vivo. 1144 27

Thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) has proven to be beneficial for acute stroke management, despite the narrow window of opportunity for treatment and the increased risk of haemorrhage. Because of the latter, recent studies have attempted to identify compounds that may be given concomitantly with alteplase to reduce the haemorrhage rate Matrix metalloproteinase (MMP) inhibitors have been proposed as potential combination therapy candidates because they prevent MMP-induced production of the cytokine tumour necrosis factor-alpha (TNFalpha), as well as membrane and vessel remodelling following ischaemia. Spin trap agents also have been put forward due to their free radical scavenging capabilities. In the rabbit large clot embolism model, alteplase effectively lysed blood clots, whether or not other drugs were used in combination. However, haemorrhage rate also was increased compared with that in control animals. The alteplase-induced haemorrhage rate was reduced significantly by administration of the MMP inhibitor batimastat (BB-94) or the spin trap agent alpha-phenyl-N-t-butylnitrone (PBN). Other rodent studies have also demonstrated that PBN is effective in decreasing the haemorrhage rate following alteplase administration. Overall, preclinical studies indicate that MMP inhibition or free radical scavenging in combination with alteplase may circumvent the high risk of haemorrhaging with alteplase.
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PMID:Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. 1170 Jan 47

Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-Cys-Gly-Val-Pro-Asp-NH2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.
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PMID:Inhibition of human MDA-MB-231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen. 1223 May 59

Acquired abdominal aortic aneurysms are usually associated with a mural thrombus through which blood continues to flow. Some early data suggest that aneurysmal evolution correlates with the biological activity of the thrombus. Our hypothesis was therefore that the thrombus could adsorb blood components and store, release, and participate in the activation of proteases involved in aneurysmal evolution. For this purpose, we have explored both the metalloproteinase and fibrinolytic systems in the thrombus and the wall of human aneurysms. We have first investigated blood clot formation and lysis in vitro. Spontaneous clotting induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis progressively released more MMP-9 in a time-dependent manner (P < 0.01). After selective isolation, we demonstrated that polymorphonuclear leukocytes are the main source of MMP-9 release during clot formation. Protease content was then analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms sampled during surgical repair. In 15 aneurysms, the liquid phase at the interface between the thrombus and the wall was sampled separately. Both thrombus and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the thrombus than in the wall. The liquid interface also contained active MMP-9. Immunohistochemistry of the thrombus confirmed these findings, showing the presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co-localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin activity was present in both thrombus and wall. In the liquid interface, plasmin-alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the wall, suggesting that plasminogen present in the thrombus could be activated by factors secreted by the arterial wall. This was demonstrated in vitro, in which co-incubation of thrombus and wall extracts generated plasmin in the presence of a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing plasma components could act as a source of proteases in aneurysms that may play a critical role in enlargement and rupture.
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PMID:Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. 1241 17

We evaluated the expression of two extra-cellular protease systems in a model of spontaneous cerebrovascular pathology: spontaneously hypertensive stroke-prone rats (SHRSP). The appearance of brain damage in individual animals was imaged and followed by means of magnetic resonance imaging (MRI). In situ zymography of brain slices obtained 3 days after the appearance of brain damage showed an increase in plasminogen activator (PA)/plasmin activity that co-localised with the cerebral damage detected by MRI; there was also concomitant accumulation/activation of inflammatory cells in the damaged area. Proteolytic activity was inhibited by the urokinase-specific inhibitor amiloride but not by an antibody against tissue-type plasminogen activator (t-PA). SDS-PAGE zymography of brain extracts revealed the presence of 58 kDa plasminogen-dependent lysis areas in the ischemic and non-ischemic tissues, and a 33 kDa lysis area in ischemic tissue only. An antibody against t-PA inhibited the former, whereas the latter was inhibited by amiloride. The specific induction of urokinase-type plasminogen activator (u-PA) in the damaged tissue was further confirmed by the fact that both u-PA protein mass and mRNA were markedly increased in the damaged cerebral areas. Concomitant metalloproteinase-2 (MMP-2) activation was only observed in the damaged area. These data suggest that u-PA is expressed and selectively catalyses proteolysis in the injured area of spontaneous brain damage in SHRSP.
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PMID:Endogenous proteolytic activity in a rat model of spontaneous cerebral stroke. 1274 36

We have recently reported that osteopontin (OPN) induces nuclear factor kappaB (NFkappaB)-mediated promatrix metalloproteinase-2 activation through IkappaBalpha/IKK signaling pathways and that curcumin (diferulolylmethane) down-regulates these pathways (Philip, S., and Kundu, G. C. (2003) J. Biol. Chem. 278, 14487-14497). However, the molecular mechanism by which upstream kinases regulate the OPN-induced NFkappaB activation and urokinase type plasminogen activator (uPA) secretion in human breast cancer cells is not well defined. Here we report that OPN induces the phosphatidylinositol 3'-kinase (PI 3'-kinase) activity and phosphorylation of Akt in highly invasive MDA-MB-231 and low invasive MCF-7 cells. The OPN-induced Akt phosphorylation was inhibited when cells were transfected with a dominant negative mutant of the p85 domain of PI 3-kinase (Deltap85) and enhanced when cells were transfected with an activated form of PI 3-kinase (p110CAAX), indicating that PI 3'-kinase is involved in Akt phosphorylation. OPN enhances the interaction between IkappaBalpha kinase (IKK) and phosphorylated Akt. OPN also induces NFkappaB activation through phosphorylation and degradation of IkappaBalpha by inducing the IKK activity. However, both pharmacological (wortmannin and LY294002) and genetic (Deltap85) inhibitors of PI 3'-kinase inhibited OPN-induced Akt phosphorylation, IKK activity, and NFkappaB activation through phosphorylation and degradation of IkappaBalpha. OPN also enhances uPA secretion, cell motility, and extracellular matrix invasion. Furthermore, cells transfected with Deltap85 or the super-repressor form of IkappaBalpha suppressed the OPN-induced uPA secretion and cell motility, whereas cells transfected with p110CAAX enhanced these effects. Pretreatment of cells with PI 3-kinase inhibitors or NFkappaB inhibitory peptide (SN-50) reduced the OPN-induced uPA secretion, cell motility, and invasion. To our knowledge, this is first report that OPN induces NFkappaB activity and uPA secretion by activating PI 3'-kinase/Akt/IKK-mediated signaling pathways and further demonstrates a functional molecular link between OPN-induced PI 3'-kinase-dependent Akt phosphorylation and NFkappaB-mediated uPA secretion, and all of these ultimately control the motility of breast cancer cells.
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PMID:Osteopontin stimulates cell motility and nuclear factor kappaB-mediated secretion of urokinase type plasminogen activator through phosphatidylinositol 3-kinase/Akt signaling pathways in breast cancer cells. 1277 Nov 44

The primary pathology of pre-eclampsia is thought be a defect in placentation due to failure of trophoblast invasion. Here, we aim to identify the expression profile of invasion-associated genes in the pre-eclamptic placenta. Messenger RNA (mRNA) expression levels of extracellular matrix molecule-related genes in five pre-eclamptic placentas and in five strictly matched normal placentas were assayed using complementary DNA (cDNA) microarrays representing over 220 human cytokine-associated or hormone-associated genes. Results demonstrated greater than two-fold higher expression of 18 extracellular matrix molecule genes, including cadherin, collagen, integrin and selectin, in the pre-eclamptic placenta. Extracellular matrix molecule degradation-related genes, including matrix metalloproteinase (MMP)-10, MMP-13, MMP-15, tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-3, plasminogen and plasminogen activator, were also highly expressed in the pre-eclamptic placenta, compared to the normal placenta. Results suggest that the abnormal expression profiles of extracellular matrix molecules and degrading proteinases might be associated with the pathogenesis of pre-eclampsia.
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PMID:Expression profile of trophoblast invasion-associated genes in the pre-eclamptic placenta. 1286 18

A central tenet of fibrinolysis is that tissue plasminogen activator-dependent (t-PA- dependent) conversion of plasminogen to active plasmin requires the presence of the cofactor/substrate fibrin. However, previous in vitro studies have suggested that the endothelial cell surface protein annexin II can stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin. Here, homozygous annexin II-null mice displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. While these animals demonstrated normal lysis of a fibrin-containing plasma clot, t-PA-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of annexin II-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and an annexin II peptide mimicking sequences necessary for t-PA binding blocked endothelial cell invasion of Matrigel implants in wild-type mice. In addition, annexin II-deficient mice displayed markedly diminished neovascularization of fibroblast growth factor-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from annexin II-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 and -13. These data establish annexin II as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.
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PMID:Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. 1470 7

Matrix metalloproteinase 13 (MMP-13), urokinase type plasminogen activator (uPA), and plasminogen activator inhibitor type-1 (PAI-1) have been reported to be involved in aseptic loosening of artificial hip joints. This study for the first time presents the protein levels of all of these factors in synovial-like interfaces between bone and prosthesis and in pseudocapsular tissues surrounding the artificial joint in patients with aseptic loosening (n=17) measured by ELISA. No differences were observed in the antigen expression of MMP-13, uPA, and PAI-1, comparing interface and pseudocapsular tissue. Also, no significant correlation between the protein expression of these factors and years from arthroplasty to revision or to type of fixation (cemented vs. cementless) was observed. As control, MMP-13, uPA, and PAI-1 antigen levels were also determined in the synovium of patients with osteoarthritis (n=10). Yet, the antigen levels of MMP-13, uPA, and PAI-1 in tissue specimens from patients with aseptic loosening of artificial hip joints were significantly higher compared to their expression in synovial capsular tissues obtained from patients with osteoarthritis. In conclusion, this study shows that elevated protein levels of uPA, PAI-1, and MMP-13 in periprosthetic pseudocapsular and interface tissues from patients after total hip replacement due to aseptic loosening seem not to be associated with the patient outcome.
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PMID:Protein expression of MMP-13, uPA, and PAI-1 in pseudocapsular and interface tissue around implants of loose artificial hip joints and in osteoarthritis. 1506 75

Secretory phospholipase A(2) (sPLA(2)), abundantly expressed in various cells including fibroblasts, is able to promote proliferation and migration. Degradation of collagenous extracellular matrix by matrix metalloproteinase (MMP) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, tumor invasion, and metastasis. Here we show that group IB PLA(2) increased pro-MMP-2 activation in NIH3T3 fibroblasts. MMP-2 activity was stimulated by group IB PLA(2) in a dose- and time-dependent manner. Consistent with MMP-2 activation, sPLA(2) decreased expression of type IV collagen. These effects are due to the reduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) and the activation of the membrane type1-MMP (MT1-MMP). The decrease of TIMP-2 levels in conditioned media and the increase of MT1-MMP levels in plasma membrane were observed. In addition, treatment of cells with decanoyl Arg-Val-Lys-Arg-chloromethyl ketone, an inhibitor of pro-MT1-MMP, suppressed sPLA(2)-mediated MMP-2 activation, whereas treatment with bafilomycin A1, an inhibitor of H(+)-ATPase, sustained MMP-2 activation by sPLA(2). The involvement of phosphatidylinositol 3-kinase (PI3K) and Akt in the regulation of MMP-2 activity was further suggested by the findings that PI3K and Akt were phosphorylated by sPLA(2). Expression of p85alpha and Akt mutants, or pretreatment of cells with LY294002, a PI3K inhibitor, attenuated sPLA(2)-induced MMP-2 activation and migration. Taken together, these results suggest that sPLA(2) increases the pro-MMP-2 activation and migration of fibroblasts via the PI3K and Akt-dependent pathway. Because MMP-2 is an important factor directly involved in the control of cell migration and the turnover of extracellular matrix, our study may provide a mechanism for sPLA(2)-promoted fibroblasts migration.
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PMID:Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migration via the phosphatidylinositol 3-kinase and Akt pathway. 1522 Mar 45


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