Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to determine the effects of tumour necrosis factor alpha (TNF), interleukin-1 alpha (IL-1alpha), macrophage colony-stimulating factor (MCSF) and transforming growth factor beta (TGFbeta) on the secretion of matrix metalloproteinases (MMP), human chorionic gonadotrophin (HCG) and fetal fibronectin (fFN) by purified first trimester cytotrophoblastic cells (CTB) in vitro. CTB were obtained from legal abortions and cultured in vitro in the presence or absence of the different cytokines. Secreted gelatinases were analysed in the culture supernatants by zymography, by measurements of the total gelatinolytic activity and by enzyme immunoassays. HCG and fFN were measured by commercially available immunoassays. TNF increased the total gelatinolytic activity by increasing MMP-9 activity (P = 0.025-0.0177) but decreased MMP-2 activity (P < 0.03) and immunoreactivity (P < 0.05), fFN (P < 0.02) and HCG (P < 0.01). IL-1alpha significantly increased the secretion of fFN (P < 0.02), the activity (P < 0.02) and immunoreactivity (P < 0.05) of MMP-9 but had no effect on the other parameters. MCSF increased MMP-9 immunoreactivity (P < 0.05) and moderately decreased HCG. TGFbeta inhibited total gelatinolytic activity, MMP-9 activity and immunoreactivity, but was without effect on MMP-2 concentrations and activity. TGFbeta decreased HCG (P < 0.041) and increased fFN (P < 0.042). Our results indicate that TGFbeta, TNF and IL-1alpha are important regulators of trophoblastic MMP secretion.
Mol Hum Reprod 1999 Mar
PMID:Effects of tumour necrosis factor-alpha, interleukin-1 alpha, macrophage colony stimulating factor and transforming growth factor beta on trophoblastic matrix metalloproteinases. 1033 60

Remodeling of extracellular matrix (ECM) is one of the key events in many developmental processes. In the present study, a temporal profile of gelatinase activities in regenerating salamander limbs was examined zymographically. In addition, the effect of retinoic acid (RA) on these enzyme activities was examined to relate the pattern-duplicating effect of RA in limb regenerates with gelatinase activities. During regeneration, various types of gelatinase activities were detected, and these activities were at their maximum levels at the dedifferentiation stage. Upon treatment with chelating agents EDTA and 1,10-phenanthroline, the enzyme activities were inhibited indicating that those enzymes are likely matrix metalloproteinases (MMPs). Considering the molecular sizes and the decrease of molecular sizes by treatment with p-aminophenylmercuric acetate, an artificial activator of proMMP, some of the gelatinases expressed during limb regeneration are presumed to be MMP-2 and MMP-9. In RA-treated regenerates, overall gelatinase activities increased, especially the MMP-2-like gelatinase activity which increased markedly. These results suggest that MMP-2-like and MMP-9-like gelatinases play a role in ECM remodeling during regeneration, and that gelatinases are involved in the excessive dedifferentiation after RA treatment.
Mol Cells 1999 Apr 30
PMID:Modulation of gelatinase activity correlates with the dedifferentiation profile of regenerating salamander limbs. 1034 Apr 64

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
Am J Respir Cell Mol Biol 1999 Jun
PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

Hoxa-10 is an AbdominalB-like homeobox gene that is expressed in the developing genitourinary tract during embryogenesis and in the adult uterus during early pregnancy. Null mutation of Hoxa-10 in the mouse causes both male and female infertility. Defective implantation and decidualization resulting from the loss of maternal Hoxa-10 function in uterine stromal cells is the cause of female infertility. However, the mechanisms by which Hoxa-10 regulates these uterine events are unknown. We have identified two potential mechanisms for these uterine defects in Hoxa-10(-/-) mice. First, two PGE2 receptor subtypes, EP3 and EP4, are aberrantly expressed in the uterine stroma in Hoxa-10(-/-) mice, while expression of several other genes in the stroma (TIMP-2, MMP-2, ER, and PR) and epithelium (LIF, HB-EGF, Ar, and COX-1) are unaffected before implantation. Further, EP3 and EP4 are inappropriately regulated by progesterone (P4) in the absence of Hoxa-10, while PR, Hoxa-11 and c-myc, three other P4-responsive genes respond normally. These results suggest that Hoxa-10 specifically mediates P4 regulation of EP3 and EP4 in the uterine stroma. Second, since Hox genes are implicated in local cell proliferation, we also examined steroid-responsive uterine cell proliferation in Hoxa-10(-/-) mice. Stromal cell proliferation in mutant mice in response to P4 and 17beta-estradiol (E2 was significantly reduced, while epithelial cell proliferation was normal in response to E2. These results suggest that stromal cell responsiveness to P4 with respect to cell proliferation is impaired in Hoxa-10(-/-) mice, and that Hoxa-10 is involved in mediating stromal cell proliferation. Collectively, these results suggest that Hoxa-10 mutation causes specific stromal cell defects that can lead to implantation and decidualization defects apparently without perturbing epithelial cell functions.
Mol Endocrinol 1999 Jun
PMID:Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. 1037 98

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.
Int J Mol Med 1999 Aug
PMID:Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer. 1040 90

The myocardium contains a collagen matrix composed primarily of collagen and fibronectin, which are major determinants of the myocardial architecture, structural integrity and mechanical properties. The present study was undertaken to determine the age-related changes of the accumulation and degradation of the collagen matrix in Syrian myopathic hamsters, of the Bio 14.6 and Bio 53.58 strains. Those hamsters were used as models for hypertrophic and dilated cardiomyopathy, respectively. The heart to body weight ratio in the Bio 14.6 strains was higher (P<0.05) than that in the age-matched F1b strains. In the Bio 53.58 strains, the heart to body weight ratio was higher at 8 and 42 weeks of age than that in the F1b strains. The collagen content increased from 22 weeks of age in both Bio hamsters compared with age-matched F1b hamsters (P<0.05). In both cardiomyopathic hamsters, the mRNA expressions for type I and type III collagen and fibronectin all increased with aging; however, the fibronectin expression in the Bio 14.6 strains increased more at 22 weeks of age than at 42 weeks of age. The left ventricular MMP-1, MMP-2 and MMP-9 activities in Bio 53.58 strains increased with aging. However, in the Bio 14.6 strains, although MMP-1 activities increased with aging, MMP-2 and MMP-9 activities decreased at 42 weeks of age in comparison to those at 22 weeks of age. Thus, the MMP activation differed between two cardiomyopathic models at the stage of heart failure, although the collagen synthesis was elevated in both models. In conclusion, it would seem that the relative balance between the synthesis and the removal of collagen may contribute to the changes in the left ventricular geometry in two different types of cardiomyopathy.
J Mol Cell Cardiol 1999 Sep
PMID:Extracellular matrix regulation in the development of Syrian cardiomyopathic Bio 14.6 and Bio 53.58 hamsters. 1047 45

After coronary artery bypass surgery, saphenous vein graft occlusion occurs through tissue remodeling. Although a likely trigger, the role of preparative mechanical injury incurred by the graft is not yet understood. We studied the early effects of simple mechanical injury on human saphenous vein grafts by exposing them to longitudinal stretch, a deformation which potentially occurs during surgery. We then maintained ex vivo for up to 7 days matched pairs of experimentally stretched and nonstretched (control) vein segments and examined the expression and activation of matrix metalloproteinases (MMPs) and integrin alphav, molecules implicated in vascular remodeling. At peak expression on day 3, stretched vein secreted 177 +/- 16% active MMP-2 (P < 0.01), 161 +/- 36% (P < 0.05) pro-MMP-9, and contained 206 +/- 18% (P < 0.01) alphav, a receptor for active MMP-2, compared to control. In situ gelatinase activity was present in the intima and adventitia of stretched veins, but not of control, and correlated spatially with expression of alphav. Stretch also increased severalfold cell proliferation (1.27 +/- 0.4 vs. 0.23 +/- 0.05% in control, P < 0.05), as assessed by bromodeoxyuridine incorporation. Furthermore, we found that cell proliferation colocalized with gelatinase activity and alphav in the adventitia. Our results show that a single longitudinal stretch of vein grafts produces significant changes in the expression and activation of key molecules in vascular remodeling. We also found support for the notion that the adventitial layer contributes to vein graft remodeling.
Exp Mol Pathol 1999 Aug
PMID:Mechanical stretching of human saphenous vein grafts induces expression and activation of matrix-degrading enzymes associated with vascular tissue injury and repair. 1048 41

Tumour invasion and trophoblastic invasion share the same biochemical mediators: the matrix metalloproteinases (MMP) and their inhibitors. In contrast to tumour invasion of a host tissue, trophoblastic invasion during implantation and placentation is stringently controlled both in tissue localization and developmental stage. The factors responsible for these important regulatory processes are unknown, but in-vitro studies point to endometrial cytokines and growth factors as possible candidates. Here we examined the possibility that interleukin-6 (IL-6), a trophoblastic and endometrial cytokine, represents such a regulatory factor. Purified first trimester cytotrophoblastic cells (CTB) were cultured for 4 days in presence or absence of increasing concentrations of IL-6. MMP-2 and MMP-9 bioactivity (zymography) and immunoactivity were measured in the culture supernatants together with total human chorionic gonadotrophin (HCG), fetal fibronectin (FFN) and leptin. IL-6 did not change the cytotrophoblastic secretion of FFN or total HCG. In contrast, this cytokine induced a dose-dependent stimulation of the leptin secretion and increased the activity, but not the immunoreactivity, of MMP-9 and MMP-2. These results indicate that IL-6 could be considered as an endometrio-trophoblastic regulator of cytotrophoblastic gelatinases.
Mol Hum Reprod 1999 Nov
PMID:Effects of interleukin-6 (IL-6) on cytotrophoblastic cells. 1054 68

We examined the effects of the purified ginseng components, panaxadiol (PD) and panaxatriol (PT), on the expression of matrix metalloproteinase-9 (MMP-9) in highly metastatic HT1080 human fibrosarcoma cell line. A significant down-regulation of MMP-9 by PD and PT was detected by Northern blot analysis. However, the expression of MMP-2 was not changed by treatment with PD and PT. Quantitative gelatin based zymography confirmed a markedly reduced expression of MMP-9, but not MMP-2 in the treatment of PD and PT. To investigate whether the reduced level of MMP-9 by PD and PT affects the invasive capacity of HT1080 cells, we conducted an in vitro invasion assay with PD and PT treated cells. The results of the in vitro invasion assay revealed that PD and PT reduced tumor cell invasion through a reconstituted basement membrane in the transwell chamber. Because of the similarity of chemical structure between PD, PT and dexamethasone (Dexa), a synthetic glucocorticoid, we investigated whether the down-regulation of MMP-9 by PD and PT were mediated by the nuclear translocation of glucocorticoid receptor (GR). Increased GR in the nucleus of HT1080 human fibrosarcoma cells treated by PD and PT was detected by immunocytochemistry. Western blot and gel retardation assays confirmed the increase of GR in the nucleus after treatment with PD and PT. These results suggest that GR-induced down-regulation of MMP-9 by PD and PT contributes to reduce the invasive capacity of HT1080 cells.
Mol Cells 1999 Oct 31
PMID:Glucocorticoid receptor-induced down-regulation of MMP-9 by ginseng components, PD and PT contributes to inhibition of the invasive capacity of HT1080 human fibrosarcoma cells. 1059 35

We have studied the enzymatic gelatinolytic activity of matrix metalloproteinases (MMPs) present in cerebrospinal fluid (CSF) of samples obtained from 67 individuals, twenty-one nonneurological patients (considered controls) and 46 subjects with various neurological disorders e.g., vascular lesions, demyelination, inflammatory, degenerative and prion diseases. Biochemical characterization of MMPs, a family of neutral proteolytic enzymes involved in extracellular matrix modeling, included determination of substrate specificity and Ca+2 dependency, as well as the effects of protease inactivators, carboxylic and His (histidine) residue modifiers, and antibiotics. Whereas all CSF samples expressed MMP-2 (gelatinase A) activity, it corresponded in most cases (normal and pathological samples) to its latent form (proenzyme; pMMP-2). In general, inflammatory neurological diseases (especially meningitis and neurocisticercosis) were associated with the presence of a second enzyme, MMP-9 (or gelatinase B). Whereas MMP-9 was found in the CSF of every tropical spastic paraparesis patient studied, its presence in samples from individuals with vascular lesions was uncommon. Patients blood-brain barrier damage was ascertained by determining total CSF protein content using both, the conventional polyacrylamide gel electrophoresis procedure under denaturing conditions and capillary zone electrophoresis.
Res Commun Mol Pathol Pharmacol 1999
PMID:Gelatinase activity of matrix metalloproteinases in the cerebrospinal fluid of various patient populations. 1060 77


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