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: EC:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some studies have shown an association between vitamin C disposability (Vit C), and the development of premature rupture of membranes (RPM). However, vitamin C role in the metabolism of collagen upon chorioamnion tissue, has not been analyzed. In this study the effect of modulation with different vit C concentrations in culture cells derived from human amnion, was analyzed. Vit C concentrations were used in order to cover physiological range (29.0 micrograms/ml). After stimulation the cells media were analyzed for enzymatic activity of metalloproteinases with extracellular matrix (MMP), and relative quantity of MMP-1, MMP-2 and MMP-9, was quantified, by immune transference, using monospecific polyclonal antibodies. The activity, as well as protein decreased in amniotic cells media, in a direct way as to vit C concentration, so, at the highest used concentrations (100 micrograms/ml), the least MMP activity/quantity, was obtained. These results show a finding not described until now, which permits to establish a direct connection between vit C availability and increase in collagen degradation. According to results, the less availability of vit C, the greater degradation of collagen, which should lead to a mechanical support loss and eventual fetal membranes rupture.
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PMID:[Dietetic factors and premature rupture of fetal membranes. Effect of vitamin C on collagen degradation in the chorioamnion]. 776 72

Immunohistochemical studies of prostate carcinoma reveal that most primary carcinomas, including high-grade tumors, are surrounded by a basal lamina composed of laminin, type IV collagen, and entactin. In addition to the expected laminin subchains A, B1, B2, subchains M and S are also found. Tenascin, found around normal glands, is seen in 60% of carcinomas. The basal cells of the normal gland express several integrin alpha units including alpha 2,3,4,5,6, and v. Both beta 1 and beta 4 subunits are observed. These integrin units are polarized at the base of the cells where they codistribute with the surrounding extracellular matrix. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures, as detected by transmission electron microscopy (TEM). In carcinoma, the beta 4 is not observed and the alpha 6 and beta 1 subunits are variably expressed. The integrin expression in carcinoma is diffuse in the cytoplasmic membrane and not restricted to the basal aspects of the cell. In addition, type VII collagen and the BP 180 protein which are associated with hemidesmosomes are lost, although the BP 230, plectin, and HD1 proteins are variably expressed. Using immunohistochemistry and northern analysis we observed three metalloproteinases in prostate carcinoma--matrilysin, gelatinase A, and gelatinase B. Western blotting and zymogram analysis reveal that of these three, only matrilysin appears to be present in its active form. Recent in situ hybridization studies reveal focal expression of the matrilysin mRNA in 25/33 primary carcinomas. Matrilysin also appears to be highly expressed in prostatic ducts and atrophic glands. Expression of the three metalloproteinases is also seen in prostatic intraepithelial neoplasia lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adhesion molecules, extracellular matrix, and proteases in prostate carcinoma. 782 96

Type XIV collagen is a newly described member of the fibril-associated collagens with interrupted triple helices (FACITs). Expression of this collagen has been localized to various embryonic tissues, suggesting that it has a functional role in development. All FACITs thus far described (types IX, XII, XIV, and XVI) contain a highly homologous carboxyl-terminal triple helical domain designated COL1. We have studied the capacity of various matrix metalloproteinases (interstitial collagenase, stromelysin, matrilysin, and 92-kDa gelatinase) to degrade the COL1 domain of collagen XIV. We found that only 92-kDa gelatinase cleaves COL1. Furthermore, digestion of whole native collagen XIV by the 92-kDa gelatinase indicates that this enzyme specifically attacks the carboxyl-terminal triple helix-containing region of the molecule. COL1 is cleaved by 92-kDa gelatinase at 30 degrees C, a full 5-6 degrees C below the melting temperature (Tm) of this domain; native collagen XIV is also degraded at 30 degrees C. In comparison to interstitial collagenase degradation of its physiologic native type I collagen substrate, the 92-kDa enzyme cleaved COL1 (XIV) with comparable catalytic efficacy. Interestingly, following thermal denaturation of the COL1 fragment, its susceptibility to 92-kDa gelatinase increases, but only to a degree that leaves it several orders of magnitude less sensitive to degradation than denatured collagens I and III. These data indicate that native COL1 and collagen XIV are readily and specifically cleaved by 92-kDa gelatinase. They also suggest a role for 92-kDa gelatinase activity in the structural tissue remodeling of the developing embryo.
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PMID:Degradation of the COL1 domain of type XIV collagen by 92-kDa gelatinase. 783 60

Matrix metalloproteinase 7 (MMP-7) has been purified as an inactive zymogen of M(r) 28,000 (proMMP-7) from the culture medium of CaR-1 human rectal carcinoma cells. The NH2-terminal sequence of proMMP-7 is Lys-Pro-Lys-Pro-Gln-Glu, which is identical to that of matrilysin. The zymogen is activated by 4-aminophenylmercuric acetate (APMA), yielding an intermediate form of M(r) 21,000 and an active species of M(r) 19,000 which shows the new NH2-terminal sequence of Tyr78-Ser-Leu-Phe-Pro-Asn-Ser. Although trypsin fully activates the zymogen, the activation rate by plasmin or leukocyte elastase is confined to approximately 50%. ProMMP-7 can be activated by MMP-3 (stromelysin 1) to its full activity in a single-step mechanism and generates the same NH2 terminus obtained by APMA activation, whereas MMP-1 (tissue collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) do not have such an effect. On the other hand, proMMP-1 is activated by MMP-7 to an activity similar to that obtained by APMA and the activation by MMP-7 is enhanced up to approximately 6.5 fold in the presence of APMA. This enhanced activity is donated by specific cleavage at the Gln80-Phe81 bond of proMMP-1. MMP-7 can also activate proMMP-9 up to approximately 50% of the full activity with a new NH2 terminus of Leu16-Arg-Thr-(Asn)-Leu. Incubation of proMMP-2 or proMMP-3 with MMP-7 results in no activation of these proMMPs. MMP-7 degrades type IV collagen, laminin-1, fibronectin, proteoglycan, type I gelatin, and insoluble elastin. These results suggest that in vivo MMP-7 may play a role in degradation of extracellular matrix macromolecules in concert with MMP-1, -3, and -9 under pathological conditions.
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PMID:Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. 789 11

The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS). Puromycin aminonucleoside (PAN) was injected intraperitoneally in rats and the right kidney was removed on day 22. Nephrotic rats received successive intraperitoneal injections of PAN on days 27, 34, and 41. Control rats were subjected to a nephrectomy or a sham operation on day 22. Animals were divided into six groups. In group 1, the PAN-injected rats were fed a standard diet containing 22% protein. In group 2, the PAN-injected rats were fed a low protein diet containing 6% protein, starting on the same day as the first PAN injection. In group 3, the nephrectomized rats without PAN were fed a standard diet. In group 4, the nephrectomized rats without PAN were fed a low protein diet for the same period. In group 5, the sham operated rats were fed a standard diet. In group 6, the sham operated rats were fed a low protein diet for the same period. Rats were sacrificed on days 0, 60 or 80 after the initial PAN or saline injection. The percentage of sclerotic glomeruli in group 1 rats increased markedly with time, reaching 77% on day 80. The mRNA levels encoding for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-2, TIMP-1 and TIMP-2 increased significantly as glomerulosclerosis progressed, whereas MMP-1 and MMP-3 mRNA levels were unchanged, and no MMP-9 mRNA was detected throughout the experiments. In group 2, the low protein diet reduced the prevalence of glomerulosclerosis and attenuated the increased mRNA expression for ECM components, MMP-2, TIMP-1 and TIMP-2 in FGS glomeruli. In groups 3 through 6, mRNA levels for ECM components decreased with age, whereas those for MMPs and TIMPs changed little throughout the experiments. Immunofluorescence studies revealed the accumulation of types I, III and IV collagens, laminin, and HSPG in the sclerotic area and low protein diet attenuated the accumulation of these proteins. These data suggest that glomerulosclerosis may result from an imbalance among ECM components, MMPs and TIMPs and that a low protein diet attenuates the otherwise increased levels of mRNA for ECM components, MMP-2, TIMP-1 and TIMP-2 in glomerulosclerosis.
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PMID:Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. 793 7

Myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). In renovascular hypertension, this presents as a reactive perivascular and interstitial fibrosis in not only the pressure overloaded, hypertrophied left ventricle but also the normotensive, nonhypertrophied right ventricle. It therefore would appear that circulating hormonal and not hemodynamic factors are responsible for this adverse fibrous tissue response. To ascertain whether the RAAS effector hormones angiotensin II (AII) or aldosterone (ALDO) directly stimulate collagen synthesis or inhibit collagenase production we used cell culture. Adult rat cardiac fibroblasts (Fb) were cultured since these cells express mRNA for types I and III collagens, the major fibrillar collagens in the heart, and collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Collagen synthesis, determined by 3H-proline incorporation, and collagenase activity were measured in confluent, quiescent Fb after 24 h incubation with various concentrations of AII or ALDO (10(-11)-10(-6)M) in the presence or absence of either 10(-5)M type 1 (DuP 753) and type 2 (PD 123177) AII or 10(-9)-3 x 10(-6)M ALDO (spironolactone) receptor antagonists, respectively. Collagen synthesis, normalized per total protein synthesis, increased significantly (P < 0.005) after incubation with either 10(-9)M ALDO (5.9 +/- 1.0%) or 10(-7)M AII (5.3 +/- 1.2%) compared with untreated control cells (2.9 +/- 0.5%) of the same passage (p6-p10). This increase in collagen synthesis could be completely abolished by either types 1 or 2 AII receptor antagonists in AII stimulated Fb or the competitive ALDO receptor antagonist, spironolactone, at equimolar concentration in ALDO stimulated Fb. AII significantly decreased collagenase activity which could be completely abolished by PD 123177, but not DuP 753, while ALDO had no effect on collagenase activity. The mineralocorticoid, ALDO, stimulates collagen synthesis in cultured adult rat cardiac Fb in concentrations similar to those found in plasma in renovascular hypertension and this response appears to occur via type I corticoid receptors. AII appears to stimulate collagen synthesis by both type 1 and 2 AII receptors, but only in high concentrations that could be generated locally within the myocardium. In addition, AII unlike ALDO inhibits collagenase activity that could be attenuated only by type 2 receptor blockade. These findings suggest a direct interaction between ALDO, AII and cardiac Fb in mediating myocardial fibrosis in hypertensive heart disease.
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PMID:Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. 796 49

The extra-cellular matrix (ECM) related antigens, type IV collagen, laminin, M(r) 68,000 laminin receptor (LR), M(r) 72,000 type IV collagenase (MMP-2), its inhibitor TIMP-2, and alpha 2-macroglobulin expression have been immunohistochemically investigated in 100 cases of human gastric carcinoma with a 5-yr follow up. Basement membranes were inversely related to tumoral differentiation. At the early intramucosal stage of both intestinal and diffuse histological types, TIMP-2 was expressed by the majority of tumor cells (60/63%), whereas MMP-2+ and LR+ cells were in the minority (24/19%, 23/0%, respectively). At the early submucosal stage, TIMP-2+ cells moderately decreased in both histological types (49/49%), whereas a consistently higher number of both MMP-2+ and LR+ cells were detected only in the diffuse carcinomas (72%). In the advanced stage, the expression of TIMP-2 further declined (22/24%), although the other two antigens increased or maintained high levels of expression. AMG+ cells never exceeded 10% in either histological type at any stage. In the liver metastases, both MMP-2+ and LR+ cells were more numerous than in the primary tumor (P < 0.002 and P < 0.01). Patients who died from their primary tumor had higher percentages of LR+, MMP-2+, and AMG+ cells and lower percentages of TIMP-2+ cells with respect to survivors. We believe evaluation of ECM-related antigens, and especially TIMP-2, may help determine a confident prognosis for gastric cancer.
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PMID:Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane. 800 47

Collagenase and stromelysin have a premier role in the irreversible degradation of the extracellular matrix seen in rheumatic disease. It is therefore no surprise that considerable attention has been devoted to developing strategies to reduce their levels in diseased joints. Most efforts have focused on inhibiting the activity of the enzymes, either by increasing the concentration of natural inhibitors such as the TIMPs or by introducing into the joint synthetic compounds that will complex with the enzymes and inactivate them. There have also been studies directed at inhibiting enzyme synthesis. These preclinical studies have been carried out in cell-free and/or cell culture systems and in animal models. Despite promising preclinical data, there have been no stunning successes in the clinical arena. The reasons for this are several. In part, they are rooted in the technical difficulties associated with designing inhibitors of enzyme activity that are of high affinity, and then delivering them to the affected joints while still maintaining specificity and efficacy. The complicated structure of the proteoglycan and collagen that comprise articular cartilage, along with the biochemistry of inflamed synovial tissue, only compound the difficulties. In addition to these technical problems, the lack of fundamental knowledge about the biochemistry and molecular biology of the enzymes has handicapped our efforts. We are just resolving the crystal structure of the metalloproteinases (108) and beginning to understand the mechanisms controlling gene expression (67, 68, 70-72). These advances represent significant achievements in metalloproteinase enzymology and biology and should form the scientific basis for a new generation of effective therapies. For example, knowledge of the active site as derived from the crystal structure of the enzymes may facilitate the development of tightly-binding specific inhibitors which function well in vivo. Similarly, based on our current understanding of mechanisms controlling the regulation of both the TIMP genes and the MMP genes, we are beginning to elucidate how to turn these genes on or off, and hopefully, to modulate disease accordingly. Indeed, although some studies are still at a preclinical level, these possible approaches are becoming a reality (109). Arthritic diseases in general, and rheumatoid arthritis in particular, represent a complicated multifaceted set of clinical disorders. The clinical symptoms and pathologic features result from a cascade of biologic pathways that involve acute and chronic inflammation, the immune response, and metalloproteinase biochemistry.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? 771 15

We reported that interstitial collagenase is produced by keratinocytes at the edge of ulcers in pyogenic granuloma, and in this report, we assessed if production of this metalloproteinase is a common feature of the epidermal response in a variety of wounds. In all samples of chronic ulcers, regardless of etiology, and in incision wounds, collagenase mRNA, localized by in situ hybridization, was prominently expressed by basal keratinocytes bordering the sites of active re-epithelialization indicating that collagenolytic activity is a characteristic response of the epidermis to wounding. No expression of mRNAs for 72- and 92-kD gelatinases or matrilysin was seen in keratinocytes, and no signal for any metalloproteinase was detected in normal epidermis. Immunostaining for type IV collagen showed that collagenase-positive keratinocytes were not in contact with an intact basement membrane and, unlike normal keratinocytes, expressed alpha 5 beta 1 receptors. These observations suggest that cell-matrix interactions influence collagenase expression by epidermal cells. Indeed, as determined by ELISA, primary cultures of human keratinocytes grown on basement membrane proteins (Matrigel; Collaborative Research Inc., Bedford, MA) did not express significant levels of collagenase, whereas cells grown on type I collagen produced markedly increased levels. These results suggest that migrating keratinocytes actively involved in re-epithelialization acquire a collagenolytic phenotype upon contact with the dermal matrix.
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PMID:Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. 825 40

Structural luteolysis was found decades ago to be induced by PRL in the hypophysectomized rat, but the mechanisms of this process are unknown. To gain information on mechanisms of luteal involution, we developed an animal model that circumvented complex surgery and provided ample tissue for analyses. Gonadotropin-synchronized ovulation and luteinization were induced in immature rats, followed by treatment with ergot alkaloid and PRL. PRL-induced structural luteolysis, as shown by loss of luteal weight, protein, and DNA after pretreatment with ergot alkaloid, was evident after 36 h. Ascorbic acid depletion was rapid, severe, and lasting in luteal tissue during structural luteolysis, but lipid peroxidation or depletion of vitamin E was not evident. PRL treatment of animals with functional corpora lutea did not induce luteal involution. Significantly, after natural functional luteolysis occurred, PRL was highly effective in inducing structural luteolysis. Thus, either natural or ergot-induced functional luteolysis permitted the luteolytic expression of PRL. A greater depletion of protein than DNA was seen during PRL-induced structural luteolysis and was associated with a significant increase in neutral caseinase activity in luteal extracts. Caseinase activity was markedly reduced by calcium chelators and profoundly inhibited by the chelator orthophenanthroline; only slightly reduced activity was seen with serine, aspartate, or cysteine proteinase inhibitors. These findings implicate metalloproteinase (MMP) as the relevant caseinase that was increased during structural luteolysis. The major proteinase identified by zymography had apparent sizes of 72 and 66 kilodaltons (kDa), and slight but detectable activity was also seen at 92 and 84 kDa. Organomercurial treatment caused a major shift of the 72-kDa band to 66 kDa and the 92-kDa band to 84 kDa, confirming MMP-2 and MMP-9 by activation of latent activity of each MMP, respectively. Structural luteolysis caused a significant increase in the activated 66-kDa form and the latent 72-kDa form of MMP-2, which occurred before a loss of luteal weight or protein. As MMP-2 degrades collagen (type IV) in basement membranes, we conclude that an early event in PRL-induced structural luteolysis is the degradation of extracellular matrix. This conclusion is further emphasized by the marked and lasting depletion of ascorbic acid, a vitamin long known to serve an essential role in collagen synthesis.
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PMID:Coordinate induction and activation of metalloproteinase and ascorbate depletion in structural luteolysis. 834 7


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