Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A lot of parallels have been described between invasion of malignant tumor cells and leukocyte movement during inflammatory responses. Concerning these similarities, we investigated the function of cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via inhibition of stress-activated MAP-kinases, in regulation of expression of proteolytic enzymes and in vitro invasion of malignant melanoma cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting and confocal microscopy. Cells showed a constitutive expression of matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or urokinase-type plasminogen activator (uPA) was not detected by Northern blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted in downregulation of MMP-2 mRNA and protein levels as well as gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2 mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059 changed proliferation of cells. The results suggest that stress-activated protein kinases like p38MAPK are involved in regulation of expression of MMP-2 as well as in vitro invasion of malignant melanoma cells. Inhibitors of p38MAPK may be promising substances to interfere with a signaling cascade associated with invasion of malignant tumor cells.
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PMID:An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. 1191 86

Periodontitis is associated with enhanced production of cytokines, prostaglandins and matrix metalloproteinases (MMPs). The aim of this study was to investigate the production and regulation of MMP-1 and MMP-3 in human gingival fibroblasts challenged with the cytokines interleukin-lbeta (IL-1beta), tumor necrosis factor alpha (TNFalpha) or epidermal growth factor (EGF). The results showed that gingival fibroblasts constitutively produce MMP-1 and MMP-3, and that the cytokines IL-1beta, TNFalpha and EGF increase both MMP-1 and MMP-3 production in gingival fibroblasts. The upregulation by the cytokines was apparent at 8 h of incubation and increased thereafter continuously during 48 h of incubation. The upregulation of MMPs, induced by IL-1beta or TNFalpha, was reduced by the cyxlooxygenase-2 (COX-2) inhibitor NS-398, the p38 MAP-kinase inhibitor SB 203580, and the tyrosine kinase inhibitor herbimycin A. In addition, MMP-1 and MMP-3 production, induced by IL-1beta, TNFalpha or EGF, was strongly reduced by the presence of the glucocorticoid dexamethasone. Our findings demonstrate that the cytokines IL-1beta, TNFalpha and EGF, respectively, enhance both MMP-1 and MMP-3 production in human gingival fibroblasts, and that the signal pathways COX-2, MAP-kinases and tyrosine kinases are partly involved in the production of MMPs.
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PMID:Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. 1220 92

Inflammatory changes invoked by the intrauterine device (IUD) are reviewed. Insertion of IUD initiates a foreign body reaction by causing minor localized tissue injury, which leads to vascular and cellular changes. Progesterone exerts a local and systemic effect and it changes the morphological and biochemical responses on the endometrium depending on the amount of progesterone released from the device. There is an increase in the concentration of neutral proteases such as collagenase, elastase, plasminogen activator, and trypsin like enzymes. The alpha-macroglobulin appears to be the most effective inhibitor of polymorphonuclear collagenase. The IUD initiated inflammation is characterized by an increase in the vascular permeability and transport of IgG. High levels of B4, C4 and D4, members of the lekotriene family, have been postulated to induce microcirculatory alterations in vivo, (Dahlin et al). Aspirin and indomethacin partially prevent the inflammatory changes induced by IUD, (Chowdhary, 1975). Nonsteroidal drugs, indomethacin, diclofenac, meclofenamic acid, flufenamic acid and naproxen may act by inhibiting prostaglandin synthesis. Nonsteroidal anti-inflammatory agents may be able to inhibit the proteinase stimulated proteolytic and collagenolytic activity resulted by migration of leukocytes and macrophages.
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PMID:Inflammatory changes in intrauterine contraceptive devices. 1231 39

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.
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PMID:Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes. 1501 31

Insulin resistance is a cardinal feature of type 2 diabetes and also a consequence of trauma such as surgery. Directly after surgery and cell isolation, adipocytes were insulin resistant, but this was reversed after overnight incubation in 10% CO(2) at 37 degrees C. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1 was insulin sensitive, but protein kinase B (PKB) and downstream metabolic effects exhibited insulin resistance that was reversed by overnight incubation. MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. Phosphorylation of MAP-kinase was not caused by collagenase treatment during cell isolation and was present also in tissue pieces that were not subjected to cell isolation procedures. The insulin resistance directly after surgery and cell isolation was different from insulin resistance of type 2 diabetes; adipocytes from patients with type 2 diabetes remained insulin resistant after overnight incubation. IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. These findings suggest a new approach in the study of surgery-induced insulin resistance and indicate that human adipocytes should recover after surgical procedures for analysis of insulin signalling. Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes.
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PMID:Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. 1563 39

Retinoic acid and its synthetic analogs exert major effects on many biological processes including cell proliferation and differentiation and are now considered as promising pharmacological agents for prevention and treatment of various cancers. The capacity of retinoids to inhibit AP1-responsive genes seems to be the basis for the chemopreventive and chemotherapeutic effects of these agents against hyperproliferative diseases. However, the molecular basis of retinoid antiproliferative properties remains to this day largely unknown. Here, we showed that retinoids inhibit phorbol ester-induced MMP-1 and MMP-3 expression in human breast cancer cells. Transcriptional interference was observed for both retinoid agonist and antagonist treatments, revealing separated transactivation and transrepression functions of retinoids. In addition, we examined MAP kinases as potential targets of retinoid signalling in human breast cancer cells and demonstrated that retinoids repress AP1-responsive gene expression by inhibiting MKK6/p38 and mainly MEK/ERK signalling pathways. On the contrary, the JNK-dependent pathway was not identified as a molecular relay for AP1 activity and was insensitive to retinoid treatments. Finally, we established that overexpressed c-fos and c-jun partially abolished the ability of retinoids to inhibit AP1 activity, suggesting that c-jun and/or c-fos containing dimers may constitute one target of retinoids for transrepression of AP1. All together, our data help to improve our understanding of how retinoids antagonize AP1 activity and may regulate tumoral cell proliferation.
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PMID:Retinoids interfere with the AP1 signalling pathway in human breast cancer cells. 1617 68

The hypothesis was tested that bovine preantral follicles can be stimulated to grow in vitro by FSH and by the mitogens, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), but not by transforming growth factor-beta (TGFbeta), which generally inhibits EGF and bFGF action. Preantral follicles, 60 to 179 mum in diameter, were isolated from fetal ovaries by treatment with collagenase and DNase and cultured for 6 d in serum-free medium, with or without FSH and growth factors. Basic FGF (50 ng/ml), and to a lesser extent FSH (100 ng/ml) and EGF (50 ng/ml), stimulated thymidine incorporation by granulosa cells in bovine preantral follicles compared to control cultures (8-, 4- and 2.5-fold the labeling index of the controls; P < 0.05). Alone TGFbeta (10 ng/ml) had no effect on (3)H-thymidine incorporation, but it completely inhibited the bFGF- but not the FSH-stimulated increase in the labeling index and mean follicular diameter of preantral follicles (P < 0.05). By the end of the culture period oocytes in most treatments had degenerated, and the few surviving oocytes were in preantral follicles cultured with FSH or bFGF. Progesterone accumulation was greater (P < 0.05) in the presence of FSH (100 ng/ml) or EGF (50 ng/ml) than with bFGF, TGFbeta or control medium. Basic FGF strongly inhibited the effect of FSH on progesterone secretion (P < 0.05). Only FSH stimulated the conversion of exogenous testosterone to estradiol and both bFGF and TGFbeta markedly inhibited FSH-stimulated estradiol accumulation. These results indicate that proliferation of granulosa cells of bovine preantral follicles can be stimulated by bFGF, FSH and EGF, whereas TGFbeta inhibits growth, and that they are steroidogenically active in culture. Basic FGF and TGFbeta antagonize FSH-stimulated steroid production by granulosa cells of cultured bovine preantral follicles.
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PMID:FSH and growth factors affect the growth and endocrine function in vitro of granulosa cells of bovine preantral follicles. 1672 44

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal - placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.
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PMID:The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. 1725 97

The present study was designed to incubate luteal cells isolated from pseudopregnant cats and to investigate the effects of cholesterol and cAMP on luteal progesterone production. Corpora lutea were collected from the cats on days 10 and 15 of pseudopregnancy. Luteal cells were isolated from the ovaries by collagenase digestion. Steroidogenic luteal cells were stained for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity. Cells (2 x 10(4)) staining positive for 3beta-HSD were cultured for up to 7 days. The cells were treated with 22(R)-hydroxycholesterol (22R-HC) and dibutyryl cyclic AMP (dbcAMP) on days 1, 3 and 7. Treatment of cells with 22R-HC resulted in a dose-dependent increase (p<0.001) in progesterone production. When 22R-HC was used at a concentration of 10 microg/ml, it resulted in 2.7- and 5.1-fold increases in progesterone production on days 3 and 5, respectively. When the dose was doubled (20 microg/ml), treated cells produced four times more progesterone on days 3 and 7, and three times more on day 5. By day 7, progesterone production increased up to 9.1 times more than the control. Incubation of cells with both concentrations of dbcAMP (0.1 mM and 1 mM) resulted in significant stimulations of progesterone on days 5 and 7 (p<0.001). However, on day 3, only higher doses of dbcAMP (1 mM) resulted in significant stimulation (p<0.05). Progesterone production was increased up to 2- and 2.9-fold of the control when cells were treated with lower concentration of dbcAMP (0.1 mM) on days 5 and 7, respectively. Incubation of cells with 1 mM concentrations of dbcAMP induced a 3.2-fold increase on day 5 and a 5-fold increase on day 7. In conclusion, a successful incubation was performed for long-life culturing of luteal cells collected from pseudopregnant cats. The method works well and allows for optimal growth and development of cells in the culture. The present study also demonstrated that incubating cat luteal cells with 22R-HC and dbcAMP induces a significant increase in luteal progesterone synthesis.
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PMID:Effects of cholesterol and cAMP on progesterone production in cultured luteal cells isolated from pseudopregnant cat ovaries. 1913 21

Ultraviolet (UV) irradiation induces the expression of matrix metalloproteinases (MMPs), disturbing the metabolism of extracellular matrix (ECM), and causes the characteristic changes of photoaging in skin. Inhibition of induction of MMPs is suggested to alleviate photoaging induced by UV irradiation. Zeatin, purified from Zea mays, is a member of the cytokinin group of plant growth factors, the activity of which is attributed to its more stable trans form. In this study, we investigated the effect of trans-Zeatin on UVB-induced matrix metalloproteinase-1 (MMP-1) expression in cultured human skin fibroblasts (HSFs) and studied the mechanisms of its actions. We found that pretreatment with trans-Zeatin significantly inhibits UVB-induced MMP-1 expression and c-Jun activation in a dose-dependent manner. We also observed that trans-Zeatin inhibits UVB-induced phosphorylation of ERK, JNK and p38 MAP kinases (MAPKs) dose-dependently. As expected, PD98059, an ERK inhibitor, SP600125, a JNK inhibitor and SB203580, a p38 MAPK inhibitor effectively inhibit UVB-induced phosphorylation of ERK, JNK and p38 MAPKs, respectively. Moreover, the inhibitory mechanism of trans-Zeatin was further demonstrated in MMP-1 secretion using MAPK-specific inhibitors. PD98059, SP600125 and SB203580 suppressed UVB-induced MMP-1 secretion, which is consistent with the above results. Collectively, our results suggest that trans-Zeatin inhibits UVB-induced MMP-1 expression, which may be mediated by inhibition of ERK, JNK and p38 MAPKs signaling pathways in HSFs. Trans-Zeatin is a potential agent for the management of skin photoaging.
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PMID:Trans-Zeatin inhibits UVB-induced matrix metalloproteinase-1 expression via MAP kinase signaling in human skin fibroblasts. 1928 33


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