Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to investigate the influence of insulin on lipopolysaccharide (LPS)-induced acute lung injury. Diabetic male Wistar rats (alloxan, 42 mg/kg, i.v., 30 days) and controls were instilled with saline containing LPS (750 microg/0.4 mL) or saline alone. The following analyses were performed 6 h there after: (a) total and differential cell counts in bronchoalveolar lavage (BAL) fluid, (b) quantification of tumor necrosis factor alpha, interleukin (IL) 1beta, IL-10, and cytokine-induced neutrophil chemoattractant 1 in the BAL (enzyme-linked immunosorbent assay), (c)immunohistochemistry for intercellular adhesion molecule 1 and E-selectin on lung vessels, and (d) quantification of metalloproteinases (MMP) 2 and 9 in the BAL (zymography). Relative to controls, diabetic rats exhibited a reduction in the number of neutrophils (80%) and reduced concentrations of tumor necrosis factor alpha (56%), IL-1beta (66%), and IL-10 (35%) after LPS instillation. Cytokine-induced neutrophil chemoattractant 1 levels did not differ between groups. Increased levels of MMP-2 (90%) and MMP-9 (500%) were observed in diabetic rats compared with controls. Treatment of diabetic rats with neutral protamine Hagedorn insulin (4 IU, s.c.), 2 h before LPS instillation, completely restored the number of neutrophils and concentrations of cytokines in the BAL fluid. Despite no significant differences between diabetic and control groups, there was a remarkable increase in intercellular adhesion molecule 1 and E-selectin expression on lung vessels after insulin treatment. Levels of MMP-2 and MMP-9 did not change after treatment with insulin. Levels of corticosterone were equivalent among groups. Data presented suggest that insulin modulates the production/release of cytokines and the expression of adhesion molecules controlling, therefore, neutrophil migration during the course of LPS-induced acute lung inflammation.
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PMID:Modulation of lipopolysaccharide-induced acute lung inflammation: Role of insulin. 1655 58

It has been well established that invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP), a multifunctional membrane-tethered enzyme, functions in cancer cells as a mediator of pericellular proteolysis and directly cleaves several cell surface receptors, including CD44. In this report, we confirm that adhesion of diabetogenic T cells promotes the activation of endogenous MT1-MMP. Activated protease then cleaves CD44 in adherent T cells. We have validated that the T cell CD44 receptor is critical for the adhesion of diabetogenic insulin-specific, CD8-positive, K(d)-restricted cells to the matrix as well as for the subsequent transmigration of the adherent T cells through the endothelium and homing of the transmigrated T cells into the pancreatic islets. We have determined that the inhibition of MT1-MMP by low dosages of AG3340 (a subnanomolar range hydroxamate inhibitor of MMPs that has been widely tested in cancer patients) inhibited both T cell MT1-MMP activity and MT1-MMP-dependent shedding of CD44, immobilized T cells on the endothelium, repressed the homing of diabetogenic T cells into the pancreatic islets, reduced insulitis and mononuclear cell infiltration, and promoted either the recovery or the rejuvenation of the functional insulin-producing beta cells in diabetic NOD mice with freshly developed type I diabetes (IDDM). We believe our data constitute a mechanistic and substantive rationale for clinical trials of selected MT1-MMP inhibitors in the therapy of IDDM in humans.
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PMID:Mechanistic insights into targeting T cell membrane proteinase to promote islet beta-cell rejuvenation in type 1 diabetes. 1694 Jan 51

Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, beta-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes.
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PMID:Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes. 1736 74

Arterial hypertension is associated with organ dysfunctions, but the mechanisms are uncertain. We hypothesized that enhanced proteolytic activity in the microcirculation of spontaneously hypertensive rats (SHRs) may be a pathophysiological mechanism causing cell membrane receptor cleavage and examine this for 2 different receptors. Immunohistochemistry of matrix-degrading metalloproteinases (matrix metalloproteinase [MMP]-9) protein shows enhanced levels in SHR microvessels, mast cells, and leukocytes compared with normotensive Wistar-Kyoto rats. In vivo microzymography shows cleavage by MMP-1 and -9 in SHRs that colocalizes with MMP-9 and is blocked by metal chelation. SHR plasma also has enhanced protease activity. We demonstrate with an antibody against the extracellular domain that the insulin receptor-alpha density is reduced in SHRs, in line with elevated blood glucose levels and glycohemoglobin. There is also cleavage of the binding domain of the leukocyte integrin receptor CD18 in line with previously reported reduced leukocyte adhesion. Blockade of MMPs with a broad-acting inhibitor (doxycycline, 5.4 mg/kg per day) reduces protease activity in plasma and microvessels; blocks the proteolytic cleavage of the insulin receptor, the reduced glucose transport; normalizes blood glucose levels and glycohemoglobin levels; and reduces blood pressure and enhanced microvascular oxidative stress of SHRs. The results suggest that elevated MMP activity leads to proteolytic cleavage of membrane receptors in the SHR, eg, cleavage of the insulin receptor-binding domain associated with insulin resistance.
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PMID:Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. 1854 34

To gain insight into the pathogenesis of hepatic fibrosis related to insulin resistance, we have examined the effects of euglycemic hyperinsulinemia on three matrix metalloproteinases (MMP-2, MMP-9, and MT1-MMP) and on two major tissue inhibitors of MMPs (TIMP-1 and TIMP-2) in liver of insulin-sensitive and insulin-resistant rats. Four hours of insulin infusion (4.8 mU.kg(-1).min(-1)) without or with lipid-heparin infusion (to produce insulin resistance) decreased hepatic MMP-2 mRNA (by RT-PCR), pro-MMP-2, MMP-2, MMP-9, and MT1-MMP (all by Western blots) and the gelatinolytic activity of MMP-2 (by gelatin zymography) by approximately 60-80%. Hyperinsulinemia ( approximately 1.6 mmol/l) increased TIMP-1 and TIMP-2 concentrations (by ELISA) in insulin-sensitive and insulin-resistant rats. Phosphoinositide 3-kinase was activated by insulin in insulin-sensitive rats and inhibited in insulin-resistant rats. Extracellular signal-regulated kinases 1/2 (ERK1/2) were activated by insulin in insulin-sensitive rats and partially inhibited in insulin-resistant rats; c-jun NH(2)-terminal kinase-1 (JNK1), JNK2/3, or p38 MAPK were only activated by lipid but not by insulin. We conclude that hyperinsulinemia, whether or not associated with insulin resistance, shifts the MMP/TIMP balance toward reduction of extracellular matrix degradation and thus may promote the development of hepatic fibrosis.
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PMID:Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors. 1866 96

In search of an autologous vascularized skin substitute, we treated full-thickness wounds (FTWs) with autologous platelet-rich plasma gel (APG) in which we embedded endothelial progenitor cells (EPCs) and basal cell keratinocytes (KCs). We cultivated autologous KCs in low-serum conditions and expanded autologous EPCs from venous blood. FTWs (n = 55) were created on the backs of four pigs, covered with wound chambers, and randomly assigned to the following treatments: (1) APG, (2) APG + KCs, (3) APG + EPCs, (4) APG + KCs + EPCs, and (5) saline. All wounds were biopsied to measure neovascularization (lectin Bandeiraea Simplicifolia-1 (BS-1), alpha smooth muscle actin [alphaSMA], and membrane type 1 matrix metalloproteinase (MT1-MMP)), matrix deposition (fibronectin, collagen type I/III, and alphavbeta3), and reepithelialization. Wound fluids were analyzed for protein expression. All APG-treated wounds showed more vascular structures (p < 0.001), and the addition of EPCs further improved neovascularization, as confirmed by higher lectin, alphaSMA, and MT1-MMP. APG groups had higher collagen I/III (p < 0.05), alphavbeta3, and fibronectin content (p < 0.001), and they exhibited higher concentrations of platelet-derived growth factor subunit bb, basic fibroblast growth factor, hepatocyte growth factor, insulin growth factor-1, transforming growth factor-beta1 and -beta3, matrix metalloproteinase-1 and -z9, and tissue-inhibiting matrix metalloproteinase-1 and -2. Applying APG + KCs resulted in the highest reepithelialization rates (p < 0.001). No differences were found for wound contraction by planimetry. In this porcine FTW model, APG acts as a supportive biomatrix that, along with the embedded cells, improves extracellular matrix organization, promotes angiogenesis, and accelerates reepithelialization.
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PMID:A plasma-based biomatrix mixed with endothelial progenitor cells and keratinocytes promotes matrix formation, angiogenesis, and reepithelialization in full-thickness wounds. 1908 5

The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.
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PMID:Matrix metalloproteinases, T cell homing and beta-cell mass in type 1 diabetes. 1925 Oct 49

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. We have previously shown significant therapeutic activity for recombinant adenoviruses expressing dominant-negative insulin-like growth factor-I receptor (IGF-IR/dn), including suppression of tumor invasion. In this study, we sought to evaluate the mechanism of inhibition of invasion and the relationship between IGF-IR and matrix metalloproteinase (MMP) activity in GI carcinomas. We analyzed the role of IGF-IR on invasion in three GI cancer cell lines, colorectal adenocarcinoma, HT29; pancreatic adenocarcinoma, BxPC3 and gastric adenocarcinoma, MKN45, using a modified Boyden chamber method and subcutaneous xenografts in nude mice. The impact of IGF-IR signaling on the expression of MMPs and the effects of blockade of matrilysin or IGF-IR on invasiveness were assessed using recombinant adenoviruses, a tyrosine kinase inhibitor NVP-AEW541 and antisense matrilysin. Invasive subcutaneous tumors expressed several MMPs. IGF-IR/dn reduced the expression of these MMPs but especially matrilysin (MMP-7). Insulin-like growth factor (IGF) stimulated secretion of matrilysin and IGF-IR/dn blocked IGF-mediated matrilysin induction in three GI cancers. Both IGF-IR/dn and inhibition of matrilysin reduced in vitro invasion to the same degree. NVP-AEW541 also reduced cancer cell invasion both in vitro and in murine xenograft tumors via suppression of matrilysin. Thus, blockade of IGF-IR is involved in the suppression of cancer cell invasion through downregulation of matrilysin. Strategies of targeting IGF-IR may have significant therapeutic utility to prevent invasion and progression of human GI carcinomas.
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PMID:Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin. 1949 5

Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, anti-atherogenic, and anti-proliferative effects. The expression of specific adiponectin receptors in the placenta and in the endometrium suggests a role for this cytokine in placental development, but this role has not yet been elucidated. The invasion of trophoblast cells during the first trimester of pregnancy being crucial to placentation process, we have studied adiponectin effects on human trophoblast invasive capacities. We found that adiponectin stimulated human trophoblast cell migration in HTR-8/SVneo cells in a dose-independent manner. In addition, adiponectin also significantly enhanced invasion of HTR-8/SVneo cells and of human extravillous trophoblast from first trimester placenta. These pro-invasive effects of adiponectin in human trophoblasts seem to be mediated in part via increased matrix metalloproteinases (MMP2 and MMP9) activities and via repression of TIMP2 mRNA expression. Our results suggest that adiponectin could be a positive regulator of the early invasion process by modulating the MMP/TIMP balance. Moreover, these results provide an insight into the role of adiponectin in pathological conditions characterized by insufficient or excessive trophoblast invasion.
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PMID:Effects of adiponectin on human trophoblast invasion. 2067 5

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility.
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PMID:Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers. 2204 63


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