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Sample records for matrix factors mmp-2

  1. Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis▿ †

    PubMed Central

    Dean, Richard A.; Butler, Georgina S.; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R.; Courty, José; Overall, Christopher M.

    2007-01-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2−/− mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2−/− cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis. PMID:17908800

  2. Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura.

    PubMed

    Gonçalves, Flavia M; Martins-Oliveira, Alisson; Lacchini, Riccardo; Belo, Vanessa A; Speciali, Jose G; Dach, Fabíola; Tanus-Santos, Jose E

    2013-01-01

    Matrix metalloproteinases (MMP) are involved in the disruption of blood-brain barrier (BBB) during migraine attacks. In the present study, we hypothesized that two functional polymorphisms (C(-1306)T and C(-735)T) in MMP-2 gene and MMP-2 haplotypes are associated with migraine and modify MMP-2 and tissue inhibitor of MMP (TIMP)-2 levels in migraine. Genotypes for MMP-2 polymorphisms were determined by real time-PCR using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by gelatin zymography and ELISA, respectively, in 148 healthy women without history of migraine and in 204 women with migraine (153 without aura; MWA, and 51 with aura; MA). Patients with MA had higher plasma MMP-2 concentrations and MMP-2/TIMP-2 ratios than patients with MWA and controls (P<0.05). While MMP-2 genotype and haplotype distributions for the polymorphisms were similar among the groups (P>0.05), we found that the CC genotype for C(-735)T polymorphism and the CC haplotype were associated with higher plasma MMP-2 concentrations in MA group (P<0.05). Our findings may help to understand the role of MMP-2 and its genetic variants in the pathophysiology of migraine and to identify a particular group of migraine patients with increased MMP-2 levels that would benefit from the use of MMP inhibitors.

  3. Platelet-derived growth factor-D modulates extracellular matrix homeostasis and remodeling through TIMP-1 induction and attenuation of MMP-2 and MMP-9 gelatinase activities

    SciTech Connect

    Borkham-Kamphorst, Erawan Alexi, Pascal; Tihaa, Lidia; Haas, Ute; Weiskirchen, Ralf

    2015-02-13

    Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor involved in the regulation of several cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by binding to and activating its cognate receptor PDGFR-β. After bile duct ligation or in the carbon tetrachloride-induced hepatic fibrosis model{sub ,} PDGF-D showed upregulation comparable to PDGF-B. Moreover, adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liver fibrosis. We here investigated the molecular mechanism of PDGF-D involvement in liver fibrogenesis. Therefore, the GRX mouse cell line was stimulated with PDGF-D and evaluated for fibrotic markers and PDGF-D signaling pathways in comparison to the other PDGF isoforms. We found that PDGF-D failed to enhance Col I and α-smooth muscle actin (α-SMA) production but has capacity to upregulate expression of the tissue inhibitor of metalloprotease 1 (TIMP-1) resulting in attenuation of MMP-2 and MMP-9 gelatinase activity as indicated by gelatinase zymography. This phenomenon was restored through application of a PDGF-D neutralizing antibody. Unexpectedly, PDGF-D incubation decreased both PDGFR-α and -β in mRNA and protein levels, and PDGF-D phosphorylated typrosines specific for PDGFR-α and -β. We conclude that PDGF-D intensifies fibrogenesis by interfering with the fibrolytic activity of the TIMP-1/MMP system and that PDGF-D signaling is mediated through both PDGF-α and -β receptors. - Highlights: • PDGF-D signals through PDGF receptor type α and β. • PDGF-D modulates extracellular matrix homeostasis and remodeling. • Like PDGF-B, PDGF-D triggers phosphorylation of PLC-γ, Akt/PKB, JNK, ERK1/2, and p38. • PDGF-D induces TIMP-1 expression through ERK and p38 MAPK. • PDGF-D attenuates MMP-2 and MMP-9 gelatinase activities.

  4. Molecular design of a highly selective and strong protein inhibitor against matrix metalloproteinase-2 (MMP-2).

    PubMed

    Higashi, Shouichi; Hirose, Tomokazu; Takeuchi, Tomoka; Miyazaki, Kaoru

    2013-03-29

    Synthetic inhibitors of matrix metalloproteinases (MMPs), designed previously, as well as tissue inhibitors of metalloproteinases (TIMPs) lack enzyme selectivity, which has been a major obstacle for developing inhibitors into safe and effective MMP-targeted drugs. Here we designed a fusion protein named APP-IP-TIMP-2, in which the ten amino acid residue sequence of APP-derived MMP-2 selective inhibitory peptide (APP-IP) is added to the N terminus of TIMP-2. The APP-IP and TIMP-2 regions of the fusion protein are designed to interact with the active site and the hemopexin-like domain of MMP-2, respectively. The reactive site of the TIMP-2 region, which has broad specificity against MMPs, is blocked by the APP-IP adduct. The recombinant APP-IP-TIMP-2 showed strong inhibitory activity toward MMP-2 (Ki(app) = 0.68 pm), whereas its inhibitory activity toward MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, or MT1-MMP was six orders of magnitude or more weaker (IC50 > 1 μm). The fusion protein inhibited the activation of pro-MMP-2 in the concanavalin A-stimulated HT1080 cells, degradation of type IV collagen by the cells, and the migration of stimulated cells. Compared with the decapeptide APP-IP (t½ = 30 min), APP-IP-TIMP-2 (t½ ≫ 96 h) showed a much longer half-life in cultured tumor cells. Therefore, the fusion protein may be a useful tool to evaluate contributions of proteolytic activity of MMP-2 in various pathophysiological processes. It may also be developed as an effective anti-tumor drug with restricted side effects.

  5. Active G protein-coupled receptors (GPCR), matrix metalloproteinases 2/9 (MMP2/9), heparin-binding epidermal growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) are necessary for trenbolone acetate-induced alterations in protein turnover rate of fused bovine satellite cell cultures.

    PubMed

    Thornton, K J; Kamanga-Sollo, E; White, M E; Dayton, W R

    2016-06-01

    Trenbolone acetate (TBA), a testosterone analog, increases protein synthesis and decreases protein degradation in fused bovine satellite cell (BSC) cultures. However, the mechanism through which TBA alters these processes remains unknown. Recent studies indicate that androgens improve rate and extent of muscle growth through a nongenomic mechanism involving G protein-coupled receptors (GPCR), matrix metalloproteinases (MMP), heparin-binding epidermal growth factor (hbEGF), the epidermal growth factor receptor (EGFR), erbB2, and the insulin-like growth factor-1 receptor (IGF-1R). We hypothesized that TBA activates GPCR, resulting in activation of MMP2/9 that releases hbEGF, which activates the EGFR and/or erbB2. To determine whether the proposed nongenomic pathway is involved in TBA-mediated alterations in protein turnover, fused BSC cultures were treated with TBA in the presence or absence of inhibitors for GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R, and resultant protein synthesis and degradation rates were analyzed. Assays were replicated at least 9 times for each inhibitor experiment utilizing BSC cultures obtained from at least 3 different steers that had no previous exposure to steroid compounds. As expected, fused BSC cultures treated with 10 n TBA exhibited increased ( < 0.05) protein synthesis rates and decreased ( < 0.05) protein degradation rates when compared to control cultures. Treatment of fused BSC cultures with 10 n TBA in the presence of inhibitors for GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R suppressed ( < 0.05) TBA-mediated increases in protein synthesis rate. Alternatively, inhibition of GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R in the presence of 10 n TBA each had no ( > 0.05) effect on TBA-mediated decreases in protein degradation. However, inhibition of both EGFR and erbB2 in the presence of 10 n TBA resulted in decreased ( < 0.05) ability of TBA to decrease protein degradation rate. Additionally, fused BSC cultures treated with 10 n

  6. Active G protein-coupled receptors (GPCR), matrix metalloproteinases 2/9 (MMP2/9), heparin-binding epidermal growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) are necessary for trenbolone acetate-induced alterations in protein turnover rate of fused bovine satellite cell cultures.

    PubMed

    Thornton, K J; Kamanga-Sollo, E; White, M E; Dayton, W R

    2016-06-01

    Trenbolone acetate (TBA), a testosterone analog, increases protein synthesis and decreases protein degradation in fused bovine satellite cell (BSC) cultures. However, the mechanism through which TBA alters these processes remains unknown. Recent studies indicate that androgens improve rate and extent of muscle growth through a nongenomic mechanism involving G protein-coupled receptors (GPCR), matrix metalloproteinases (MMP), heparin-binding epidermal growth factor (hbEGF), the epidermal growth factor receptor (EGFR), erbB2, and the insulin-like growth factor-1 receptor (IGF-1R). We hypothesized that TBA activates GPCR, resulting in activation of MMP2/9 that releases hbEGF, which activates the EGFR and/or erbB2. To determine whether the proposed nongenomic pathway is involved in TBA-mediated alterations in protein turnover, fused BSC cultures were treated with TBA in the presence or absence of inhibitors for GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R, and resultant protein synthesis and degradation rates were analyzed. Assays were replicated at least 9 times for each inhibitor experiment utilizing BSC cultures obtained from at least 3 different steers that had no previous exposure to steroid compounds. As expected, fused BSC cultures treated with 10 n TBA exhibited increased ( < 0.05) protein synthesis rates and decreased ( < 0.05) protein degradation rates when compared to control cultures. Treatment of fused BSC cultures with 10 n TBA in the presence of inhibitors for GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R suppressed ( < 0.05) TBA-mediated increases in protein synthesis rate. Alternatively, inhibition of GPCR, MMP2/9, hbEGF, EGFR, erbB2, or IGF-1R in the presence of 10 n TBA each had no ( > 0.05) effect on TBA-mediated decreases in protein degradation. However, inhibition of both EGFR and erbB2 in the presence of 10 n TBA resulted in decreased ( < 0.05) ability of TBA to decrease protein degradation rate. Additionally, fused BSC cultures treated with 10 n

  7. TIMP-2 (tissue inhibitor of metalloproteinase-2) regulates MMP-2 (matrix metalloproteinase-2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP.

    PubMed Central

    Bernardo, M Margarida; Fridman, Rafael

    2003-01-01

    The matrix metalloproteinase (MMP)-2 has a crucial role in extracellular matrix degradation associated with cancer metastasis and angiogenesis. The latent form, pro-MMP-2, is activated on the cell surface by the membrane-tethered membrane type 1 (MT1)-MMP, in a process regulated by the tissue inhibitor of metalloproteinase (TIMP)-2. A complex of active MT1-MMP and TIMP-2 binds pro-MMP-2 forming a ternary complex, which permits pro-MMP-2 activation by a TIMP-2-free neighbouring MT1-MMP. It remains unclear how MMP-2 activity in the pericellular space is regulated in the presence of TIMP-2. To address this question, the effect of TIMP-2 on MMP-2 activity in the extracellular space was investigated in live cells, and their isolated plasma membrane fractions, engineered to control the relative levels of MT1-MMP and TIMP-2 expression. We show that both free and inhibited MMP-2 is detected in the medium, and that the net MMP-2 activity correlates with the level of TIMP-2 expression. Studies to displace MT1-MMP-bound TIMP-2 in a purified system with active MMP-2 show minimal displacement of inhibitor, under the experimental conditions, due to the high affinity interaction between TIMP-2 and MT1-MMP. Thus inhibition of MMP-2 activity in the extracellular space is unlikely to result solely as a result of TIMP-2 dissociation from its complex with MT1-MMP. Consistently, immunoblot analyses of plasma membranes, and surface biotinylation experiments show that the level of surface association of TIMP-2 is independent of MT1-MMP expression. Thus low-affinity binding of TIMP-2 to sites distinct to MT1-MMP may have a role in regulating MMP-2 activity in the extracellular space generated by the ternary complex. PMID:12755684

  8. The Matrix Metalloproteinase Gene GmMMP2 Is Activated in Response to Pathogenic Infections in Soybean1

    PubMed Central

    Liu, Yongqing; Dammann, Christian; Bhattacharyya, Madan K.

    2001-01-01

    Matrix metalloproteinases (MMPs) play an important role in host defense responses against pathogens in mammals where their activities lead to the production of antimicrobial peptides. We have identified a novel soybean (Glycine max) metalloproteinase gene, GmMMP2, that is transcriptionally up-regulated in infected tissues. The deduced amino acid sequence indicates that this gene belongs to the MMP family. It is a preproprotein containing an N-terminal signal peptide, a cysteine switch, a zinc-binding catalytic motif, and a C-terminal transmembrane domain. The GmMMP2 expressed in and purified from Escherichia coli exhibited an in vitro enzymatic activity in digesting myelin basic protein. All plant metalloproteinases reported so far have no known functions. However, they have been suggested to be involved in extracellular cell matrix degradation during development or senescence. Our investigations demonstrate that the GmMMP2 transcript levels were rapidly increased in compatible and incompatible interactions of soybean tissues with the oomycete pathogen Phytophthora sojae or the bacterial pathogen Pseudomonas syringae pv. glycinea. In agreement with the GmMMP2 activation, a metalloproteinase activity was gradually increased in suspension-cultured cells following the bacterial infection. GmMMP2 was also activated in response to wounding and dehydration. However, GmMMP2 activation did not correlate with the oxidative burst leading to the hypersensitive response cell death or the tissue senescence progress that involves programmed cell death. Our investigations suggest that GmMMP2 may be involved in a novel defense response of soybean against pathogenic infections. PMID:11743122

  9. Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer.

    PubMed

    Schmalfeldt, B; Prechtel, D; Härting, K; Späthe, K; Rutke, S; Konik, E; Fridman, R; Berger, U; Schmitt, M; Kuhn, W; Lengyel, E

    2001-08-01

    Proteases are linked to the malignant phenotype of different solid tumors. Therefore, the expression of the matrix metalloproteinase (MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) in the progression of ovarian cancer was investigated. Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were analyzed in tissue extracts of 19 cystadenomas and 18 low malignant potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian cancer stage International Federation of Gynecology and Obstetrics IIIc/IV and their corresponding omentum metastases by quantitative gelatin zymography and Western blot. In the same tissue extracts, antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA. Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but increased significantly from LMP tumors to advanced ovarian cancers. The highest values of all of the proteolytic factors were detected in omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in ovarian cancer (66%) and corresponding metastases (93%) but never in benign or LMP tumors. The activation rate of MMP-2 to its active isoform was higher in the metastases. Comparing both proteolytic systems, higher PAI-1 concentrations were consistently found in cancers with high pro-MMP-9 expression. These data indicate that members of the plasminogen activator system, as well as the metalloproteinases MMP-2/9, increase with growing malignant potential of ovarian tumors. These findings are of particular relevance to the development of protease inhibitors as new therapeutic approaches in ovarian cancer.

  10. Role of immunohistochemical overexpression of matrix metalloproteinases MMP-2 and MMP-11 in the prognosis of death by ovarian cancer.

    PubMed

    Périgny, Martine; Bairati, Isabelle; Harvey, Isabelle; Beauchemin, Michel; Harel, François; Plante, Marie; Têtu, Bernard

    2008-02-01

    Matrix metalloproteinases (MMPs) are enzymes thought to be involved in tumor invasion. We hypothesized that MMP-2 and MMP-11 overexpression was associated with the aggressiveness of ovarian carcinoma. This study was performed on samples from 100 patients with stage III ovarian carcinomas treated surgically between 1990 and 2000. Immunohistochemical staining was performed on ovarian tumors and peritoneal implants using monoclonal antibodies. Overexpression was defined as more than 10% of cells expressing the marker. Multivariate analyses showed that only MMP-2 overexpression by cancer cells in peritoneal implants was associated with a significant risk of death by disease (hazard ratio, 2.65; 95% confidence interval, 1.41-4.97; P =.003). MMP-11 overexpression was not predictive of survival. These results suggest that MMP-2 overexpression by cancer cells in peritoneal implants and not in the primary ovarian cancer is predictive of ovarian cancer prognosis and more likely reflects the presence of particularly aggressive clones of cancer cells.

  11. Smoothelin-B is not a target of matrix metalloproteinase (MMP)-2 in the vasculature of endotoxemic rats.

    PubMed

    de Souza, Priscila; Mazzaron de Castro, Michele; Goobie, Gillian; da Silva-Santos, Jose Eduardo; Schulz, Richard

    2014-10-01

    Smoothelin-B (SMTL-B) and calponin-1 are important regulators of vascular contraction. SMTL-B contains a calponin-homology domain and is structurally similar to cardiac troponin T. As calponin-1 and troponin T are proteolyzed by intracellular matrix metalloproteinase (MMP)-2 in oxidative stress injury, we hypothesized that SMTL-B is also cleaved by MMP-2 and contributes to lipopolysaccharide (LPS)-induced vascular hypocontractility. Rats received ONO-4817 (an MMP inhibitor) or its vehicle, 2 h prior to being administered lipopolysaccharide (LPS). LPS-induced aorta hypocontractility to potassium chloride or phenylephrine, and reduction of calponin-1 levels, were abolished by ONO-4817 at 6 but not 3 h after LPS. However, the level of SMTL-B was unaltered in LPS aortas and further unaffected by ONO-4817. Despite the importance of SMTL-B in vascular tone, it is not a target of MMP-2 in LPS-induced hypocontractility. PMID:25272092

  12. CIL-102 induces matrix metalloproteinase-2 (MMP-2)/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability.

    PubMed

    Liu, Wen-Hsin; Chen, Yeh-Long; Chang, Long-Sen

    2012-12-01

    This study explores the CIL-102 suppression mechanism on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia K562 cells. CIL-102 attenuated K562 cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels. Moreover, CIL-102 reduced luciferase activity of MMP-2/MMP-9 promoter constructs and MMP-2/MMP-9 mRNA stability. CIL-102 treatment induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Transfection of constitutively active MEK1 restored MMP-2 and MMP-9 promoter activity in CIL-102-treated cells, while suppression of p38 MAPK/JNK activation abolished CIL-102-induced MMP-2/MMP-9 mRNA decay. CIL-102-induced p38 MAPK/JNK activation led to protein phosphatase 2A-mediated tristetraprolin (TTP) down-regulation. The reduction in TTP-KH-type splicing regulatory protein (KSRP) complexes formation promoted KSRP-mediated MMP-2/MMP-9 mRNA decay in CIL-102-treated K562 cells. Moreover, CIL-102 reduced invasion and MMP-2/MMP-9 expression in breast and liver cancer cells. Taken together, our data indicate that CIL-102 induces MMP-2/MMP-2 down-regulation via simultaneous suppression of genetic transcription and mRNA stability, and suggest a potential utility for CIL-102 in reducing MMP-2/MMP-9-mediated cancer progression.

  13. Epidermal growth factor receptor regulates MT1-MMP and MMP-2 synthesis in SiHa cells via both PI3-K/AKT and MAPK/ERK pathways.

    PubMed

    Zhang, Zongfeng; Song, Tiefang; Jin, Yinglan; Pan, Jiaqi; Zhang, Liying; Wang, Lingdi; Li, Peiling

    2009-08-01

    Matrix metalloproteinase 2 (MMP-2) and membrane type 1 matrix metalloproteinase (MT1-MMP) have been identified as important participants in tumor invasion, metastasis, and angiogenesis. Membrane type 1 matrix metalloproteinase has also been recognized as a major activator of MMP-2. The purpose of this study was to investigate epidermal growth factor (EGF) mediating signal pathways in the regulation of MMP-2 and MT1-MMP in SiHa cells, a cervical cancer cell line. We showed here that EGF induced the expression of MT1-MMP and inhibited the expression of MMP-2 at both the mRNA and protein levels. Membrane type 1 matrix metalloproteinase induction was blocked by mitogen-activated protein kinase or extracellular signal-regulated kinase inhibitors PD98059 and U0126 but not by phosphatidylinositol-3 kinase (PI3-K) inhibitors LY294002 and wortmannin. Interestingly, the mitogen-activated protein kinase or extracellular signal-regulated kinase inhibitors PD98059 and U0126 actually increased MMP-2 mRNA and protein synthesis, whereas the PI3-K inhibitors LY294002 and wortmannin further suppressed the expression of MMP-2. Our results suggest that EGF receptor up-regulated the expression of MT1-MMP and down-regulated the synthesis of MMP-2 through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway while concomitantly transmitting a mild positive regulatory signal to the expression of MMP-2 via the PI3-K/AKT pathway in SiHa cells. Furthermore, we found that EGF elevated the activity of MMP-2 in culture media.

  14. Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation.

    PubMed

    Chen, Hongyan; Yuan, Yi; Zhang, Chunpeng; Luo, Aiping; Ding, Fang; Ma, Jianlin; Yang, Shouhui; Tian, Yanyan; Tong, Tong; Zhan, Qimin; Liu, Zhihua

    2012-05-18

    S100 proteins have been implicated in tumorigenesis and metastasis. As a member of S100 proteins, the role of S100A14 in carcinogenesis has not been fully understood. Here, we showed that ectopic overexpression of S100A14 promotes motility and invasiveness of esophageal squamous cell carcinoma cells. We investigated the underlying mechanisms and found that the expression of matrix metalloproteinase (MMP)-2 is obviously increased after S100A14 gene overexpression. Inhibition of MMP2 by a specific MMP2 inhibitor at least partly reversed the invasive phenotype of cells overexpressing S100A14. By serendipity, we found that S100A14 could affect p53 transactivity and stability. Thus, we further investigated whether the effect of MMP2 by S100A14 is dependent on p53. A series of biochemical assays showed that S100A14 requires functional p53 to affect MMP2 transcription, and p53 potently transrepresses the expression of MMP2. Finally, RT-quantitative PCR analysis of human breast cancer specimens showed a significant correlation between S100A14 mRNA expression and MMP2 mRNA expression in cases with wild-type p53 but not in cases with mutant p53. Collectively, our data strongly suggest that S100A14 promotes cell motility and invasiveness by regulating the expression and function of MMP2 in a p53-dependent manner. PMID:22451655

  15. Downregulation of matrix metalloproteinase-2 (MMP-2) utilizing adenovirus-mediated transfer of small interfering RNA (siRNA) in a novel spinal metastatic melanoma model.

    PubMed

    Tsung, Andrew J; Kargiotis, Odysseas; Chetty, Chandramu; Lakka, Sajani S; Gujrati, Meena; Spomar, Daniel G; Dinh, Dzung H; Rao, Jasti S

    2008-03-01

    Matrix metalloproteinases (MMPs) comprise a class of secreted zinc-dependent endopeptidases implicated in the metastatic potential of tumor cells due to their ability to degrade the extracellular matrix (ECM) and basement membrane. Matrix metalloproteinase-2 (MMP-2) has been detected in high levels and correlates with invasiveness in human melanoma. We have studied the effect of adenovirus-mediated transfer of small interfering RNA (siRNA) against MMP-2 in the human melanoma cell line A2058. The delivery of these double-stranded RNA molecules represents an efficient technology in silencing disease-causing genes with known sequences at the post-transcriptional level. siRNA against MMP-2 mRNA (Ad-MMP-2) was found to decrease MMP-2 protein expression and activity in melanoma cells as demonstrated by western blotting and gelatin zymography. Furthermore, infection of cells with Ad-MMP-2 inhibited cellular migration and invasion as indicated by spheroid and matrigel assays. We also observed dose-dependent suppression of vascular network formation in an angiogenesis assay. Finally, we developed a nude mouse spinal metastatic model to investigate the local effects of tumor metastasis. Intravenous tail vein injection with Ad-MMP-2 on days 5, 9 and 11 after tumor implantation resulted in complete retention of neurological function as compared to control and scrambled vector (Ad-SV)-treated groups that showed complete paraplegia by day 14+/-2 days. Hematoxylin and eosin staining revealed decreased tumor size in the Ad-MMP-2-treated animals. This novel experimental model revealed that adenoviral-mediated transfer of RNA interference against MMP-2 results in the retention of neurological function and significantly inhibited tumor growth.

  16. Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression*

    PubMed Central

    Song, Chenlin; Zhu, Songcheng; Wu, Chuanyue; Kang, Jiuhong

    2013-01-01

    Aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Some HDAC inhibitors are widely considered as promising anticancer therapeutics. A major obstacle for development of HDAC inhibitors as highly safe and effective anticancer therapeutics is that our current knowledge on the contributions of different HDACs in various cancer types remains scant. Here we report that the expression level of HDAC10 was significantly lower in patients exhibiting lymph node metastasis compared with that in patients lacking lymph node metastasis in human cervical squamous cell carcinoma. Forced expression of HDAC10 in cervical cancer cells significantly inhibited cell motility and invasiveness in vitro and metastasis in vivo. Mechanistically, HDAC10 suppresses expression of matrix metalloproteinase (MMP) 2 and 9 genes, which are known to be critical for cancer cell invasion and metastasis. At the molecular level, HDAC10 binds to MMP2 and -9 promoter regions, reduces the histone acetylation level, and inhibits the binding of RNA polymerase II to these regions. Furthermore, an HDAC10 mutant lacking histone deacetylase activity failed to mimic the functions of full-length protein. These results identify a critical role of HDAC10 in suppression of cervical cancer metastasis, underscoring the importance of developing isoform-specific HDAC inhibitors for treatment of certain cancer types such as cervical squamous cell carcinoma. PMID:23897811

  17. Histone deacetylase (HDAC) 10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase (MMP) 2 and 9 expression.

    PubMed

    Song, Chenlin; Zhu, Songcheng; Wu, Chuanyue; Kang, Jiuhong

    2013-09-27

    Aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Some HDAC inhibitors are widely considered as promising anticancer therapeutics. A major obstacle for development of HDAC inhibitors as highly safe and effective anticancer therapeutics is that our current knowledge on the contributions of different HDACs in various cancer types remains scant. Here we report that the expression level of HDAC10 was significantly lower in patients exhibiting lymph node metastasis compared with that in patients lacking lymph node metastasis in human cervical squamous cell carcinoma. Forced expression of HDAC10 in cervical cancer cells significantly inhibited cell motility and invasiveness in vitro and metastasis in vivo. Mechanistically, HDAC10 suppresses expression of matrix metalloproteinase (MMP) 2 and 9 genes, which are known to be critical for cancer cell invasion and metastasis. At the molecular level, HDAC10 binds to MMP2 and -9 promoter regions, reduces the histone acetylation level, and inhibits the binding of RNA polymerase II to these regions. Furthermore, an HDAC10 mutant lacking histone deacetylase activity failed to mimic the functions of full-length protein. These results identify a critical role of HDAC10 in suppression of cervical cancer metastasis, underscoring the importance of developing isoform-specific HDAC inhibitors for treatment of certain cancer types such as cervical squamous cell carcinoma.

  18. Enhancement of Matrix Metalloproteinase-2 (MMP-2) as a Potential Chondrogenic Marker during Chondrogenic Differentiation of Human Adipose-Derived Stem Cells.

    PubMed

    Arai, Yoshie; Park, Sunghyun; Choi, Bogyu; Ko, Kyoung-Won; Choi, Won Chul; Lee, Joong-Myung; Han, Dong-Wook; Park, Hun-Kuk; Han, Inbo; Lee, Jong Hun; Lee, Soo-Hong

    2016-01-01

    Human adipose-derived stem cells (hASCs) have a capacity to undergo adipogenic, chondrogenic, and osteogenic differentiation. Recently, hASCs were applied to various fields including cell therapy for tissue regeneration. However, it is hard to predict the direction of differentiation of hASCs in real-time. Matrix metalloproteinases (MMPs) are one family of proteolytic enzymes that plays a pivotal role in regulating the biology of stem cells. MMPs secreted by hASCs are expected to show different expression patterns depending on the differentiation state of hASCs because biological functions exhibit different patterns during the differentiation of stem cells. Here, we investigated proteolytic enzyme activity, especially MMP-2 activity, in hASCs during their differentiation. The activities of proteolytic enzymes and MMP-2 were higher during chondrogenic differentiation than during adipogenic and osteogenic differentiation. During chondrogenic differentiation, mRNA expression of MMP-2 and the level of the active form of MMP-2 were increased, which also correlated with Col II. It is concluded that proteolytic enzyme activity and the level of the active form of MMP-2 were increased during chondrogenic differentiation, which was accelerated in the presence of Col II protein. According to our findings, MMP-2 could be a candidate maker for real-time detection of chondrogenic differentiation of hASCs. PMID:27322256

  19. Enhancement of Matrix Metalloproteinase-2 (MMP-2) as a Potential Chondrogenic Marker during Chondrogenic Differentiation of Human Adipose-Derived Stem Cells

    PubMed Central

    Arai, Yoshie; Park, Sunghyun; Choi, Bogyu; Ko, Kyoung-Won; Choi, Won Chul; Lee, Joong-Myung; Han, Dong-Wook; Park, Hun-Kuk; Han, Inbo; Lee, Jong Hun; Lee, Soo-Hong

    2016-01-01

    Human adipose-derived stem cells (hASCs) have a capacity to undergo adipogenic, chondrogenic, and osteogenic differentiation. Recently, hASCs were applied to various fields including cell therapy for tissue regeneration. However, it is hard to predict the direction of differentiation of hASCs in real-time. Matrix metalloproteinases (MMPs) are one family of proteolytic enzymes that plays a pivotal role in regulating the biology of stem cells. MMPs secreted by hASCs are expected to show different expression patterns depending on the differentiation state of hASCs because biological functions exhibit different patterns during the differentiation of stem cells. Here, we investigated proteolytic enzyme activity, especially MMP-2 activity, in hASCs during their differentiation. The activities of proteolytic enzymes and MMP-2 were higher during chondrogenic differentiation than during adipogenic and osteogenic differentiation. During chondrogenic differentiation, mRNA expression of MMP-2 and the level of the active form of MMP-2 were increased, which also correlated with Col II. It is concluded that proteolytic enzyme activity and the level of the active form of MMP-2 were increased during chondrogenic differentiation, which was accelerated in the presence of Col II protein. According to our findings, MMP-2 could be a candidate maker for real-time detection of chondrogenic differentiation of hASCs. PMID:27322256

  20. The role of hypoxia inducible factor-1α in the increased MMP-2 and MMP-9 production by human monocytes exposed to nickel nanoparticles

    PubMed Central

    WAN, RONG; MO, YIQUN; CHIEN, SUFAN; LI, YIHUA; LI, YIXIN; TOLLERUD, DAVID J.; ZHANG, QUNWEI

    2016-01-01

    Nickel is an important economic commodity, but it can cause skin sensitization and may cause lung diseases such as lung fibrosis, pneumonitis, bronchial asthma and lung cancer. With development of nanotechnology, nano-sized nickel (Nano-Ni) and nano-sized titanium dioxide (Nano-TiO2) particles have been developed and produced for many years with new formulations and surface properties to meet novel demands. Our previous studies have shown that Nano-Ni instilled into rat lungs caused a greater inflammatory response as compared with standard-sized nickel (5 μm) at equivalent mass concentrations. Nano-Ni caused a persistent high level of inflammation in lungs even at low doses. Recently, several studies have shown that nanoparticles can translocate from the lungs to the circulatory system. To evaluate the potential systemic effects of metal nanoparticles, we compared the effects of Nano-Ni and Nano-TiO2 on matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) gene expression and activity. Our results showed that exposure of human monocyte U937 to Nano-Ni caused dose- and time- dependent increase in MMP-2 and MMP-9 mRNA expression and pro-MMP-2 and pro-MMP-9 activity, but Nano-TiO2 did not. Nano-Ni also caused dose- and time- related increase in tissue inhibitor of metalloproteinases 1 (TIMP-1), but Nano-TiO2 did not. To determine the potential mechanisms involved, we measured the expression of hypoxia inducible factor 1α (HIF-1α) in U937 cells exposed to Nano-Ni and Nano-TiO2. Our results showed that exposure to Nano-Ni caused HIF-1α accumulation in the nucleus. Furthermore, pre-treatment of U937 cells with heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), prior to exposure to Nano-Ni significantly abolished Nano-Ni-induced MMP-2 and MMP-9 mRNA upregulation and increased pro-MMP-2 and pro-MMP-9 activity. Our results suggest that HIF-1α accumulation may be involved in the increased MMP-2 and MMP-9 production in U937 cells

  1. Sphingosine-1-phosphate induces human endothelial VEGF and MMP-2 production via transcription factor ZNF580: Novel insights into angiogenesis

    SciTech Connect

    Sun, Hui-Yan; Wei, Shu-Ping; Xu, Rui-Cheng; Xu, Peng-Xiao; Zhang, Wen-Cheng

    2010-05-07

    Sphingosine-1-phosphate (S1P)-induced migration and proliferation of endothelial cells are critical for angiogenesis. C2H2-zinc finger (ZNF) proteins usually play an essential role in altering gene expression and regulating the angiogenesis. The aim of this study is to investigate whether a novel human C2H2-zinc finger gene ZNF580 (Gene ID: 51157) is involved in the migration and proliferation of endothelial cells stimulated by S1P. Our study shows that EAhy926 endothelial cells express S1P1, S1P3 and S1P5 receptors. Furthermore, S1P upregulates both ZNF580 mRNA and protein levels in a concentration- and time-dependent manner. SB203580, the specific inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, blocks the S1P-induced upregulation of ZNF580. Moreover, overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) expression as well as the migration and proliferation of EAhy926 endothelial cells. These results elucidate the important role that ZNF580 plays in the process of migration and proliferation of endothelial cells, which provides a foundation for a novel approach to regulate angiogenesis.

  2. Compounds isolated from Ageratum houstonianum inhibit the activity of matrix metalloproteinases (MMP-2 and MMP-9): An oncoinformatics study

    PubMed Central

    Verma, Anupriya; Rizvi, Syed Mohd. Danish; Shaikh, Sibhghatulla; Ansari, Mohd. Afaque; Shakil, Shazi; Ghazal, Fauzia; Siddiqui, Mohd. Haris; Haneef, Mohd.; Rehman, Ajijur

    2014-01-01

    Background: In osteosarcoma tissue, both MMP-2 and MMP-9 are over expressed compared to their expression in non-affected stromal tissue. Hence, gelatinases are attractive targets for anti-osteosarcoma drugs. Objective: To study the inhibitory activity of compounds isolated from Ageratum houstonianum against MMP-2 and MMP-9 by in-silico approach. Material and Methods: We performed docking study using ‘Autodock 4.2’ between 1,2-benzenedicarboxylic acid-bis (2-ethylhexyl) ester; squalene; 3,5-bis (1,1-dimethylethyl) phenol; pentamethyl tetrahydro-5H-chromene; (1, 4-cyclohexylphenyl) ethanone and 6-vinyl-7-methoxy-2,2-dimethylchromene with MMP-2 and MMP-9. Results: Among all six compounds isolated from Ageratum houstonianum, (1, 4-cyclohexylphenyl) ethanone showed the maximum potential as a putative inhibitor of both MMP-2 and MMP-9 enzymes with reference to ΔG (−7.95 and −8.2 kcal/mol, respectively) and Ki (1.48 and 0.98 μM, respectively) values. Total intermolecular energy of docking for (1, 4-cyclohexylphenyl) ethanone-MMP catalytic domain-interaction was found to be −8.55 kcal/mol for MMP-2 and −9.21 kcal/mol for MMP-9. Conclusion: This study explores molecular interactions between human MMPs (MMP-2 and MMP-9) and six natural compounds. This study predicts that (1,4-cyclohexylphenyl) ethanone is a more efficient inhibitor of human MMP-2 and MMP-9 enzymes compared to the other natural compounds used in this study with reference to Ki and ΔG values. PMID:24695379

  3. Matrix Metalloproteinase 2 (MMP-2) Plays a Critical Role in the Softening of Common Carp Muscle during Chilled Storage by Degradation of Type I and V Collagens.

    PubMed

    Xu, Chao; Wang, Cheng; Cai, Qiu-Feng; Zhang, Qian; Weng, Ling; Liu, Guang-Ming; Su, Wen-Jin; Cao, Min-Jie

    2015-12-30

    Matrix metalloproteinases (MMPs) are proposed to play important roles in the degradation of collagens, thus causing the post-mortem softening of fish muscle, although the specific mechanism remains largely unresolved. Previously, we reported the existence of gelatinase-like proteinases in common carp (Cyprinus carpio) muscle. The primary structures of these proteinases, however, have never been investigated. In the present study, two MMPs with molecular masses of 66 and 65 kDa were purified to homogeneity from common carp muscle by ammonium sulfate fractionation and a series of column chromatographies. Matrix-assisted laser desorption/ionization-tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS/MS) analysis indicated that they are completely identical to MMP-2 from common carp. During chilled storage of common carp at 4 °C, the enzymatic activity of MMP-2 increased to 212% in 12 h while the texture profile increased over the first 2 h and gradually decreased. On the other hand, type V collagen was purified to homogeneity and a specific polyclonal antibody against this protein was prepared. Both type I and V collagens were effectively hydrolyzed by MMP-2 at 30 °C and even at 4 °C. Furthermore, injection of metalloproteinase proteinase inhibitor EDTA into the blood vessel of live common carp suppressed post-mortem tenderization significantly. All of these results confirmed that MMP-2 is a major proteinase responsible for the degradation of collagens, resulting in the softening of fish muscle during chilled storage. PMID:26653826

  4. Contributions of Ocular Surface Components to Matrix-Metalloproteinases (MMP)-2 and MMP-9 in Feline Tears following Corneal Epithelial Wounding

    PubMed Central

    Petznick, Andrea; Madigan, Michele C.; Garrett, Qian; Sweeney, Deborah F.; Evans, Margaret D. M.

    2013-01-01

    Purpose This study investigated ocular surface components that contribute to matrix-metalloproteinase (MMP)-2 and MMP-9 found in tears following corneal epithelial wounding. Methods Laboratory short-haired cats underwent corneal epithelial debridement in one randomly chosen eye (n = 18). Eye-flush tears were collected at baseline and during various healing stages. Procedural control eyes (identical experimental protocol as wounded eyes except for wounding, n = 5) served as controls for tear analysis. MMP activity was analyzed in tears using gelatin zymography. MMP staining patterns were evaluated in ocular tissues using immunohistochemistry and used to determine MMP expression sites responsible for tear-derived MMPs. Results The proMMP-2 and proMMP-9 activity in tears was highest in wounded and procedural control eyes during epithelial migration (8 to 36 hours post-wounding). Wounded eyes showed significantly higher proMMP-9 in tears only during and after epithelial restratification (day 3 to 4 and day 7 to 28 post-wounding, respectively) as compared to procedural controls (p<0.05). Tears from wounded and procedural control eyes showed no statistical differences for pro-MMP-2 and MMP-9 (p>0.05). Immunohistochemistry showed increased MMP-2 and MMP-9 expression in the cornea during epithelial migration and wound closure. The conjunctival epithelium exhibited highest levels of both MMPs during wound closure, while MMP-9 expression was reduced in conjunctival goblet cells during corneal epithelial migration followed by complete absence of the cells during wound closure. The immunostaining for both MMPs was elevated in the lacrimal gland during corneal healing, with little/no change in the meibomian glands. Conjunctival-associated lymphoid tissue (CALT) showed weak MMP-2 and intense MMP-9 staining. Conclusions Following wounding, migrating corneal epithelium contributed little to the observed MMP levels in tears. The major sources assessed in the present study

  5. Preliminary evidence for a matrix metalloproteinase-2 (MMP-2)-dependent shedding of soluble CD40 ligand (sCD40L) from activated platelets.

    PubMed

    Reinboldt, Stephan; Wenzel, Folker; Rauch, Bernhard H; Hohlfeld, Thomas; Grandoch, Maria; Fischer, Jens W; Weber, Artur-Aron

    2009-09-01

    Platelets are the major source of soluble CD40 ligand (sCD40L) in the blood. It has been demonstrated that CD40L is cleaved from the surface of activated platelets to release sCD40L. However, the enzyme involved in sCD40L shedding has not been identified yet. Using a panel of pharmacological inhibitors of serine, cysteine, aspartate, or metalloproteinases, preliminary evidence is presented for the hypothesis that matrix metalloproteinase-2 (MMP-2) might be the protease, primarily responsible for CD40L cleavage from platelet surface. PMID:19811225

  6. TGF-β1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-κB.

    PubMed

    Wang, Yequan; Tang, Zhenyu; Xue, Ruyue; Singh, Gurinder K; Lv, Yonggang; Shi, Kunning; Cai, Kaiyong; Deng, Linhong; Yang, Li

    2011-06-01

    The adult human anterior cruciate ligament (ACL) has poor functional healing response. Transforming growth factor (TGF)-β1 enhances the wound repair by stimulating matrix proteins deposition as well as the proliferation and migration of cells. However, the function of the TGF-β1-induced matrix metalloproteinases' (MMPs) activities in the wound healing process is poorly understood. In this study, exogenous MMP-2 is added to mimic the TGF-β1-induced MMP-2 expression. Role of NF-κB pathway is further examined. Our results show that TGF-β1 induces dramatic elevation of MMP-2 activities and the MMP-2/tissue inhibitors of metalloproteinases ratio. Furthermore, the exogenous MMP-2 significantly promoted in vitro wound healing abilities of ACL fibroblasts that are significantly blocked with the addition of its inhibitors. TGF-β1 also increases the proliferation of ACL fibroblasts whereas MMP-2 alone does not, indicating that MMP-2 activities are not involved in the proliferation. TGF-β1-induced MMP-2 activity is inhibited by Bay11-7082 and Bay11-7085 (NF-κB inhibitors). Our results demonstrate that increased TGF-β1 facilitates the ACL healing process by promoting the fibroblasts migration and proliferation. The migration process is mediated by MMP-2 and NF-κB pathway is involved in TGF-β1-mediated MMP-2 release.

  7. Simvastatin induces NFκB/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells.

    PubMed

    Chen, Ying-Jung; Chang, Long-Sen

    2014-12-15

    The aim of the present study was to explore the signaling pathways associated with the effect of simvastatin on matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in human leukemia K562 cells. In sharp contrast to its insignificant effect on MMP-2, simvastatin down-regulated MMP-9 protein expression and mRNA levels in K562 cells. Simvastatin-induced Pin1 down-regulation evoked NFκB/p65 degradation. Meanwhile, simvastatin induced JNK-mediated c-Jun and ATF-2 activation. Over-expression of Pin1 suppressed simvastatin-induced MMP-9 down-regulation. Treatment with SP600125 (a JNK inhibitor) or knock-down of JNK1 reduced MMP-2 expression in simvastatin-treated cells. Simvastatin enhanced the binding of c-Jun/ATF-2 with the MMP-2 promoter. Down-regulation of c-Jun or ATF-2 by siRNA revealed that c-Jun/ATF-2 activation was crucial for MMP-2 expression. Suppression of p65 activation or knock-down of Pin1 by shRNA reduced MMP-2 and MMP-9 expression in K562 cells. Over-expression of constitutively active JNK1 rescued MMP-2 expression in Pin1 shRNA-transfected cells. Simvastatin treatment also suppressed MMP-9 but not MMP-2 expression in human leukemia U937 and KU812 cells. Taken together, our data indicate that simvastatin-induced p65 instability leads to MMP-9 down-regulation in leukemia cells, while simvastatin-induced JNK1/c-Jun/ATF-2 activation maintains the MMP-2 expression underlying p65 down-regulation.

  8. Activation of pro-(matrix metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type-MMP-dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species.

    PubMed Central

    Lafleur, M A; Hollenberg, M D; Atkinson, S J; Knäuper, V; Murphy, G; Edwards, D R

    2001-01-01

    Thrombin, a critical enzyme in the coagulation cascade, has also been associated with angiogenesis and activation of the zymogen form of matrix metalloproteinase-2 (MMP-2 or gelatinase-A). We show that thrombin activated pro-MMP-2 in a dose- and time-dependent manner in cultured human umbilical-vein endothelial cells (HUVECs) to generate a catalytically active 63 kDa protein that accumulated as the predominant form in the conditioned medium. This 63 kDa thrombin-activated MMP-2 is distinct from the 62 kDa species found following concanavalin A or PMA stimulated pro-MMP-2 activation. Hirudin and leupeptin blocked thrombin-induced pro-MMP-2 activation, demonstrating that the proteolytic activity of thrombin is essential. However, activation was also dependent upon membrane-type-MMP (MT-MMP) action, since it was blocked by EDTA, o-phenanthroline, hydroxamate metalloproteinase inhibitors, tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-4, but not TIMP-1. Thrombin inefficiently cleaved recombinant 72 kDa pro-MMP-2, but efficiently cleaved the 64 kDa MT-MMP-processed intermediate form in the presence of cells. Thrombin also rapidly (within 1 h) increased cellular MT-MMP activity, and at longer time points (>6 h) it increased expression of MT1-MMP mRNA and protein. Thus signalling via proteinase-activated receptors (PARs) may play a role in thrombin-induced MMP-2 activation, though this does not appear to involve PAR1, PAR2, or PAR4 in HUVECs. These results indicate that in HUVECs the activation of pro-MMP-2 by thrombin involves increased MT-MMP activity and preferential cleavage of the MT-MMP-processed 64 kDa MMP-2 form in the presence of cells. The integration of these proteinase systems in the vascular endothelium may be important during thrombogenesis and tissue remodelling associated with neovascularization. PMID:11415441

  9. Preliminary evaluation of inhibition of matrix-metalloprotease MMP-2 and MMP-9 by Passiflora edulis and P foetida aqueous extracts.

    PubMed

    Puricelli, L; Dell'Aica, I; Sartor, L; Garbisa, S; Caniato, R

    2003-04-01

    Fruit's decoctions of Passiflora edulis and P. foetida var. albiflora were evaluated for the inhibition of activity of gelatinase MMP-2 and MMP-9, two metallo-proteases involved in the tumour invasion, metastasis and angiogenesis. Both water extracts, at different concentrations, inhibited the enzymes. PMID:12727500

  10. Imagerie moleculaire de la MMP-2

    NASA Astrophysics Data System (ADS)

    Lebel, Rejean

    MMPs (matrix metalloproteinases) are enzymes involved in tissue architecture remodelling and cell migration. MMP-2, particularly, was found to be a biomarker of the progression or prognosis of several pathologies, such as arthritis, atherosclerosis, infarct and cancer. Yet, its exact role in these pathologies is still uncertain. For these reasons, it is critical to develop new tools to enable the specific and non invasive study of MMP-2. As of now, a large number of optical probes (optical imaging), contrast agents (magnetic resonance imaging) and radiotracers (positron emission tomography, single photon emission tomography) have been published in the literature. However, none of the molecules allows for the specific quantification of MMP-2, particularly against MMP-9 which cleaves similar substrates. This thesis describes our progress in the development of new molecules capable of targeting and allowing the imaging of MMP-2. All tested molecules were fond to be quickly activated by MMP-2 and to be selective when compared with MMP3, MMP-7 and MMP-9. First, a contrast agent named PCA2-switch is tested in a mouse subcutaneous tumor model, and allows us to differentiate between tumors with low or high levels of MMP-2 activity. We also developed a panel of activatable fluorescent probes, one of which was found to be highly specific to MMP-2 (low activation by MMP9, efficient quenching). However, an extensive set of control experiments does not enable to conclude on the specificity of the probes in vivo. One of the principal limitations of many studies in the field of MMP imaging is the lack of proper controls, including unspecific uptake controls. The last section of this thesis discusses the impact of the EPR (enhanced permeability and retention) effect on the uptake of a non-specific probe in a subcutaneous tumor model treated with radiotherapy. Proper control experiments that should be performed when testing new MMP-2 probes are discussed. Keywords: Matrix

  11. Therapy of psoriasis with narrowband ultraviolet-B light influences plasma concentrations of MMP-2 and TIMP-2 in patients

    PubMed Central

    Głażewska, Edyta Katarzyna; Niczyporuk, Marek; Ławicki, Sławomir; Szmitkowski, Maciej; Zajkowska, Monika; Będkowska, Grażyna Ewa; Przylipiak, Andrzej

    2016-01-01

    Background Matrix metalloproteinases (MMPs), which show a significant ability to cleave the components of extracellular matrix, and tissue inhibitors of metalloproteinases (TIMPs), which slow down the activity of those enzymes, may be implicated in the pathogenesis and spread of psoriatic disease. This study aims to analyze plasma levels of MMP-2 and TIMP-2 in plaque psoriasis patients before and after the course of narrowband ultraviolet-B (NBUVB) therapy with respect to disease advancement. Patients and methods A total of 49 patients suffering from plaque psoriasis and 40 healthy volunteers were enrolled into the study. Plasma levels of MMP-2 and TIMP-2 were determined using enzyme-linked immunosorbent assay, while Psoriasis Area and Severity Index (PASI) was used to define the disease advancement. Results The results showed increased plasma levels of MMP-2 and TIMP-2, but this change was significant only in case of MMP-2 in total psoriatic group compared to healthy subjects. Moreover, there was an increase in the concentrations of chosen factors with an increase in the severity of the disease. The NBUVB therapy causes a decline in the concentration of the analyzed enzyme and its inhibitor, although this change was statistically significant in the total psoriatic group only in case of MMP-2. There was also a positive correlation between MMP-2, TIMP-2, and PASI score value. Conclusion Our study highlights a possible important role of MMP-2 in the activity of psoriasis and clearance of disease symptoms. Moreover, plasma MMP-2 seems to be a valuable psoriasis biomarker. PMID:27799779

  12. Combined effects of TNF-α, IL-1β, and HIF-1α on MMP-2 production in ACL fibroblasts under mechanical stretch: an in vitro study.

    PubMed

    Wang, Yequan; Tang, Zhenyu; Xue, Ruyue; Singh, Gurinder K; Shi, Kunning; Lv, Yonggang; Yang, Li

    2011-07-01

    The dynamics between inflammatory factors, mechanical stress, and healing factors, in an intra-articular joint, are very complex after injury. Injury to intra-articular tissue [anterior cruciate ligament (ACL), synovium] results in hypoxia, accumulation of various pro-inflammatory factors, cytokines, and metalloproteases. Although the presence of increased amounts of matrix-metalloproteinases (MMP) in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP-2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury, inflammation and hypoxia induced factor-1α (HIF-1α) on induction of MMP-2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF-α and IL-1β elevate the activity of MMP-2 in a dose- and time-dependent manner. In addition, mechanical stretch further enhances the MMP-2 protein levels with TNF-α, IL-1β, and their mixture. CoCl(2) -induced HIF-1α (100 and 500 µM) also increases the levels and activity of MMP-2. Mechanical stretch has a strong additional effect on MMP-2 production with HIF-1α. Our results conclude that mechanical injury, HIF-1α and inflammatory factors collectively induce increased MMP-2 production in ACL fibroblasts, which was inhibited by NF-κB pathway inhibitor (Bay-11-7082).

  13. Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase

    PubMed Central

    De Groef, Lies; Salinas-Navarro, Manuel; Van Imschoot, Griet; Libert, Claude; Vandenbroucke, Roosmarijn E.; Moons, Lieve

    2015-01-01

    Matrix metalloproteinases (MMPs) have been designated as both friend and foe in the central nervous system (CNS): while being involved in many neurodegenerative and neuroinflammatory diseases, their actions appear to be indispensable to a healthy CNS. Pathological conditions in the CNS are therefore often related to imbalanced MMP activities and disturbances of the complex MMP-dependent protease network. Likewise, in the retina, various studies in animal models and human patients suggested MMPs to be involved in glaucoma. In this study, we sought to determine the spatiotemporal expression profile of MMP-2 in the excitotoxic retina and to unravel its role during glaucoma pathogenesis. We reveal that intravitreal NMDA injection induces MMP-2 expression to be upregulated in the Müller glia. Moreover, MMP-2 null mice display attenuated retinal ganglion cell death upon excitotoxic insult to the retina, which is accompanied by normal glial reactivity, yet reduced TNF levels. Hence, we propose a novel in vivo function for MMP-2, as an activating sheddase of tumor necrosis factor (TNF). Given the pivotal role of TNF as a proinflammatory cytokine and neurodegeneration-exacerbating mediator, these findings generate important novel insights into the pathological processes contributing to glaucomatous neurodegeneration and into the interplay of neuroinflammation and neurodegeneration in the CNS. PMID:26451076

  14. Expression of MMP-2, MMP-9, and urokinase-type plasminogen activator in cervical intraepithelial neoplasia.

    PubMed

    No, Jae Hong; Jo, Hoenil; Kim, Su-Hyeong; Park, In-Ae; Kang, Daehee; Lee, Chae Hyeong; Han, Seung-Su; Kim, Jae Weon; Park, Noh-Hyun; Kang, Soon-Beom; Song, Yong-Sang

    2009-08-01

    Matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) are important factors for cancer invasion and metastasis, degrading the extracellular matrix. They are also associated with angiogenesis. Angiogenic phenotype is another feature of high-grade cervical intraepithelial neoplasia (CIN). However, their associations with the progression of low-grade CIN to high-grade CIN are unexplored. We investigated whether these proteolytic enzyme expressions correlate with the progression of CIN. A total of 39 paraffin-embedded specimens from 10 patients with CIN grade 1, nine with CIN grade 2, and 20 with CIN grade 3 were assessed immunohistochemically by specific antibodies against MMP-2, MMP-9, and uPA. MMP-9 expression was higher in CIN 3 lesions (47.4%) than in CIN 1 (22.2%) and CIN 2 (20.2%) lesions, although the difference failed to reach statistical significance. The expression level of uPA and MMP-2 was not associated with the grade of CIN lesions. Interestingly, we found a significant association between expressions of uPA and MMP-2 (P= 0.028). Our results suggest that MMP-9 might play a role in the progression of CIN.

  15. FTY-720P Suppresses Osteoclast Formation by Regulating Expression of Interleukin-6 (IL-6), Interleukin-4 (IL-4), and Matrix Metalloproteinase 2 (MMP-2)

    PubMed Central

    Zhang, Dawei; Huang, Yongjun; Huang, Zongwen; Zhang, Rongkai; Wang, Honggang; Huang, Dong

    2016-01-01

    Background Osteoclast formation is closely related to the immune system. FTY720, a new immunosuppressive agent, has some functions in immune regulation. Its main active ingredients become FTY-720P in vivo by phosphorylation modification. The objective of this study was to determine the effects of FTY-720 with various concentrations on osteoclasts in vitro. Material/Methods RAW264.7 cells and bone marrow-derived mononuclear phagocytes (BMMs) were treated with RANKL to obtain osteoclasts in vitro. To investigate the role of FTY-720 in osteoclast formation, trap enzyme staining was performed and the number of osteoclasts was counted. Bone slices were stained with methylene blue, we counted the number of lacunae after bone slices were placed into dishes together with osteoclasts, and we observed the effect and function of FTY-720 in osteoclasts induced by RAW264.7 cells and BMMs. Then, we used a protein array kit to explore the effects of FTY-720P on osteoclasts. Results The results of enzyme trap staining and F-actin staining experiments show that, with the increasing concentration of FTY-720P, the number of osteoclast induced by RAW264.7 cells and BMMs gradually decreased (P<0.05), especially when the FTY-720P concentration reached 1000 ng/ml, and the number of osteoclasts formed was the lowest (P<0.05). With bone lacuna toluidine blue staining, the results also show that, with the increasing concentration of FTY-720P, the number of bone lacuna gradually decreased (P<0.05), and the number of lacunae is lowest when the concentration reached 800 ng/ml. Finally, protein array results showed that IL-4, IL-6, IL-12, MMP-2, VEGF-C, GFR, basic FGF, MIP-2, and insulin proteins were regulated after FTY-720P treatment. Conclusions FTY-720P can suppress osteoclast formation and function, and FTY-720P induces a series of cytokine changes. PMID:27344392

  16. TGF-{beta}1 increases invasiveness of SW1990 cells through Rac1/ROS/NF-{kappa}B/IL-6/MMP-2

    SciTech Connect

    Binker, Marcelo G.; Binker-Cosen, Andres A.; Gaisano, Herbert Y.; Cosen, Rodica H. de; Cosen-Binker, Laura I.

    2011-02-04

    Research highlights: {yields} Rac1 mediates TGF-{beta}1-induced SW1990 invasion through MMP-2 secretion and activation. {yields} NADPH-generated ROS act downstream of Rac1 in TGF-{beta}1-challenged SW1990 cells. {yields} TGF-{beta}1-stimulated ROS activate NF-{kappa}B in SW1990 cells. {yields} NF{kappa}B-induced IL-6 release is required for secretion and activation of MMP-2 in SW1990 cells. -- Abstract: Human pancreatic cancer invasion and metastasis have been found to correlate with increased levels of active matrix metalloproteinase 2 (MMP-2). The multifunctional cytokine transforming growth factor beta 1 (TGF-{beta}1) has been shown to increase both secretion of MMP-2 and invasion by several pancreatic cancer cell types. In the present study, we investigated the signaling pathway involved in TGF-{beta}1-promoted MMP-2 secretion and invasion by human pancreatic cancer cells SW1990. Using specific inhibitors, we found that stimulation of these tumor cells with TGF-{beta}1 induced secretion and activation of the collagenase MMP-2, which was required for TGF-{beta}1-stimulated invasion. Our results also indicate that signaling events involved in TGF-{beta}1-enhanced SW1990 invasiveness comprehend activation of Rac1 followed by generation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate-oxidase, activation of nuclear factor-kappa beta, release of interleukin-6, and secretion and activation of MMP-2.

  17. In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors.

    PubMed

    Roomi, M W; Monterrey, J C; Kalinovsky, T; Rath, M; Niedzwiecki, A

    2010-03-01

    Matrix metalloproteinases (MMPs) secreted by cervical and ovarian cancer, especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 expression in cervical and ovarian cancer cell lines. Human cervical (HeLa and DoTc2-4510) and ovarian (SK-OV-3) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. HeLa and SK-OV-3 cell lines expressed MMP-2 whereas DoTc2-4510 cells expressed MMP-9. Treatment of cervical cancer cell lines (HeLa and DoTc2-4510) with PMA had no effect on MMP-2 expression and a moderate stimulatory effect in ovarian cancer cell line SK-OV-3. MMP-9 was stimulated by phorbol 12-myristate 13-acetate in HeLa cells and enhanced in DoTc2-4510. Tumor necrosis factor-alpha and interleukin-1beta, had slight inhibitory effect on HeLa cell expression of MMP-2 while lipopolysaccharide stimulated MMP-2 in HeLa cells. Doxycycline, epigallocatechin gallate, a nutrient mixture, actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in HeLa and SK-OV-3 cell lines and inhibited MMP-9 in DoTc2-4510. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in ovarian and cervical cancer cell lines, suggesting these agents may be effective strategies to treat these cancers.

  18. Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma.

    PubMed

    Kesanakurti, D; Chetty, C; Rajasekhar Maddirela, D; Gujrati, M; Rao, J S

    2012-12-20

    Gliomas display anoikis resistance, enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies. Our studies on increased anoikis sensitization in matrix metalloproteinase-2 (MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 (PAK4) inhibition, prompting us to further investigate the role of PAK4 in glioma. Here, we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades. The siRNA-mediated PAK4 knockdown elevated anoikis, and inhibited invasion and migration by downregulating MMP-2, αvβ3-integrin and phospho-epidermal growth factor receptor (phospho-EGFR). The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells. Most importantly, glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain. Individual EGFR/ErbB2 inhibitor and αvβ3 antibody treatments in PAK4si-treated cells indicated the regulation of αvβ3/EGFR survival signaling by PAK4. Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines. Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death, and severely inhibited invasive and migratory properties in these cells. PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2, β3-integrin and phospho-EGFR levels in tumors. Our findings indicate a physical association between PAK4 and MMP-2, and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment.

  19. Does MMP-2 expression and secretion change with increasing serial passage of keratocytes in culture?

    PubMed

    Sandeman, S R; Faragher, R G; Allen, M C; Liu, C; Lloyd, A W

    2001-02-01

    The effects of ageing on matrix metalloprotease degradation of the extracellular matrix during corneal wound healing are largely unknown. The following study used an in vitro model of ageing to assess changes in MMP-2 RNA expression and protein secretion. Early passage (EP) EK1.BR keratocyte cultures from 14 to 18 cumulative population doublings (cpds) and late passage (LP) cultures from 40 to 47 cpds were used to isolate protein and mRNA samples. Total protein from EP and LP cultures was measured using the Bradford protein assay. Zymographic analysis of EP and LP samples was carried out to compare MMP-2 activity. Northern blot analysis was used to assess changes in MMP-2 mRNA expression by EP and LP cultures, using a digoxigenin (DIG) based chemiluminescent detection system. LP cultures secreted more total protein per cell. MMP-2 but not MMP-9 activity was detected in keratocyte cultures. Densitometric analysis of zymograms and calculation of MMP-2 activity indicated a significant increase in MMP-2 activity per cell (P<0.05, n=11). No difference was observed in the levels of MMP-2 mRNA expressed by EP and LP cultures. An increase in MMP-2 activity per cell by LP cultures suggests that senescent keratocytes increase their degradative capacity. Similar changes in the keratocyte phenotype within the ageing cornea may alter the balanced response necessary for adequate wound healing and may have implications for the therapeutic use of MMP inhibitors in the eye.

  20. Stoichiometric expression of MMP-2/TIMP-2 in benign and malignant tumours of the salivary gland.

    PubMed

    Kolude, Bamidele; Adisa, Akinyele Olumuyiwa; Lawal, Ahmed Oluwatoyin; Adeyemi, Bukola Folasade; Akinyamoju, Akindayo Olufunto

    2015-04-01

    The aim of this study was to determine the expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitors of matrix metalloproteinase 2 (TIMP-2) and the MMP-2/TIMP-2 expression ratio in salivary gland tumours (SGTs). Forty-three FFPE SGTs were prepared for antibody processing to MMP-2 and TIMP-2. Two investigators utilizing Sinicrope's method scored the uptake of immuno-stains. Cytoplasmic staining was considered as positive. Data was analysed using SPSS version 20. The significance level was set at p < 0.05. In benign SGTs, the mean score for MMP-2 was not significantly lower than that of TIMP-2 (p = 0.37). However, the mean scores for MMP-2 stain intensity and proportion were significantly higher in malignant than benign SGTs (p = 0.01 and p = 0.02 respectively). There was no significant difference in the mean MMP-2/TIMP-2 expression ratio of the malignant SGTs according to histological grade and histogenesis (p = 0.4 and p = 0.19 respectively). The MMP-2/TIMP-2 expression ratio has a higher prognostic value than the separate expressions of MMP-2 and TIMP-2.

  1. Thrombin stimulates VSMC proliferation through an EGFR-dependent pathway: involvement of MMP-2.

    PubMed

    Smiljanic, Katarina; Obradovic, Milan; Jovanovic, Aleksandra; Djordjevic, Jelena; Dobutovic, Branislava; Jevremovic, Danimir; Marche, Pierre; Isenovic, Esma R

    2014-11-01

    In this study, the role of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), heparin-binding EGF-like growth factor (HB-EGF), general metalloproteinases, matrix metalloproteinases-2 (MMP-2) in mediating the mitogenic action of thrombin in rat vascular smooth muscle cells (VSMC) was investigated. The incubation of rat VSMC with thrombin (1 U/ml) for 5 min resulted in significant (p < 0.001) increase of ERK1/2 phosphorylation by 8.7 ± 0.9-fold, EGFR phosphorylation by 8.5 ± 1.3-fold (p < 0.001) and DNA synthesis by 3.6 ± 0.4-fold (p < 0.001). Separate 30-min pretreatments with EGFR tyrosine kinase irreversible inhibitor, 10 µM PD169540 (PD), and 20 µM anti-HB-EGF antibody significantly reduced thrombin-stimulated EGFR and ERK1/2 phosphorylation by 81, 72 % and by 48 and 61 %, respectively. Furthermore, the same pretreatments with PD or anti-HB-EGF antibody reduced thrombin-induced VSMC proliferation by 44 and 45 %, respectively. In addition, 30-min pretreatments with 10 µM specific MMP-2 inhibitor significantly reduced thrombin-stimulated phosphorylation of both EGFR and ERK1/2 by 25 %. Moreover, the same pretreatment with MMP-2 inhibitor reduced thrombin-induced VSMC proliferation by 45 %. These results show that the thrombin-induced DNA synthesis correlates with the level of ERK1/2 activation rather than EGFR activation. These results further suggest that thrombin acts through EGFR and ERK 1/2 signaling pathways involving MMP-2 to upregulate proliferation of VSMC.

  2. 133 Corticosteroid Rreatment Reduces Tissue Eosinophilia and the Expression of Matrix Metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9) and Their Tissue Inhibitor (TIMP-1) in Nasal Polyps

    PubMed Central

    de Borja Callejas, Fco; Martínez-Antón, Asunción; Roca-Ferrer, Jordi; Alobid, Isam; Picado, César; Mullol, Joaquim

    2012-01-01

    Background Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play an important role in both inflammation and remodeling of nasal polyposis. The aim of the current study was to compare the expression levels of MMPs and TIMP-1 between nasal mucosa and polyps, and to evaluate the effect of corticosteroid treatment in their expression in nasal polyps. Methods Nasal mucosa (NM, n = 12) were obtained from patients undergoing nasal corrective surgery while nasal polyp biopsies (NP, n = 33) were obtained from patients before (week 0) and after 2 (week 2) and 12 (week 12) weeks of corticoisteroid treatment (oral prednisone for 2 weeks and intranasal budesonide for 12 weeks). Matrix metalloproteases (MMP-1, MMP-2, MMP-7, MMP-9) and tissue inhibitor of metalloproteinases type 1 (TIMP-1) expression was evaluated by immunohistochemistry in tissue structural cells (epithelium, glands, vessels) and eosinophils. Results MMP and TIMP-1 expression were found in the epithelium, glands, vessels (in both NM and NP), and in eosinophils (only in NP). Expression of MMP-7 in epithelium (34% of tissues) and MMP-9 (19%) in glands was lower (P < 0.05) in NP than in NM (78 and 67%, respectively). Corticoisteroid treatment reduced tissue eosinophilia (Eos/5 fields) at week 2 (8.0 ± 2.9, P = 0.001) and week 12 (10.0 ± 2.3, P < 0.003) compared to week 0 (25.5 ± 8.4); and also decreased the expression of MMPs and TIMP-1 in eosinophils at week 2 and week 12 compared to week 0 (P < 0.05). In the epithelium, corticosteroids increased MMP-7 and TIMP-1 at week 2 and week 12, while decreased MMP-9 at week 12 (P < 0.05). In vessels, corticosteroids increased MMP-9 at week 2 and decreased MMP-1 at week 12 (P < 0.05). No effects were found in the glands. Conclusions Treatment of nasal polyposis with corticosteroids reduces both tissue eosinophilia and MMP expression in eosinophils while modifying the expression of remodeling markers in nasal polyp structural cells.

  3. TIMP-2 Is Required for Efficient Activation of proMMP-2 in Vivo*

    PubMed Central

    Wang, Zhiping; Juttermann, Ruth; Soloway, Paul D.

    2009-01-01

    Matrix metalloproteinases (MMPs) are synthesized as latent proenzymes. A proteolytic cleavage event involving processing of the cysteine-rich N-terminal propeptide is required for their full activation. Previous in vitro studies indicated that activation of proMMP-2 can occur through formation of a trimolecular complex between MMP-14, TIMP-2, and proMMP-2 at the cell surface. Using TIMP-2-deficient mice and cells derived from them, TIMP-2 was shown to be required for efficient proMMP-2 activation both in vivo and in vitro. The requirement for TIMP-2 was not cell-autonomous as exogenously added TIMP-2 could restore activation of proMMP-2 to TIMP-2-deficient cells. Mutant mice were overtly normal, viable, and fertile on the C57BL/6 background, indicating that both TIMP-2 and activated proMMP-2 are dispensable for normal development. PMID:10827175

  4. Physical exercise modulates the level of serum MMP-2 and MMP-9 in patients with breast cancer

    PubMed Central

    Giganti, Maria Gabriella; Tresoldi, Ilaria; Sorge, Roberto; Melchiorri, Giovanni; Triossi, Tamara; Masuelli, Laura; Lido, Paolo; Albonici, Loredana; Foti, Calogero; Modesti, Andrea; Bei, Roberto

    2016-01-01

    Matrix metalloproteinases (MMPs) exhibit an important function in extracellular matrix degradation. MMPs modulate the activation of growth factors, cytokines and metastasis. At present, the effect of exercise on serum levels of MMP-2 and −9 remains unclear. The aim of the present study was to investigate the effect of various physical activities on the circulating levels of MMP-2 and −9 in breast cancer (BC) survivors and healthy subjects. A total of 66 female subjects were enrolled in the present study. The cohort included 46 BC survivors and 20 healthy subjects divided into 5 groups: Group A (17 BC survivors, participating in recreational dragon boat paddling), group B (14 BC survivors, participating in recreational physical activity), group C (15 sedentary BC survivors), group D (10 healthy subjects, participating in recreational physical activity) and group E (10 sedentary healthy subjects). ELISA assays revealed a significant increase in the level of circulating MMP-2 in group B compared with all other groups. Recreational physical activity increased the levels of MMP-9 in healthy subjects (group D vs. E), however, the differences were not statistically significant, while in the BC survivor groups the results were opposite, with exercise reducing MMP-9 levels (group B vs. C). Furthermore, a significant increase in MMP-2 was observed in group B lymph node metastasis-positive (N+) subjects compared with group A and C N+ subjects. Thus, the results of the present study indicate that various physical activities modulate the levels of circulating MMP-2 and −9 in BC survivors, and the same exercise program induces a different effect when undertaken by healthy subjects and BC survivors. These results may have important implications with regard to the selection of appropriate physical activities for BC survivors, leading to improvements to their survival and prevention of recurrence, as well as amelioration of physical function, quality of life and fatigue.

  5. Physical exercise modulates the level of serum MMP-2 and MMP-9 in patients with breast cancer

    PubMed Central

    Giganti, Maria Gabriella; Tresoldi, Ilaria; Sorge, Roberto; Melchiorri, Giovanni; Triossi, Tamara; Masuelli, Laura; Lido, Paolo; Albonici, Loredana; Foti, Calogero; Modesti, Andrea; Bei, Roberto

    2016-01-01

    Matrix metalloproteinases (MMPs) exhibit an important function in extracellular matrix degradation. MMPs modulate the activation of growth factors, cytokines and metastasis. At present, the effect of exercise on serum levels of MMP-2 and −9 remains unclear. The aim of the present study was to investigate the effect of various physical activities on the circulating levels of MMP-2 and −9 in breast cancer (BC) survivors and healthy subjects. A total of 66 female subjects were enrolled in the present study. The cohort included 46 BC survivors and 20 healthy subjects divided into 5 groups: Group A (17 BC survivors, participating in recreational dragon boat paddling), group B (14 BC survivors, participating in recreational physical activity), group C (15 sedentary BC survivors), group D (10 healthy subjects, participating in recreational physical activity) and group E (10 sedentary healthy subjects). ELISA assays revealed a significant increase in the level of circulating MMP-2 in group B compared with all other groups. Recreational physical activity increased the levels of MMP-9 in healthy subjects (group D vs. E), however, the differences were not statistically significant, while in the BC survivor groups the results were opposite, with exercise reducing MMP-9 levels (group B vs. C). Furthermore, a significant increase in MMP-2 was observed in group B lymph node metastasis-positive (N+) subjects compared with group A and C N+ subjects. Thus, the results of the present study indicate that various physical activities modulate the levels of circulating MMP-2 and −9 in BC survivors, and the same exercise program induces a different effect when undertaken by healthy subjects and BC survivors. These results may have important implications with regard to the selection of appropriate physical activities for BC survivors, leading to improvements to their survival and prevention of recurrence, as well as amelioration of physical function, quality of life and fatigue. PMID

  6. Fibronectin induces MMP2 expression in human prostate cancer cells.

    PubMed

    Moroz, Andrei; Delella, Flávia K; Lacorte, Lívia M; Deffune, Elenice; Felisbino, Sérgio L

    2013-01-25

    High-grade prostate cancers express high levels of matrix metalloproteinases (MMPs), major enzymes involved in tumor invasion and metastasis. However, the tumor cell lines commonly employed for prostate cancer research express only small amounts of MMPs when cultivated as monolayer cultures, in common culture media. The present study was conducted to ascertain whether culture conditions that include fibronectin can alter MMP2 and MMP9 expression by the human prostatic epithelial cell lines RWPE-1, LNCaP and PC-3. These cells were individually seeded at 2×10(4) cells/cm(2), cultivated until they reached 80% confluence, and then exposed for 4h to fibronectin, after which the conditioned medium was analyzed by gelatin zymography. Untreated cells were given common medium. Only RWPE-1 cells express detectable amounts of MMP9 when cultivated in common medium, whereas the addition of fibronectin induced high expression levels of pro and active forms of MMP2 in all tested cell lines. Our findings demonstrate that normal and tumor prostate cell lines express MMP2 activity when in contact with extracellular matrix components or blood plasma proteins such as fibronectin. Future studies of transcriptomes and proteomes in prostate cancer research using these cell lines should not neglect these important conclusions.

  7. Investigation of a MMP-2 Activity-Dependent Anchoring Probe for Nuclear Imaging of Cancer

    PubMed Central

    Temma, Takashi; Hanaoka, Hirofumi; Yonezawa, Aki; Kondo, Naoya; Sano, Kohei; Sakamoto, Takeharu; Seiki, Motoharu; Ono, Masahiro; Saji, Hideo

    2014-01-01

    Purpose Since matrix metalloproteinase-2 (MMP-2) is an important marker of tumor malignancy, we developed an original drug design strategy, MMP-2 activity dependent anchoring probes (MDAP), for use in MMP-2 activity imaging, and evaluated the usefulness of this probe in in vitro and in vivo experiments. Methods We designed and synthesized MDAP1000, MDAP3000, and MDAP5000, which consist of 4 independent moieties: RI unit (111In hydrophilic chelate), MMP-2 substrate unit (short peptide), anchoring unit (alkyl chain), and anchoring inhibition unit (polyethylene glycol (PEGn; where n represents the approximate molecular weight, n = 1000, 3000, and 5000). Probe cleavage was evaluated by chromatography after MMP-2 treatment. Cellular uptake of the probes was then measured. Radioactivity accumulation in tumor xenografts was evaluated after intravenous injection of the probes, and probe cleavage was evaluated in tumor homogenates. Results MDAP1000, MDAP3000, and MDAP5000 were cleaved by MMP-2 in a concentration-dependent manner. MDAP3000 pretreated with MMP-2 showed higher accumulation in tumor cells, and was completely blocked by additional treatment with an MMP inhibitor. MDAP3000 exhibited rapid blood clearance and a high tumor accumulation after intravenous injection in a rodent model. Furthermore, pharmacokinetic analysis revealed that MDAP3000 exhibited a considerably slow washout rate from tumors to blood. A certain fraction of cleaved MDAP3000 existed in tumor xenografts in vivo. Conclusions The results indicate the possible usefulness of our MDAP strategy for tumor imaging. PMID:25010662

  8. Possible Mechanisms of Di(2-ethylhexyl) Phthalate-Induced MMP-2 and MMP-9 Expression in A7r5 Rat Vascular Smooth Muscle Cells

    PubMed Central

    Shih, Mei-Fen; Pan, Kuang-Hung; Cherng, Jong Yuh

    2015-01-01

    Proliferation and migration of vascular smooth muscle cells (VSMC) are important in the development and/or progression of many cardiovascular diseases, including atherosclerosis. Evidence shows that matrix metalloproteinase (MMP)-2 and MMP-9 are related to the pathogenesis of atherosclerosis. The expressions of MMP-2 and MMP-9 in atherosclerosis are regulated via various pathways, such as p38 mitogen activated protein kinase (MAPK), extracellular signal regulated kinase 1 and 2 (ERK1/2), Akt, and nuclear factor kappa (NF-κB). Di(2-ethylhexyl) phthalate (DEHP) has been shown to induce atherosclerosis by increasing tumor necrosis factor (TNF)-α, interleukin (IL)-6, and intercellular adhesion molecule (ICAM) productions. However, whether DEHP poses any effects on MMP-2 or MMP-9 expression in VSMC has not yet been answered. In our studies, rat aorta VSMC was treated with DEHP (between 2 and 17.5 ppm) and p38 MAPK, ERK1/2, Akt, NF-κB, and MMP-2 and MMP-9 proteins and activities were measured. Results showed that the presence of DEHP can induce higher MMP-2 and MMP-9 expression than the controls. Similar results on MMP-regulating proteins, i.e., p38 MAPK, ERK1/2, Akt, and NF-κB, were also observed. In summary, our current results have showed that DEHP can be a potent inducer of atherosclerosis by increasing MMP-2 and MMP-9 expression at least through the regulations of p38 MAPK, ERK1/2, Akt, and NF-κB. PMID:26690114

  9. Possible Mechanisms of Di(2-ethylhexyl) Phthalate-Induced MMP-2 and MMP-9 Expression in A7r5 Rat Vascular Smooth Muscle Cells.

    PubMed

    Shih, Mei-Fen; Pan, Kuang-Hung; Cherng, Jong Yuh

    2015-12-04

    Proliferation and migration of vascular smooth muscle cells (VSMC) are important in the development and/or progression of many cardiovascular diseases, including atherosclerosis. Evidence shows that matrix metalloproteinase (MMP)-2 and MMP-9 are related to the pathogenesis of atherosclerosis. The expressions of MMP-2 and MMP-9 in atherosclerosis are regulated via various pathways, such as p38 mitogen activated protein kinase (MAPK), extracellular signal regulated kinase 1 and 2 (ERK1/2), Akt, and nuclear factor kappa (NF-κB). Di(2-ethylhexyl) phthalate (DEHP) has been shown to induce atherosclerosis by increasing tumor necrosis factor (TNF)-α, interleukin (IL)-6, and intercellular adhesion molecule (ICAM) productions. However, whether DEHP poses any effects on MMP-2 or MMP-9 expression in VSMC has not yet been answered. In our studies, rat aorta VSMC was treated with DEHP (between 2 and 17.5 ppm) and p38 MAPK, ERK1/2, Akt, NF-κB, and MMP-2 and MMP-9 proteins and activities were measured. Results showed that the presence of DEHP can induce higher MMP-2 and MMP-9 expression than the controls. Similar results on MMP-regulating proteins, i.e., p38 MAPK, ERK1/2, Akt, and NF-κB, were also observed. In summary, our current results have showed that DEHP can be a potent inducer of atherosclerosis by increasing MMP-2 and MMP-9 expression at least through the regulations of p38 MAPK, ERK1/2, Akt, and NF-κB.

  10. Baicalein inhibits MMP-2 expression in human ovarian cancer cells by suppressing the p38 MAPK-dependent NF-κB signaling pathway.

    PubMed

    Yan, Hao; Xin, Shaobin; Wang, Hui; Ma, Jing; Zhang, Heng; Wei, Hailing

    2015-07-01

    Matrix metalloproteinases (MMPs) secreted by ovarian cancer play essential roles in tumor invasion and metastasis. In this study, we investigated the effect of baicalein, which is isolated from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi, on human ovarian cancer cell lines by measuring MMP-2 expression, invasive potential, and the underlying molecular mechanisms. Analysis of MMP-2 was carried out by western blots and RT-PCR. The invasion ability of ovarian cancer cells was determined using a Transwell invasion assay. Nuclear factor-κB (NF-κB) and p38 MAPK activation was assessed by western blots. The results of the present study showed that baicalein reduced the expression of MMP-2 in a dose-dependent manner and the invasion of ovarian cancer cells was also significantly suppressed by baicalein. We also found that baicalein reduced the activation of NF-κB signaling molecules; in addition, the MMP-2 expression and invasion ability of ovarian cancer cells were abolished with the treatment of the NF-κB inhibitor, pyrrolidine dithiocarbamate. However, the addition of p38 MAPK inhibitor SB203580 significantly reduced the activation of NF-κB; meanwhile, baicalein was shown to exert an inhibitory effect on p38 activation. Furthermore, the MMP-2 expression and invasion ability of ovarian cancer cells were significantly inhibited by SB203580. In conclusion, baicalein inhibits the MMP-2 expression and invasion ability of ovarian cancer cells, possibly by the p38 MAPK-dependent NF-κB signaling pathway; these findings may provide insights into the potential of using baicalein as a therapeutic strategy against ovarian cancer.

  11. Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signalling

    SciTech Connect

    Kim, Beom Su; Park, Ji-Yun; Kang, Hyo-Jin; Kim, Hyung-Jin; Lee, Jun

    2014-08-08

    Graphical abstract: Schematic diagram of the angiogenic activity mechanism by FGF-2/fucoidan treatment in HUVECs. Fucoidan enhances the FGF-2-induced phosphorylation of p38, JNK, and ERK MAPKs. However, p38 and JNK were involved in AKT phosphorylation and MMP-2 activation and resulted in enhanced angiogenic activity, such as tube formation and migration, in HUVECs. - Highlights: • The angiogenic activity of fucoidan in HUVECs was explored. • Fucoidan enhanced HUVEC proliferation, migration, and tube formation. • Fucoidan enhanced angiogenesis through p38 and JNK but not ERK in HUVECs. • Fucoidan targeted angiogenesis-mediated AKT/MMP-2 signalling in HUVECs. - Abstract: Angiogenesis is an important biological process in tissue development and repair. Fucoidan has previously been shown to potentiate in vitro tube formation in the presence of basic fibroblast growth factor (FGF-2). However, the underlying molecular mechanism remains largely unknown. This study was designed to investigate the action of fucoidan in angiogenesis in human umbilical vein endothelial cells (HUVECs) and to explore fucoidan-signalling pathways. First, we evaluated the effect of fucoidan on cell proliferation. Matrigel-based tube formation and wound healing assays were performed to investigate angiogenesis. Matrix metalloproteinase-2 (MMP-2) mRNA expression and activity levels were analysed by reverse transcription polymerase chain reaction (RT-PCR) and zymography, respectively. Additionally, phosphorylation of mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) was detected by Western blot. The results indicate that fucoidan treatment significantly increased cell proliferation in the presence of FGF-2. Moreover, compared to the effect of FGF-2 alone, fucoidan and FGF-2 had a greater effect on tube formation and cell migration, and this effect was found to be synergistic. Furthermore, fucoidan enhanced the phosphorylation of extracellular signal-regulated kinase (ERK

  12. Investigation of MMP-2 and MMP-9 activities in canine sera with dilated cardiomyopathy

    PubMed Central

    Chegeni, S; Khaki, Z; Shirani, D; Vajhi, A; Taheri, M; Tamrchi, Y; Rostami, A

    2015-01-01

    Dilated cardiomyopathy (DCM) is accompanied by myocytes and connective tissue changes. Matrix metalloproteinases (MMPs) play important roles in cardiac remodeling. It seems that the gelatinases (MMP-2 and MMP-9) are effective enzymes in cardiomyopathy. Dilated cardiomyopathy was confirmed in 22 dogs (patient group) including 11 female and 11 male by clinical examination, auscultation, thoracic radiography and echocardiography. 17 healthy dogs (control group) with similar weight and breed to patients were also selected from referred cases to Small Animal Hospital of the Veterinary Faculty of Tehran University and the same diagnostic procedures were performed on them. After that, serum MMP-2 and MMP-9 of control and patient groups were measured by semi-quantitative zymography. Semiquantitative analysis of zymograms from canine serums with DCM showed that total MMP-9 in patients is more than control group, while there was no significant difference in total MMP-2 between the two groups. Pro-MMP-2 was not detected in patient group but its active form was present in both groups, of course MMP-2 activity in patients was significantly more than control. Active form of MMP-9 was detected only in patients. Although pro-MMP-9 was present in both groups, its level in control group was significantly higher than patients. The heart enlargement was observed in the left, right or both parts. Statistically significant differences in active form of MMP-2 and MMP-9 levels were observed between different groups of heart enlargement (right, left and both parts) compared to control but this difference was not significant considering chambers affected and VHS (vertebral heart score) groups. In conclusion, although there are some changes in serum MMP-2 and MMP-9 levels in canine DCM, it seems that increase of MMP-9 is more prominent than MMP-2 and neither of them were affected by heart enlargement or VHS grade. PMID:27175173

  13. Interleukin-1 and tumor necrosis factor-alpha induce collagenolysis and bone resorption by regulation of matrix metalloproteinase-2 in mouse calvarial bone cells.

    PubMed

    Kang, Bong-Seok; Park, Young-Guk; Cho, Jin-Young; Kim, June-Ki; Lee, Tae-Kyun; Kim, Dong-Wook; Gu, Yeun-Hwa; Suzuki, Ikukatsu; Chang, Young-Chae; Kim, Cheorl-Ho

    2003-08-01

    Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) greatly induces osteoclast formation and stimulates bone resorption of mouse calvaria in culture. We examined the effects of the two cytokines on the collagenolysis and bone resorption by induction of matrix metalloproteinases (MMPs). The cells were analyzed using zymographic analysis. It was shown that the mouse calvarial osteoblasts constitutively synthesize progelatinase-A (MMP-2). Interleukin-1beta markedly enhanced the messenger RNAs (mRNAs) expression of MMP-2 (gelatinase A), but slightly MMP-9 (gelatinase B), which associated with increases in bone matrix degradation. Both pro- and active-forms of MMP-2 were detected in the conditioned medium collected from calvarial cultures, and IL-1beta markedly stimulated both pro- and active-forms of the MMP-2. The expression of MMP-2 mRNAs could be detected, and they were markedly enhanced by IL-1beta on days 1 and 2. These results demonstrate that the potency of induction of MMP-2 by IL-1beta and TNF-alpha is closely linked to the respective bone-resorbing activity, suggesting that MMP-2-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines. On the other hand, when the mouse osteoblasts were stimulated with parathyroid hormone, 1,25(OH)2D3, mononuclear cell conditioned medium (MCM) and IL-1 as bone resorption agents, collagenolysis was increased by producing the active gelatinase. Interleukin-1 in stimulating bone resorption was examined using fetal mouse long bone organ culture. Interleukin-1 stimulated bone resorption and produced marked resorption when present simultaneously. Furthermore, treatment of indomethacin and dexamethasone clearly abolished the responses of IL-1alpha and IL-1beta.

  14. Effects of maternal diabetes on male offspring: high cell proliferation and increased activity of MMP-2 in the ventral prostate.

    PubMed

    Damasceno, A A; Carvalho, C P; Santos, E M B; Botelho, F V; Araújo, F A; Deconte, S R; Tomiosso, T C; Balbi, A P C; Zanon, R G; Taboga, S R; Góes, R M; Ribeiro, D L

    2014-10-01

    This study presents a comprehensive view of the histological and functional status of the prostate of adult rat offspring of mothers subjected to gestational diabetes induced by alloxan. The ventral prostate of male adult offspring of diabetic (DP) or normal (CP) mothers was evaluated for collagen fibres, cell death, fibroblasts, smooth muscle cells, cell proliferation, matrix metalloproteinases (MMPs), androgen receptors (AR), transforming growth factor β1 (TGFβ-1), catalase and total antioxidant activity. The prostates of DP animals were lower in weight than those of the CP group. The DP group also exhibited hyperglycaemia and hypotestosteronemia, higher cell proliferation and AR expression, a reduction in α-actin (possibly interfering with the reproductive function of the prostate), and enhanced activity of MMP-2, although the absolute content of MMP-2 was lower in this group. These findings were associated with increased TGFβ-1 and decreased collagen distribution. The prostates of DP rats additionally exhibited reductions in catalase and total antioxidant activity. Thus, rats developing in a diabetic intrauterine environment have glycaemic and hormonal changes that impact on the structure and physiology of the prostate in adulthood. The increased AR expression possibly leads to elevated cell proliferation. Stromal remodelling was characterized by enhanced activity of MMP-2 and collagen degradation, even with increased TGFβ-1 activation. These changes associated with increased oxidative stress might interfere with tissue architecture and glandular homeostasis. PMID:24988912

  15. Inhibition of MMP-2 and MMP-9 Activities by Limonium tetragonum Extract

    PubMed Central

    Bae, Min-Joo; Karadeniz, Fatih; Lee, Seul-Gi; Seo, Youngwan; Kong, Chang-Suk

    2016-01-01

    Matrix metalloproteinases (MMPs) are crucial extracellular matrices degrading enzymes that take important roles in metastasis of cancer progression as well as other significant conditions such as oxidative stress and hepatic fibrosis. Natural products are on the rise for their potential to provide remarkable health benefits. In this context, halophytes have been of interest in the nutraceutical field with reported instances of isolation of bioactive compounds. In this study, Limonium tetragonum, an edible halophyte, was studied for its ability to inhibit MMP-2 and -9 using HT1080 fibrosarcoma cells. Results showed that L. tetragonum extract was able to inhibit the enzymatic activity and mRNA expression of MMP-2 and -9 according to gelatin zymography and RT-PCR assays, respectively, but it was not able to significantly change the MMP pathway related factors such as tissue inhibitors of metalloproteinases. Also, Mitogen-activated protein kinases pathway-related protein levels and their phosphorylation were assayed. While the phosphorylated p38 levels were decreased, extracellular signal-regulated kinase and c-Jun N-terminal kinase were not affected by L. tetragonum treatment. In conclusion, it was suggested that L. tetragonum contains substances acting as MMP inhibitors on enzymatic activity rather than intracellular pathway intervention, which could be useful for further utilization of L. tetragonum as a source for anti-MMP agents. PMID:27069904

  16. The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway

    PubMed Central

    Tang, Lianghu; Pei, Haifeng; Yang, Yi; Wang, Xiong; Wang, Ting; Gao, Erhe; Li, De; Yang, Yongjian; Yang, Dachun

    2016-01-01

    Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14–21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-β1 (TGF-β1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-β1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1α/calpains/MMP2/TGF-β1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-β1 pathway. PMID:27453531

  17. Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signalling.

    PubMed

    Kim, Beom Su; Park, Ji-Yun; Kang, Hyo-Jin; Kim, Hyung-Jin; Lee, Jun

    2014-08-01

    Angiogenesis is an important biological process in tissue development and repair. Fucoidan has previously been shown to potentiate in vitro tube formation in the presence of basic fibroblast growth factor (FGF-2). However, the underlying molecular mechanism remains largely unknown. This study was designed to investigate the action of fucoidan in angiogenesis in human umbilical vein endothelial cells (HUVECs) and to explore fucoidan-signalling pathways. First, we evaluated the effect of fucoidan on cell proliferation. Matrigel-based tube formation and wound healing assays were performed to investigate angiogenesis. Matrix metalloproteinase-2 (MMP-2) mRNA expression and activity levels were analysed by reverse transcription polymerase chain reaction (RT-PCR) and zymography, respectively. Additionally, phosphorylation of mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) was detected by Western blot. The results indicate that fucoidan treatment significantly increased cell proliferation in the presence of FGF-2. Moreover, compared to the effect of FGF-2 alone, fucoidan and FGF-2 had a greater effect on tube formation and cell migration, and this effect was found to be synergistic. Furthermore, fucoidan enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and AKT. MMP-2 activation was also significantly increased. Specific inhibitors of p38 (SB203580) and JNK (SP600125) inhibited tube formation and wound healing, while an ERK inhibitor (PD98059) did not. MMP-2 activation and AKT phosphorylation were also attenuated and associated with the suppression of p38 and JNK phosphorylation, but not with that of ERK. These results indicate that fucoidan, in the presence of FGF-2, induces angiogenesis through AKT/MMP-2 signalling by activating p38 and JNK. These findings provide basic molecular information on the effect of fucoidan on angiogenesis in the presence of FGF-2.

  18. MMP-2 inhibition reduces renal macrophage infiltration with increased fibrosis in UUO.

    PubMed

    Nishida, Masashi; Okumura, Yasuko; Ozawa, Sei-Ichiro; Shiraishi, Isao; Itoi, Toshiyuki; Hamaoka, Kenji

    2007-03-01

    We examined the role of matrix metalloproteinase-2 (MMP-2) in renal fibrosis and its effect on interstitial macrophage infiltration in a mouse model of unilateral ureteral obstruction (UUO). TISAM, a selective inhibitor of MMP-2, was administered during early stage (day -2 to 4; protocol A) and late stage (day 7 to 13; protocol B) after UUO. Treatment with TISAM accelerated fibrosis both at day 5 (A) and at day 14 (B). The degree of macrophage infiltration was decreased by the treatment with TISAM at day 14, but not at day 5. In vitro macrophage migration assay showed a greater migration to renal tissue of control UUO kidney (day 14) than to TISAM-treated kidney, which was suppressed by preincubating macrophages with RGDS, a fibronectin degradation peptide. These results suggest that MMP-2 acts to accelerate macrophage infiltration in the late stage of UUO, possibly by degrading extracellular matrix components.

  19. Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2.

    PubMed

    Xuan, Xaioyan; Li, Shanshan; Lou, Xi; Zheng, Xianzhao; Li, Yunyun; Wang, Feng; Gao, Yuan; Zhang, Hongyan; He, Hongliu; Zeng, Qingru

    2015-05-01

    Stat3 alters the expression of its downstream genes and is associated with tumor invasion and metastasis in several human cancers. Its role in esophageal squamous cell carcinoma (ESCC) has not been well characterized. We examined the tumor sections of 100 cases of ESCC by immunohistochemistry and observed significant overexpression of Stat3 in the cytoplasm of 89% of ESCC cells and of phosphorylated Stat3 (p-Stat3) in the nuclei of 71% of ESCC when compare with normal esophageal mucosa (72%, p = 0.02; and 31%, p = 0.001). Overexpression of Stat3 and p-Stat3 positively correlated with that of matrix metalloproteinase-2 (MMP2), a known regulator for cell migration, in 65% of ESCC while only 26% shown in benign esophageal mucosa. To further investigate the association of Stat3 with tumor metastasis in vitro, invasion of EC-1 cells (a human ESCC cell line) were investigated with Boyden chambers. The results showed that transfection of Stat3 not only promoted invasion of EC-1 cells but also significantly induced MMP2 expression in a dose-dependent manner. In contrast, suppressing expression of endogenous Stat3 mRNA and protein by Stat3 siRNA significantly reduced EC-1 cell invasion and MMP2 expression. A high-affinity Stat3-binding element was localized to the positions of 648-641 bp (TTCTCGAA) in the MMP2 promoter with electrophoretic mobility shift assay. Our results suggest that Stat3, p-Stat3, and MMP2 were overexpressed in ESCC and associated with invasion of ESCC; and Stat3 up-regulated expression of MMP2 in ESCC through directly binding to the MMP2 promoter.

  20. Ovarian carcinoma cells in serous effusions show altered MMP-2 and TIMP-2 mRNA levels.

    PubMed

    Davidson, B; Reich, R; Berner, A; Givant-Horwitz, V; Goldberg, I; Risberg, B; Kristensen, G B; Trope, C G; Bryne, M; Kopolovic, J; Nesland, J M

    2001-11-01

    The expression of matrix metalloproteinases (MMP) and their inhibitor TIMP-2 in serous effusions from patients with ovarian carcinoma and its association with clinico-pathological parameters were analysed. The findings in carcinoma cells in effusions were compared with corresponding primary and metastatic lesions. Sixty-six effusions and 96 tissue sections were stained for MMP-1, MMP-2 and MMP-9 applying immunohistochemistry (IHC) and analysed for MMP-2, MMP-9 and TIMP-2 expression using mRNA in situ hybridisation (ISH). MMP-2 and MMP-9 mRNA levels in 30 effusions were subsequently analysed using reverse transcription- polymerase chain reaction (RT-PCR). MMP and TIMP expression was detected in both carcinoma and mesothelial cells in effusions. The levels were consistently higher in malignant cells, significantly so for MMP-1 (P=0.016) and MMP-2 (P=0.036) proteins, as well as for TIMP-2 mRNA (P=0.008). In tissue sections, MMP-1, MMP-2 and MMP-9 protein expression was mostly localised to tumour cells, while MMP-2, MMP-9 and TIMP-2 mRNA were predominantly detected in stromal cells. Adenocarcinoma cells in effusions showed a significant upregulation of MMP-2 expression compared with primary tumours, with a concomitant downregulation of TIMP-2. RT-PCR demonstrated the presence of MMP-2 and MMP-9 in 28/30 and 0/30 specimens, respectively. MMP and TIMP are thus mainly synthesised by cancer cells in effusions, while stromal cells have a similar role in solid tumours. MMP-1 and MMP-2 production predominates over that of MMP-9 in effusions. Increased MMP-2 and reduced TIMP-2 levels are seen in ovarian carcinoma cells in effusions, possibly marking the acquisition of a metastatic phenotype. PMID:11597382

  1. WISP-1 increases MMP-2 expression and cell motility in human chondrosarcoma cells.

    PubMed

    Hou, Chun-Han; Chiang, Yi-Chun; Fong, Yi-Chin; Tang, Chih-Hsin

    2011-06-01

    Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins. However, the effect of WISP-1 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that WISP-1 increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells (JJ012 cells). We also found that human chondrosarcoma tissues had significant expression of the WISP-1 which was higher than that in normal cartilage. α5β1 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) inhibited the WISP-1-induced increase of the migration and MMP-2 up-regulation of chondrosarcoma cells. WISP-1 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, NF-κB inhibitors also suppressed the cell migration and MMP-2 expression enhanced by WISP-1. Moreover, WISP-1 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-2 promoter. Taken together, our results indicated that WISP-1 enhances the migration of chondrosarcoma cells by increasing MMP-2 expression through the α5β1 integrin receptor, FAK, MEK, ERK, p65 and NF-κB signal transduction pathway.

  2. A Prodrug-type, MMP-2-targeting Nanoprobe for Tumor Detection and Imaging

    PubMed Central

    Wang, Yaping; Lin, Tingting; Zhang, Wenyuan; Jiang, Yifan; Jin, Hongyue; He, Huining; Yang, Victor C.; Chen, Yi; Huang, Yongzhuo

    2015-01-01

    Tumor-associated proteases (TAPs) have been intensively studied because of their critical roles in cancer development. As a case in point, expression of matrix metalloproteases (MMP) is significantly up-regulated in tumorigenesis, invasion, and metastasis among a majority of cancers. Here we present a prodrug-type, MMP-2-responsive nanoprobe system with high efficiency and low toxicity for detecting MMP-2-overexpressed tumors. The nanoprobe system is featured by its self-assembled fabrication and FRET effect. This prodrug-type nanoprobe is selectively activated by MMP-2, and thus useful for detection of the MMP-2-overexpressed cells and tumors. The nanoprobe system works successfully in various animal tumor models, including human fibrosarcoma and subcutaneous glioma xenograft. Furthermore, in order to overcome the blood brain barrier (BBB) and achieve brain tumor targeting, a transferrin-receptor targeting peptide (T7 peptide) is strategically incorporated into the nanoprobe. The T7-functionalized nanoprobe is capable of detecting the orthotopic brain tumor, with clear, real-time in vivo imaging. This method is promising for in vivo detection of brain tumor, and real-time monitor of a TAP (i.e., MMP-2). PMID:26000052

  3. MMP-2 plays an essential role in producing epithelial-mesenchymal transformations in the avian embryo.

    PubMed

    Duong, Tuan D; Erickson, Carol A

    2004-01-01

    To investigate the roles that matrix-degrading proteases may have in development of the chicken embryo, we documented the expression pattern of matrix metalloprotease-2 (MMP-2, 72-kDa type IV collagenase or gelatinase A) and perturbed its function in vitro and in vivo. MMP-2 is expressed as neural crest cells detach from the neural epithelium during an epithelial-mesenchymal transformation (EMT) but is rapidly extinguished as they disperse. It is also expressed in the sclerotome and in the dermis at the time that the EMT is initiated, and also as these cells migrate, and is down-regulated once motility has ceased. These patterns suggest that MMP-2 plays a role in cell motility during the EMT and during later morphogenesis. Inhibitors of MMPs, including BB-94 and TIMP-2 (tissue inhibitor of metalloprotease-2), prevent the EMT that generates neural crest cells, both in tissue culture and in vivo, but do not affect migration of the cells that have already detached from the neural tube. Similarly, knockdown of MMP-2 expression in the dorsal neural tube using antisense morpholino oligos perturbs the EMT, but also does not affect migration of neural crest cells after they have detached from the neural tube. On the other hand, when somites in culture are treated with TIMP-2, some mesenchymal cells are produced, suggesting that they undergo the EMT, but show greatly reduced migration through the collagen gel. MMP-2 is also expressed in mesenchyme where tissue remodeling is in progress, such as in the developing feather germs, in the head mesenchyme, in the lateral plate mesoderm, and in the limb dermis, especially in the regions where tendons are developing. Comparisons of these expression patterns in multiple embryonic tissues suggest a probable role for MMP-2 in the migration phase of the EMT, in addition to mesenchyme dispersion and tissue remodeling. Developmental Dynamics 229:42-53, 2004. PMID:14699576

  4. Synthetic Division and Matrix Factorization

    ERIC Educational Resources Information Center

    Barabe, Samuel; Dubeau, Franc

    2007-01-01

    Synthetic division is viewed as a change of basis for polynomials written under the Newton form. Then, the transition matrices obtained from a sequence of changes of basis are used to factorize the inverse of a bidiagonal matrix or a block bidiagonal matrix.

  5. Local Inflammation Alters MMP-2 and MMP-9 Gelatinase Expression Associated with the Severity of Nifedipine-Induced Gingival Overgrowth: a Rat Model Study.

    PubMed

    Li, Wu-Li; Wu, Cheng-Hai; Yang, Jun; Tang, Min; Chen, Long-Jie; Zhao, Shou-Liang

    2015-08-01

    Nifedipine-induced gingival overgrowth (NIGO) is characterized by cell proliferation and extracellular matrix (ECM) component accumulation in gingival connective tissues, with varying degrees of inflammation and fibrosis. Impaired collagen and ECM homeostasis may be among the underlying molecular mechanisms that lead to the fibrotic changes that occur in drug-induced gingival overgrowth (DIGO). Because matrix metalloproteinases (MMPs) play vital roles in regulating collagen and ECM metabolism, many studies have been performed to reveal the relationship between MMPs and DIGO. It is thought that the gelatinases MMP-2 and MMP-9, both type IV collagenases, are involved in the development of tissue inflammation and organ fibrosis. However, the few studies regarding gelatinase expression in DIGO are controversial. Recent studies have demonstrated the inhibitory effect of cyclosporine A (CsA) on gelatinase expression and/or activity; however, similar changes have yet to be detected in Nif-treated gingival tissues. In this study, we verified that Nif treatment could lead to gingival overgrowth in rats and that gingival inflammation played a pro-proliferative role in NIGO development. Additionally, we examined the temporal expression of gelatinases on days 0, 7, 14, 21, 30, and 40 during NIGO development. The aim was to investigate whether MMP-2 and MMP-9 played significant roles in regulating NIGO development and progression. MMP-2 gene expression was not altered by Nif treatment alone but was significantly inhibited by Nif treatment for 30 days in the presence of local inflammation. However, no significant alterations in MMP-2 protein expression were detected in the Nif-treated gingival tissue, regardless of the presence or absence of local inflammation. Moreover, Nif treatment could lead to transient and significant increases in MMP-9 gene and protein expression levels in the presence of local inflammation. In particular, active MMP-9 expression increased significantly

  6. Matrix factorizations and elliptic fibrations

    NASA Astrophysics Data System (ADS)

    Omer, Harun

    2016-09-01

    I use matrix factorizations to describe branes at simple singularities of elliptic fibrations. Each node of the corresponding Dynkin diagrams of the ADE-type singularities is associated with one indecomposable matrix factorization which can be deformed into one or more factorizations of lower rank. Branes with internal fluxes arise naturally as bound states of the indecomposable factorizations. Describing branes in such a way avoids the need to resolve singularities. This paper looks at gauge group breaking from E8 fibers down to SU (5) fibers due to the relevance of such fibrations for local F-theory GUT models. A purpose of this paper is to understand how the deformations of the singularity are understood in terms of its matrix factorizations. By systematically factorizing the elliptic fiber equation, this paper discusses geometries which are relevant for building semi-realistic local models. In the process it becomes evident that breaking patterns which are identical at the level of the Kodaira type of the fibers can be inequivalent at the level of matrix factorizations. Therefore the matrix factorization picture supplements information which the conventional less detailed descriptions lack.

  7. Evaluation of MMP-9 and MMP-2 and their suppressor TIMP-1 and TIMP-2 in adenocarcinoma of esophagogastric junction

    PubMed Central

    Lu, Xiaofei; Duan, Lingling; Xie, Hongqin; Lu, Xiaoxia; Lu, Daolin; Lu, Daopeng; Jiang, Nan; Chen, Yuxin

    2016-01-01

    Objective Adenocarcinoma of esophagogastric junction (AEG) is a lethal malignancy featured with early metastasis, poor prognosis, and few treatment options. Matrix metalloproteinase (MMP) and metalloproteinase suppressor (TIMP) have been considered to be associated with cancer invasion and metastasis. In our study, we evaluated expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in AEG and their correlation with clinicopathological parameters and the overall survival rate. Methods Expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in specimens from 120 AEGs were detected by immunohistochemistry. The correlations between expressions of these four proteins and clinicopathological characters were analyzed by chi-square test. Moreover, the prognostic value of these four biomarkers was evaluated by univariate analysis with Kaplan–Meier method and multivariate analysis with Cox regression model. Results The positive expression rate of MMP-9, MMP-2, TIMP-1, and TIMP-2 was 65%, 53%, 70%, and 49%, respectively, in the detected 120 AEG samples. MMP-9 was significantly associated with poorly histological differentiation (P=0.001), lymph node metastasis (P=0.007), and UICC stage (P=0.008). TIMP-1 showed significantly reversed correlations with histological differentiation (P=0.001), lymph node metastasis (P=0.007), and Union for International Cancer Control stage (P=0.008). Univariate analysis revealed that lymph node metastasis (P=0.002), depth of invasion (P=0.050), and MMP-9+/TIMP-1 phonotype (P<0.001) were significantly associated with the overall survival rate. Multivariate analyses demonstrated that MMP-9+/TIMP-1–phenotype was an independent prognostic factor in AEGs. Conclusion Detection of MMP-9 and TIMP-1 expression allows stratification of AEG patients into different survival categories and can be useful for precise individual evaluation and survival prediction. PMID:27486337

  8. Clinical significance of serum MMP-2 and MMP-7 in patients with ovarian cancer.

    PubMed

    Acar, Ayla; Onan, Anil; Coskun, Ugur; Uner, Aytug; Bagriacik, Umit; Atalay, Funda; Unsal, Diclehan Kilic; Guner, Haldun

    2008-01-01

    Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. The aim of this study was to evaluate role of serum MMP-2 and MMP-7 levels in patients with ovarian cancer. Serum levels of MMP-2 and MMP-7 were measured in 28 patients with ovarian carcinoma, 2 with borderline ovarian tumors, 10 with non-malignant gynecological disease and 30 healthy women by Enzyme-Linked Immunosorbent Assay (ELISA). Serum MMP-7 level was significantly (10.24+/-1.35 ng/ml) higher in the patients with ovarian malign tumors than healthy controls (3.29+/-1.64 ng/ml) (P<0.05). Postoperative levels of MMP-7 (7.68+/-1.17 ng/ml) were significantly lower in patients with malign ovarian tumors than those of preoperative level (10.24+/-1.35 ng/ml) (P<0.05). Serum MMP-2 levels were significantly lower in the patients with ovarian malign tumors (227.51+/-9.91 ng/ml) than those in the healthy controls (279.12+/-73 ng/ml) (P<0.05). There was no significant difference in serum levels of MMP-2 and MMP-7 in patients with benign ovarian disease when compared to healthy controls and patients with malignant disease (P>0.05). As a conclusion, MMP-7 can be a useful serum marker to show disease activity in malignant ovarian tumors.

  9. Expression of MMP-2 and MMP-9 in the rat trigeminal ganglion during the development of temporomandibular joint inflammation

    PubMed Central

    Nascimento, G.C.; Rizzi, E.; Gerlach, R.F.; Leite-Panissi, C.R.A.

    2013-01-01

    Orofacial pain is a prevalent symptom in modern society. Some musculoskeletal orofacial pain is caused by temporomandibular disorders (TMDs). This condition has a multi-factorial etiology, including emotional factors and alteration of the masticator muscle and temporomandibular joints (TMJs). TMJ inflammation is considered to be a cause of pain in patients with TMD. Extracellular proteolytic enzymes, specifically the matrix metalloproteinases (MMPs), have been shown to modulate inflammation and pain. The purpose of this investigation was to determine whether the expression and level of gelatinolytic activity of MMP-2 and MMP-9 in the trigeminal ganglion are altered during different stages of temporomandibular inflammation, as determined by gelatin zymography. This study also evaluated whether mechanical allodynia and orofacial hyperalgesia, induced by the injection of complete Freund's adjuvant into the TMJ capsule, were altered by an MMP inhibitor (doxycycline, DOX). TMJ inflammation was measured by plasma extravasation in the periarticular tissue (Evans blue test) and infiltration of polymorphonuclear neutrophils into the synovial fluid (myeloperoxidase enzyme quantification). MMP expression in the trigeminal ganglion was shown to vary during the phases of the inflammatory process. MMP-9 regulated the early phase and MMP-2 participated in the late phase of this process. Furthermore, increases in plasma extravasation in periarticular tissue and myeloperoxidase activity in the joint tissue, which occurred throughout the inflammation process, were diminished by treatment with DOX, a nonspecific MMP inhibitor. Additionally, the increases of mechanical allodynia and orofacial hyperalgesia were attenuated by the same treatment. PMID:24270905

  10. RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation.

    PubMed

    Walsh, Naomi; Larkin, AnneMarie; Swan, Niall; Conlon, Kevin; Dowling, Paul; McDermott, Ray; Clynes, Martin

    2011-07-28

    We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

  11. Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

    PubMed Central

    Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

    2016-01-01

    Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

  12. MMP2-CLEAVAGE OF DMP1 GENERATES A BIOACTIVE PEPTIDE PROMOTING DIFFERENTIATION OF DENTAL PULP STEM/PROGENITOR CELLS

    PubMed Central

    Chaussain, Catherine; Eapen, Asha Sarah; Huet, Eric; Floris, Caroline; Ravindran, Sriram; Hao, Jianjun; Menashi, Suzanne; George, Anne

    2011-01-01

    Dentin Matrix Protein 1 (DMP1) plays a regulatory role in dentin mineralization and can also function as a signaling molecule. MMP-2 (matrix metalloproteinase-2) is a predominant protease in the dentin matrix that plays a prominent role in tooth formation and a potential role during the carious process. The possibility that MMP-2 can cleave DMP1 to release biologically active peptides was investigated in this study. DMP1, both in the recombinant form and in its native state within the dentin matrix, was shown to be a substrate for MMP-2. Proteolytic processing of DMP1 by MMP-2 produced two major peptides, one that contains the C-terminal region of the protein known to carry both the ASARM (aspartic acid and serine rich domain) domain involved in biomineralization and the DNA binding site of DMP1. In vitro experiments with recombinant N- and C-terminal polypeptides mimicking the MMP-2 cleavage products of DMP1 demonstrated an effect of the C-polypeptide on the differentiation of dental pulp stem/progenitor cells to a putative odontoblast phenotype. In vivo implantation of this peptide in a rat injured pulp model induced a rapid formation of a homogeneous dentin bridge covered by a palisade of orientated cells expressing dentin sialoprotein (DSP) and DMP1, attesting an efficient repair process. These data suggest that a peptide generated through the proteolytic processing of DMP1 by MMP-2 can regulate the differentiation of mesenchymal cells during dentinogenesis and thus sustain reparative dentin formation in pathological situations such as carious decay. In addition, these data open a new therapeutic possibility of using this peptide to regenerate dentin after an injury. PMID:19908197

  13. Correlations of MMP-2 and TIMP-2 gene polymorphisms with the risk and prognosis of gastric cancer

    PubMed Central

    Zhang, De-Yong; Wang, Jing; Zhang, Guan-Qi; Chu, Xian-Qun; Zhang, Jian-Liang; Zhou, Yong

    2015-01-01

    Aim: To investigate the correlations of MMP-2 and TIMP-2 polymorphisms with the risk and prognosis of gastric cancer (GC). Methods: With an incorporation of 254 GC patients in the case group and 250 healthy subjects enrolled as the control group, this experiment was conducted. Denaturing high performance liquid chromatography method was adopted to detect all genotypes under partial denaturation, haloptype analysis was completed with the Shesis software. Serum MMP-2 and TIMP-2 levels were determined by the immunohistochemical semi-quantitative analysis. The follow-up examination was conducted after the patients had completed systemic therapy and discharged. Results: The distribution frequencies of MMP-2-735C/T locus genotypes between groups were compared (P > 0.05). However, the distributions of alleles and genotype frequencies of MMP-2-1306C/T, TIMP-2-303G/A and -418G/C all exhibited statistical difference (all P < 0.05). The gene polymorphism of MMP-2-1306C/T was statistically correlated with the expression of MMP-2 protein (P < 0.05); the same result was also found regarding TIMP-2-303G/A (P < 0.05). The haplotype analysis revealed that the CGC frequency of the case group was apparently higher than that of the control group (P < 0.05), the positive survival rate of CGC was apparently lower than the negative one. Conclusion: MMP-2-1306C/T, TIMP-2-303G/A and -418G/C variants might be correlated with GC susceptibility. Serum MMP-2 and TIMP-2 protein levels might be associated with GC susceptibility; Additionally, CGC haplotype might be the risk factor of GC. PMID:26884955

  14. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis.

    PubMed

    Shamamian, P; Schwartz, J D; Pocock, B J; Monea, S; Whiting, D; Marcus, S G; Mignatti, P

    2001-11-01

    Gelatinase A (MMP-2), a matrix metalloproteinase (MMP) involved in tumor invasion and angiogenesis, is secreted as an inactive zymogen (proMMP-2) and activated by proteolytic cleavage. Here we report that polymorphonuclear neutrophil (PMN)-derived elastase, cathepsin G, and proteinase-3 activate proMMP-2 through a mechanism that requires membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Immunoprecipitation of human PMN-conditioned medium with a mixture of antibodies to elastase, cathepsin G, and proteinase-3 abolished proMMP-2 activation, whereas individual antibodies were ineffective. Incubation of HT1080 cells with either purified PMN elastase or cathepsin G or proteinase-3 resulted in dose-and time-dependent proMMP-2 activation. Addition of PMN-conditioned medium to MT1-MMP expressing cells resulted in increased proMMP-2 activation and in vitro invasion of extracellular matrix (ECM), but had no effect with cells that express no MT1-MMP. MMP-2 activation by PMN-conditioned medium or purified elastase was blocked by the elastase inhibitor alpha(1)-antitrypsin but not by Batimastat, an MMP inhibitor, showing that elastase activation of MMP-2 is not mediated by MMP activities. The PMN-conditioned medium-induced increase in cell invasion was blocked by Batimastat as well as by alpha(1)-antitrypsin, showing that PMN serine proteinases trigger a proteinase cascade that entails proMMP-2 activation: this gelatinase is the downstream effector of the proinvasive activity of PMN proteinases. These findings indicate a novel role for PMN-mediated inflammation in a variety of tissue remodeling processes including tumor invasion and angiogenesis. PMID:11598905

  15. Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients with Resistant Hypertension

    PubMed Central

    Lacerda, Leandro; de Faria, Ana Paula; Fontana, Vanessa; Moreno, Heitor; Sandrim, Valéria

    2015-01-01

    Background Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown. Objectives To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN (CRHTN, n=41) and uncontrolled RHTN (UCRHTN, n=35). In addition, the association of those parameters with clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was evaluate in those subgroups. Methods This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram, and laboratory tests to assess biochemical parameters. Results Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in the UCRHTN and CRHTN subgroups (P>0.05). A significant correlation was found between diastolic BP (DBP) and MMP-9/TIMP-1 ratio (r=0.37; P=0.02) and DPB and MMP-2 (r=-0.40; P=0.02) in the UCRHTN subgroup. On the other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9, MMP-2, TIMP-1, TIMP-2 and their ratios were not associated with the lack of BP control. Conclusion These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects. PMID:26039662

  16. Chlorotoxin-Fc fusion inhibits release of MMP-2 from pancreatic cancer cells.

    PubMed

    El-Ghlban, Samah; Kasai, Tomonari; Shigehiro, Tsukasa; Yin, Hong Xia; Sekhar, Sreeja; Ida, Mikiko; Sanchez, Anna; Mizutani, Akifumi; Kudoh, Takayuki; Murakami, Hiroshi; Seno, Masaharu

    2014-01-01

    Chlorotoxin (CTX) is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which inhibits low-conductance chloride channels in colonic epithelial cells. It has been reported that CTX also binds to matrix metalloproteinase-2 (MMP-2), membrane type-1 MMP, and tissue inhibitor of metalloproteinase-2, as well as CLC-3 chloride ion channels and other proteins. Pancreatic cancer cells require the activation of MMP-2 during invasion and migration. In this study, the fusion protein was generated by joining the CTX peptide to the amino terminus of the human IgG-Fc domain without a hinge domain, the monomeric form of chlorotoxin (M-CTX-Fc). The resulting fusion protein was then used to target pancreatic cancer cells (PANC-1) in vitro. M-CTX-Fc decreased MMP-2 release into the media of PANC-1 cells in a dose-dependent manner. M-CTX-Fc internalization into PANC-1 cells was observed. When the cells were treated with chlorpromazine (CPZ), the internalization of the fusion protein was reduced, implicating a clathrin-dependent internalization mechanism of M-CTX-Fc in PANC-1 cells. Furthermore, M-CTX-Fc clearly exhibited the inhibition of the migration depending on the concentration, but human IgG, as negative control of Fc, was not affected. The M-CTX-Fc may be an effective instrument for targeting pancreatic cancer.

  17. Chlorotoxin-Fc fusion inhibits release of MMP-2 from pancreatic cancer cells.

    PubMed

    El-Ghlban, Samah; Kasai, Tomonari; Shigehiro, Tsukasa; Yin, Hong Xia; Sekhar, Sreeja; Ida, Mikiko; Sanchez, Anna; Mizutani, Akifumi; Kudoh, Takayuki; Murakami, Hiroshi; Seno, Masaharu

    2014-01-01

    Chlorotoxin (CTX) is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which inhibits low-conductance chloride channels in colonic epithelial cells. It has been reported that CTX also binds to matrix metalloproteinase-2 (MMP-2), membrane type-1 MMP, and tissue inhibitor of metalloproteinase-2, as well as CLC-3 chloride ion channels and other proteins. Pancreatic cancer cells require the activation of MMP-2 during invasion and migration. In this study, the fusion protein was generated by joining the CTX peptide to the amino terminus of the human IgG-Fc domain without a hinge domain, the monomeric form of chlorotoxin (M-CTX-Fc). The resulting fusion protein was then used to target pancreatic cancer cells (PANC-1) in vitro. M-CTX-Fc decreased MMP-2 release into the media of PANC-1 cells in a dose-dependent manner. M-CTX-Fc internalization into PANC-1 cells was observed. When the cells were treated with chlorpromazine (CPZ), the internalization of the fusion protein was reduced, implicating a clathrin-dependent internalization mechanism of M-CTX-Fc in PANC-1 cells. Furthermore, M-CTX-Fc clearly exhibited the inhibition of the migration depending on the concentration, but human IgG, as negative control of Fc, was not affected. The M-CTX-Fc may be an effective instrument for targeting pancreatic cancer. PMID:24511528

  18. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  19. MMP-2 gene polymorphisms are associated with type A aortic dissection and aortic diameters in patients

    PubMed Central

    Liu, Ou; Xie, Wuxiang; Qin, Yanwen; Jia, Lixin; Zhang, Jing; Xin, Yi; Guan, Xinliang; Li, Haiyang; Gong, Ming; Liu, Yuyong; Wang, Xiaolong; Li, Jianrong; Lan, Feng; Zhang, Hongjia

    2016-01-01

    Abstract Matrix metalloproteinases-2 (MMP-2) plays an important role in the pathogenesis of type A aortic dissection (AD). The aim of this study was to evaluate the association of 3 single nucleotide polymorphisms (SNPs) in the MMP-2 gene with type A AD risk and aortic diameters in patients. We performed a case–control study with 172 unrelated type A AD patients and 439 controls. Three SNPs rs11644561, rs11643630, and rs243865 were genotyped through the MassARRAY platform. Allelic associations of SNPs and SNP haplotypes with type A AD and aortic diameters in patients were evaluated. The frequency of the G allele of the rs11643630 polymorphism was significantly lower in type A AD patients than in control subjects (odds ratio 0.705, 95% confidence interval 0.545–0.912, P = 0.008). The association remained significant after adjusting for clinical covariates (P = 0.008). Carriers of the GG genotype of the rs11643630 polymorphism had significantly smaller aortic diameters than those with GT genotype or TT genotype (P = 0.02). Further haplotype analysis identified 1 protective haplotype (GC; P = 0.008) for development of type A AD. Again, a significant correlation was observed between haplotype GC and AD size (P = 0.020). Our results suggest that MMP-2 gene polymorphisms contribute to type A AD susceptibility. In addition, MMP-2 gene SNPs are associated with AD size, which could be used as a target for the development of new drug therapy. PMID:27759651

  20. Repeated cadmium nebulizations induce pulmonary MMP-2 and MMP-9 production and emphysema in rats.

    PubMed

    Kirschvink, Nathalie; Vincke, Grégoire; Fiévez, Laurence; Onclinx, Cécile; Wirth, Delphine; Belleflamme, Michèle; Louis, Renaud; Cataldo, Didier; Peck, Michael J; Gustin, Pascal

    2005-07-01

    This study describes induction of pulmonary inflammation, production of matrix metalloprotease of type 2 (MMP-2) and type 9 (MMP-9), and emphysema in cadmium (Cd)-exposed rats. Sprague-Dawley rats were randomly distributed into two groups: one placebo-exposed group undergoing saline (NaCl 0.9%) inhalation (n=30) and one Cd-exposed group undergoing cadmium (CdCl(2) 0.1%) inhalation (n=30). The animals of the placebo- and Cd-exposed groups were divided in five subgroups (n=6). Subgroups underwent either a single exposure of 1h or repeated exposures three times weekly for 1h during 3 weeks (3W), 5 weeks (5W), 5 weeks followed by 2 weeks without exposure (5W+2) or 5 weeks followed by 4 weeks without exposure (5W+4). Each animal underwent determination of enhanced pause (Penh) as index of airflow limitation prior to the first exposure as well as before sacrifice. The animals were sacrificed the day after their last exposure. The left lung was fixed for histomorphometric analysis (determination of median interwall distance (MIWD)), whilst bronchoalveolar lavage fluid (BALF) was collected from the right lung. BALF was analyzed cytologically, and MMP-2 and MMP-9 levels were determined by gelatine zymography. Twelve rats previously instilled with pancreatic elastase were used as positive emphysema controls and underwent the same investigations. Cd-exposure induced a significant increase of BALF macrophages, neutrophils and MMP-9 up to 5W+4, whereas MMP-2 gelatinolytic activity returned to baseline levels within 5W. MIWD was significantly increased in all repeatedly Cd-exposed groups and elastase-treated rats. Penh was increased in Cd-exposed rats after a single exposure and after 3W. MMP gelatinolytic activity was significantly correlated with macrophages, neutrophils and Penh. In repeatedly exposed rats, MIWD was positively and significantly correlated with MMP gelatinolytic activity, suggesting that increased MMP-2 and MMP-9 production favours the development of emphysema.

  1. BAG3 increases the invasiveness of uterine corpus carcinoma cells by suppressing miR-29b and enhancing MMP2 expression.

    PubMed

    Habata, Shutaro; Iwasaki, Masahiro; Sugio, Asuka; Suzuki, Miwa; Tamate, Masato; Satohisa, Seiro; Tanaka, Ryoichi; Saito, Tsuyoshi

    2015-05-01

    Approximately 30% of uterine corpus carcinomas are diagnosed at an advanced stage and have a poor prognosis. Our previous study indicated that BCL2-associated athanogene 3 (BAG3) enhances matrix metalloproteinase-2 (MMP2) expression and binds to MMP2 to positively regulate the process of cell invasion in ovarian cancer cells. Recently, altered miRNA expression patterns were observed in several groups of patients with endometrial cancers. One of the altered miRNAs, miR-29b, reportedly reduces tumor invasiveness by suppressing MMP2 expression. Our aim in the present study was to examine the relationships among BAG3, miR-29b and MMP2 in endometrioid adenocarcinoma cells. We found that BAG3 suppresses miR-29b expression and enhances MMP2 expression, which in turn increases cell motility and invasiveness. Moreover, restoration of miR-29b through BAG3 knockdown reduced MMP2 expression, as well as cell motility and invasiveness. Collectively, our findings indicate that BAG3 enhances MMP2 expression by suppressing miR-29b, thereby increasing the metastatic potential of endometrioid adenocarcinomas.

  2. Low level laser therapy increases angiogenesis in a model of ischemic skin flap in rats mediated by VEGF, HIF-1α and MMP-2.

    PubMed

    Cury, Vivian; Moretti, Ana Iochabel Soares; Assis, Lívia; Bossini, Paulo; Crusca, Jaqueline de Souza; Neto, Carlos Benatti; Fangel, Renan; de Souza, Heraldo Possolo; Hamblin, Michael R; Parizotto, Nivaldo Antonio

    2013-08-01

    It is known that low level laser therapy is able to improve skin flap viability by increasing angiogenesis. However, the mechanism for new blood vessel formation is not completely understood. Here, we investigated the effects of 660 nm and 780 nm lasers at fluences of 30 and 40 J/cm(2) on three important mediators activated during angiogenesis. Sixty male Wistar rats were used and randomly divided into five groups with twelve animals each. Groups were distributed as follows: skin flap surgery non-irradiated group as a control; skin flap surgery irradiated with 660 nm laser at a fluence of 30 or 40 J/cm(2) and skin flap surgery irradiated with 780 nm laser at a fluence of 30 or 40 J/cm(2). The random skin flap was performed measuring 10×4 cm, with a plastic sheet interposed between the flap and the donor site. Laser irradiation was performed on 24 points covering the flap and surrounding skin immediately after the surgery and for 7 consecutive days thereafter. Tissues were collected, and the number of vessels, angiogenesis markers (vascular endothelial growth factor, VEGF and hypoxia inducible factor, HIF-1α) and a tissue remodeling marker (matrix metalloproteinase, MMP-2) were analyzed. LLLT increased an angiogenesis, HIF-1α and VEGF expression and decrease MMP-2 activity. These phenomena were dependent on the fluences, and wavelengths used. In this study we showed that LLLT may improve the healing of skin flaps by enhancing the amount of new vessels formed in the tissue. Both 660 nm and 780 nm lasers were able to modulate VEGF secretion, MMP-2 activity and HIF-1α expression in a dose dependent manner.

  3. WISP-1 overexpression upregulates cell proliferation in human salivary gland carcinomas via regulating MMP-2 expression

    PubMed Central

    Li, Fu-Jun; Wang, Xin-Juan; Zhou, Xiao-Li

    2016-01-01

    Background WISP-1 is a member of the CCN family of growth factors and has been reported to play an important role in tumorigenesis by triggering downstream events via integrin signaling. However, little is known about the role of WISP-1 in proliferation of salivary gland carcinoma (SGC) cells. Methods In this study, we investigated the WISP-1 expression in SGC tissues via immunohistochemical staining, Western blotting assay, and real-time quantitative polymerase chain reaction method, and then evaluated the regulatory role of WISP-1 in the growth of SGC A-253 cells. In addition, the role of MMP-2 in the WISP-1-mediated growth regulation was also investigated. Results It was demonstrated that the WISP-1 expression was upregulated at both mRNA and protein levels in 15 of 21 SGC tumor tissues, compared to the non-tumor tissues (five of 21), associated with the lymph node dissection and bone invasion. The in vitro CCK-8 assay and colony-forming assay demonstrated that the exogenous WISP-1 treatment or the WISP-1 overexpression promoted the growth of A-253 cells. In addition, we confirmed that the WISP-1 overexpression upregulated the MMP-2 expression in A-253 cells with the gain-of-function and loss-of-function strategies, and that the MMP-2 knockdown attenuated the WISP-1-mediated growth promotion of A-253 cells. Conclusion We found that WISP-1 was overexpressed in the human SGCs, and the WISP-1 overexpression promoted the salivary gland cell proliferation via upregulating MMP-2 expression. Our study recognized the oncogenic role of WISP-1 in human SGCs, which could serve as a potential target for anticancer therapy. PMID:27799801

  4. The YY1/MMP2 axis promotes trophoblast invasion at the maternal-fetal interface.

    PubMed

    Tian, Fu-Ju; Cheng, Yan-Xiang; Li, Xiao-Cui; Wang, Fa; Qin, Chuan-Mei; Ma, Xiao-Ling; Yang, Jing; Lin, Yi

    2016-05-01

    YY1 is a sequence-specific DNA-binding transcription factor that has many important biological roles. However, its function in trophoblasts at the maternal-fetal interface remains to be elucidated. In this study, we used an mRNA microarray and reverse transcription qPCR and compared the YY1 mRNA expression level in trophoblasts between patients with recurrent miscarriage (RM) and healthy control subjects. Our results revealed that YY1 mRNA expression was significantly lower in the trophoblasts of the RM group compared with the healthy control group. Furthermore, immunofluorescence and immunohistochemical data showed that YY1 was highly expressed in human placental villi during early pregnancy, especially in cytotrophoblast cells and invasive extravillous trophoblasts, and it was expressed at a much lower level in the placental villi of term pregnancy. YY1 overexpression enhanced, and knockdown repressed, the invasion and proliferation of trophoblasts. Antibody array screening revealed that YY1 significantly promoted MMP2 expression in trophoblasts. Bioinformatics analysis identified three YY1-binding sites in the MMP2 promoter region, and chromatin immunoprecipitation analysis verified that YY1 binds directly to its promoter region. Importantly, inhibition of YY1 by siRNA clearly decreased trophoblast invasion in an ex vivo explant culture model. Overall, our findings revealed a new regulatory pathway of YY1/MMP2 in trophoblast cell invasion during early pregnancy and indicated that YY1 may be involved in the pathogenesis of RM. PMID:27071480

  5. Pathway network analysis and an application to the ODE model of MMP2 activation in the early stage of cancer cell invasion

    NASA Astrophysics Data System (ADS)

    Minerva, D.; Kawasaki, S.; Suzuki, T.

    2015-03-01

    Cancer is known as the leading causes of death in the world, particularly in developing countries. Metastasis is believed as factor that make the situation worse. Cancer cell has the ability to invade and metastasize to a distant part of body. The mechanism of cancer cell invasion involving three molecules; MT1-MMP, TIMP2, and MMP2. The interaction of the three molecules activates MMP2 by cutting the MMP2 binding from a specific complex. The MMP2 activation leads to the release of cancer cell from its primary state towards distant part of body. In this paper, we will present the result of recent studies about MMP2 activation from mathematical point of view. We study the MMP2 activation model using law of mass action and conservation. We propose a method based on attachment and detachment rules and conservation law to analyze the ordinary differential equations system of pathway network associated with the MMP2 activation. As the result, we obtain possible way to suppress the spread of cancer cell.

  6. Irradiation Alters MMP-2/TIMP-2 System and Collagen Type IV Degradation in Brain

    SciTech Connect

    Lee, Won Hee; Warrington, Junie P.; Sonntag, William E.; Lee, Yong Woo

    2012-04-01

    Purpose: Blood-brain barrier (BBB) disruption is one of the major consequences of radiation-induced normal tissue injury in the central nervous system. We examined the effects of whole-brain irradiation on matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in the brain. Methods and Materials: Animals received either whole-brain irradiation (a single dose of 10 Gy {gamma}-rays or a fractionated dose of 40 Gy {gamma}-rays, total) or sham-irradiation and were maintained for 4, 8, and 24 h following irradiation. mRNA expression levels of MMPs and TIMPs in the brain were analyzed by real-time reverse transcriptase-polymerase chain reaction (PCR). The functional activity of MMPs was measured by in situ zymography, and degradation of ECM was visualized by collagen type IV immunofluorescent staining. Results: A significant increase in mRNA expression levels of MMP-2, MMP-9, and TIMP-1 was observed in irradiated brains compared to that in sham-irradiated controls. In situ zymography revealed a strong gelatinolytic activity in the brain 24 h postirradiation, and the enhanced gelatinolytic activity mediated by irradiation was significantly attenuated in the presence of anti-MMP-2 antibody. A significant reduction in collagen type IV immunoreactivity was also detected in the brain at 24 h after irradiation. In contrast, the levels of collagen type IV were not significantly changed at 4 and 8 h after irradiation compared with the sham-irradiated controls. Conclusions: The present study demonstrates for the first time that radiation induces an imbalance between MMP-2 and TIMP-2 levels and suggests that degradation of collagen type IV, a major ECM component of BBB basement membrane, may have a role in the pathogenesis of brain injury.

  7. Cadmium exposure inhibits MMP2 and MMP9 activities in the prostate and testis

    SciTech Connect

    Lacorte, Livia M.; Rinaldi, Jaqueline C.; Justulin, Luis A.; Delella, Flávia K.; Moroz, Andrei; Felisbino, Sérgio L.

    2015-02-20

    Matrix metalloproteinases (MMPs) are zinc (Zn{sup 2+}) and calcium (Ca{sup 2+}) dependant endopeptidases, capable of degradation of numerous components of the extracellular matrix. Cadmium (Cd{sup 2+}) is a well known environmental contaminant which could impair the activity of MMPs. In this sense, this study was conducted to evaluate if Cd{sup 2+} intake inhibits these endopeptidases activities at the rat prostate and testicles and if it directly inhibits the activity of MMP2 and MMP9 at gelatinolytic assays when present in the incubation buffer. To investigate this hypothesis, Wistar rats (5 weeks old), were given tap water (untreated, n = 9), or 15 ppm CdCl{sub 2} diluted in drinking water, during 10 weeks (n = 9) and 20 weeks (n = 9). The animals were euthanized and their ventral prostate, dorsal prostate, and testicles were removed. These tissue samples were processed for protein extraction and subjected to gelatin zymography evaluation. Additionally, we performed an experiment of gelatin zymography in which 5 μM or 2 mM cadmium chloride (CdCl{sub 2}) was directly dissolved at the incubation buffer, using the prostatic tissue samples from untreated animals that exhibited the highest MMP2 and MMP9 activities in the previous experiment. We have found that CdCl{sub 2} intake in the drinking water led to the inhibition of 35% and 30% of MMP2 and MMP9 (p < 0.05) at the ventral prostate and testis, respectively, in Cd{sup 2+} treated animals when compared to controls. Moreover, the activities of the referred enzymes were 80% and 100% inhibited by 5 μM and 2 mM of CdCl{sub 2}, respectively, even in the presence of 10 mM of CaCl{sub 2} within the incubation buffer solution. These important findings demonstrate that environmental cadmium contamination may deregulate the natural balance in the extracellular matrix turnover, through MMPs downregulation, which could contribute to the toxic effects observed in prostatic and testicular tissue after its

  8. Matrix metalloproteinases-2 and -9 in cervical cancer: different roles in tumor progression.

    PubMed

    Rauvala, M; Aglund, K; Puistola, U; Turpeenniemi-Hujanen, T; Horvath, G; Willén, R; Stendahl, U

    2006-01-01

    The incidence of uterine cervical cancer has increased slightly in Western countries, with an increase in relatively young women. Overexpression of matrix metalloproteinases (MMPs)-2 and -9 has turned out as a prognostic factor in many cancers. We compared the expression of the proteins MMP-2 and MMP-9 in cervical primary tumors with clinical outcome and risk factors of cervical cancer. One hundred sixty-one patients with cervical cancer treated in Umeå University Hospital or Sahlgrenska University Hospital, Sweden, between 1991 and 1995 were included in the study. Paraffin-embedded tissue samples obtained prior to treatment were examined immunohistochemically by specific antibodies for MMP-2 and MMP-9. Forty-two percent of the tumors were intensively positive for MMP-2 and 31% for MMP-9. Nineteen percent of the samples were intensively positive for both proteinases and 47% negative or weak for both. Overexpression of MMP-2 seemed to predict unfavorable survival under Kaplan-Meier analysis and in the multivariate analysis. Early sexual activity and low parity seemed to correlate to overexpression of MMP-2. MMP-9 was not associated with survival or sexual behavior. Intensive MMP-9 was noted in grade 1 tumors. We conclude that MMP-2 and MMP-9 have different roles in uterine cervical cancer. MMP-2 could be associated with aggressive behavior, but MMP-9 expression diminishes in high-grade tumors.

  9. p38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells.

    PubMed

    Hsu, Hsi-Hsien; Liu, Chung-Jung; Shen, Chia-Yao; Chen, Yi-Jyun; Chen, Li-Mien; Kuo, Wu-Hsien; Lin, Yueh-Min; Chen, Ray-Jade; Tsai, Chang-Hai; Tsai, Fuu-Jen; Huang, Chih-Yang

    2012-11-01

    Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E(2)) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E(2) to explore whether E(2) down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E(2) treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E(2) significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E(2) treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E(2) -downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E(2) /ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E(2) treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E(2) treatment simultaneously impaired cell migration by

  10. Anthocyanins protected hearts against ischemic injury by reducing MMP-2 activity via Akt/P38 pathways

    PubMed Central

    Hao, Jie; Du, Hong; Li, Weiwei; Liu, Fan; Lu, Jingchao; Yang, Xiuchun; Cui, Wei

    2016-01-01

    Growing evidences suggest that there are close associations between anthocyanins and cardiac protection. However, little is known about the detailed roles of anthocyanins in regulating extracellular matrix (ECM) remodeling. Incubation of primary cultured fibroblasts with anthocyanins reduced both intracellular collagen expression and extracellular collagen secretion. Down-regulation of collagen production was also shown in infarcted cardiac tissues after permanent coronary artery ligation in mice treated with anthocyanins. The phosphorylation levels of Akt and/or P-38 were significantly increased by anthocyanins supplementation in primary cultured fibroblasts. Gelatin zymography analysis of matrix metalloproteinase-2 (MMP-2) activity in conditioned medium collected from fibroblasts demonstrated that anthocyanins treatment significantly reduced MMP-2 activity. These results demonstrated that anthocyanins play a role in mediating myocardial ECM remodeling and that the Akt/P-38 pathways mediate these protective effects on hearts. PMID:27158396

  11. MMP2-Targeting and Redox-Responsive PEGylated Chlorin e6 Nanoparticles for Cancer Near-Infrared Imaging and Photodynamic Therapy.

    PubMed

    Hou, Wenxiu; Xia, Fangfang; Alves, Carla S; Qian, Xiaoqing; Yang, Yuming; Cui, Daxiang

    2016-01-20

    A unique matrix metalloproteinase 2-targeted photosensitizer delivery platform was developed in this study for tumor-targeting imaging and photodynamic therapy. The model photosensitizer therapeutic agent chlorin e6 (Ce6) was first covalently conjugated with matrix metalloproteinase 2-cleavable polypeptide and then modified with polyethylene glycol via a redox-responsive cleavable disulfide linker. The resultant matrix metalloproteinase 2-cleavable polypeptide modified PEGylated Ce6 (PEG-SS-Ce6-MMP2) nanoparticles, which formed via self-assembly, were observed to be monodisperse and significantly stable in aqueous solution. In addition, owing to their cellular redox-responsiveness at the cleavable disulfide linker, the PEG-SS-Ce6-MMP2 nanoparticles were able to release Ce6 rapidly. Despite displaying enhanced intracellular internalization, the synthesized PEG-SS-Ce6-MMP2 nanoparticles did not compromise their phototoxic effects toward A549 cancer cells when compared with free Ce6 and PEGylated Ce6 nanoparticles. In vivo experiments further revealed that, in contrast with the free Ce6 or with the PEGylated Ce6 nanoparticles, the PEG-SS-Ce6-MMP2 nanoparticles showed a remarkable increase in tumor-targeting ability and a significantly improved photodynamic therapeutic efficiency in A549 tumor-bearing mice. These results suggest that the PEG-SS-Ce6-MMP2 nanoparticles hold great potential for tumor-targeting imaging and photodynamic therapy.

  12. The use of MMP2 antibody-conjugated cationic microbubble to target the ischemic myocardium, enhance Timp3 gene transfection and improve cardiac function.

    PubMed

    Yan, Ping; Chen, Ko-Jie; Wu, Jun; Sun, Lu; Sung, Hsing-Wen; Weisel, Richard D; Xie, Jun; Li, Ren-Ke

    2014-01-01

    The objective of this study was to synthesize a cationic microbubble (CMB) conjugated with an antibody against matrix metalloproteinase 2 (CMBMMP2) to increase microbubble accumulation and gene transfection in the infarcted myocardium and to restore ventricular function following an ischemic insult. We previously reported that our CMBs enhanced the efficiency of gene transfection following ultrasound-targeted microbubble destruction (UTMD) in rodent hearts. Therefore, we conjugated a thiolated MMP2 antibody to the PEG chains on the CMB surface, which was verified by fluorescent microscopy. Rats underwent ischemia/reperfusion injury 3 days prior to UTMD delivery of the control or Timp3 plasmid. The CMBMMP2 improved microbubble accumulation in the infarct region, with 57% more contrast intensity compared to the non-conjugated CMB. UTMD-mediated CMBMMP2 delivery of the Timp3 gene significantly increased TIMP3 protein levels in the infarct scar and border zone at 3 days post-UTMD compared to delivery by the non-conjugated CMB. Both MMP2 and MMP9 activity were reduced in the CMBMMP2Timp3 group, which resulted in smaller and thicker infarcts and improved cardiac function. UTMD therapy with this CMBMMP2 provides an efficient platform for the targeted delivery of factors intended to preserve ventricular structure and improve cardiac function after ischemic injury.

  13. Inonotus obliquus-derived polysaccharide inhibits the migration and invasion of human non-small cell lung carcinoma cells via suppression of MMP-2 and MMP-9.

    PubMed

    Lee, Ki Rim; Lee, Jong Seok; Song, Jeong Eun; Ha, Suk Jin; Hong, Eock Kee

    2014-12-01

    Polysaccharides isolated from the fruiting body of Inonotus obliquus (PFIO) are known to possess various pharmacological properties including antitumor activity. However, the anti-metastatic effect and its underlying mechanistic signaling pathway involved these polysaccharides in human non-small cell lung carcinoma remain unknown. The present study therefore aimed to determine the anti-metastatic potential and signaling pathways of PFIO in the highly metastatic A549 cells. We found that PFIO suppressed the migration and invasive ability of A549 cells while decreasing the expression levels and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, PFIO decreased the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) as well as the expression level of COX-2, and inhibited the nuclear translocation of nuclear factor κB (NF-κB) in A549 cells. These results suggested that PFIO could suppress the invasion and migration of human lung carcinoma by reducing the expression levels and activity of MMP-2 and MMP-9 via suppression of MAPKs, PI3K/AKT, and NF-κB signaling pathways.

  14. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling.

    PubMed

    Han, Y; Wu, Z; Wu, T; Huang, Y; Cheng, Z; Li, X; Sun, T; Xie, X; Zhou, Y; Du, Z

    2016-03-03

    Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long noncoding RNA. It is associated with metastasis and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in other malignancies. But, little is known about the role of MALAT1 in glioma. In this study, quantitative reverse transcription PCR (qRT-PCR) was used to demonstrate that the expression of MALAT1 was lower than that in normal brain tissues. Stable RNA interference-mediated knockdown of MALAT1 in human glioma cell lines (U87 and U251) significantly promoted the invasion and proliferation of the glioma cells by in vitro assays. Conversely, overexpression of MALAT1 caused significant reduction in cell proliferation and invasion in vitro, and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models. Furthermore, MALAT1-mediated tumor suppression in glioma cells may be via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling activity and expression of matrix metalloproteinase 2 (MMP2). In conclusion, overall data demonstrated the tumor-suppressive role of MALAT1 in glioma by attenuating ERK/MAPK-mediated growth and MMP2-mediated invasiveness.

  15. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling

    PubMed Central

    Han, Y; Wu, Z; Wu, T; Huang, Y; Cheng, Z; Li, X; Sun, T; Xie, X; Zhou, Y; Du, Z

    2016-01-01

    Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long noncoding RNA. It is associated with metastasis and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in other malignancies. But, little is known about the role of MALAT1 in glioma. In this study, quantitative reverse transcription PCR (qRT-PCR) was used to demonstrate that the expression of MALAT1 was lower than that in normal brain tissues. Stable RNA interference-mediated knockdown of MALAT1 in human glioma cell lines (U87 and U251) significantly promoted the invasion and proliferation of the glioma cells by in vitro assays. Conversely, overexpression of MALAT1 caused significant reduction in cell proliferation and invasion in vitro, and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models. Furthermore, MALAT1-mediated tumor suppression in glioma cells may be via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling activity and expression of matrix metalloproteinase 2 (MMP2). In conclusion, overall data demonstrated the tumor-suppressive role of MALAT1 in glioma by attenuating ERK/MAPK-mediated growth and MMP2-mediated invasiveness. PMID:26938295

  16. Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis

    PubMed Central

    Sampieri, Clara Luz; de la Peña, Sol; Ochoa-Lara, Mariana; Zenteno-Cuevas, Roberto; León-Córdoba, Kenneth

    2010-01-01

    AIM: To assess expression of matrix metalloproteinases 2 (MMP2) and MMP9 in gastric cancer, superficial gastritis and normal mucosa, and to measure metalloproteinase activity. METHODS: MMP2 and MMP9 mRNA expression was determined by quantitative real-time polymerase chain reaction. Normalization was carried out using three different factors. Proteins were analyzed by quantitative gelatin zymography (qGZ). RESULTS: 18S ribosomal RNA (18SRNA) was very highly expressed, while hypoxanthine ribosyltransferase-1 (HPRT-1) was moderately expressed. MMP2 was highly expressed, while MMP9 was not detected or lowly expressed in normal tissues, moderately or highly expressed in gastritis and highly expressed in cancer. Relative expression of 18SRNA and HPRT-1 showed no significant differences. Significant differences in MMP2 and MMP9 were found between cancer and normal tissue, but not between gastritis and normal tissue. Absolute quantification of MMP9 echoed this pattern, but differential expression of MMP2 proved conflictive. Analysis by qGZ indicated significant differences between cancer and normal tissue in MMP-2, total MMP-9, 250 and 110 kDa bands. CONCLUSION: MMP9 expression is enhanced in gastric cancer compared to normal mucosa; interpretation of differential expression of MMP2 is difficult to establish. PMID:20333791

  17. Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers.

    PubMed

    Miyazaki, Daigo; Nakamura, Akinori; Fukushima, Kazuhiro; Yoshida, Kunihiro; Takeda, Shin'ichi; Ikeda, Shu-ichi

    2011-05-01

    Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as β-dystroglycan and β-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.

  18. Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging

    PubMed Central

    Cheng, Chao; Zhang, Dazhi; Zhang, Anyu; Wang, Lizhen; Jiang, Hongdie; Wang, Tao; Liu, Hongrui; Xu, Yuping; Yang, Runlin; Chen, Fei; Yang, Min; Zuo, Changjing

    2015-01-01

    Background and Objective The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. Methods C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. Results The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. Conclusions [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors. PMID:26540114

  19. A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

    PubMed Central

    Lovett, David H.; Mahimkar, Rajeev; Raffai, Robert L.; Cape, Leslie; Maklashina, Elena; Cecchini, Gary; Karliner, Joel S.

    2012-01-01

    Background Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress. Methodology and Principal Findings Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M77, thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes. Conclusion A novel N-terminal truncated intracellular isoform of MMP-2 is

  20. ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells.

    PubMed

    Jo, Yoon Kyung; Park, So Jung; Shin, Ji Hyun; Kim, Yunha; Hwang, Jung Jin; Cho, Dong-Hyung; Kim, Jin Cheon

    2011-01-28

    Autophagy is a catabolic cellular process involving self-digestion and turnover of macromolecules and entire organelles. Autophagy is primarily a protective process in response to cellular stress, but it can be associated with cell death. Genetic evidence also supports autophagy function as a tumor suppressor mechanism. To identify specific regulators to autophagy, we screened the Lopac 1280 and the Prestwick chemical libraries using a cell-based screening system with autophagy marker (green fluorescence protein conjugated LC3 protein (GFP-LC3)). We identified ARP101, a selective matrix metalloproteinase-2 (MMP-2) inhibitor as one of the most potent inducer of autophagy. ARP101 treatment was highly effective in inducing the formation of autophagosome and conversion of LC3I into LC3II. Moreover, ARP101-induced autophagy was completely blocked in mouse embryo fibroblasts that lacked autophagy related gene 5 (ATG5(-/-) MEF). Interestingly, cell death induced by ARP101 was not inhibited by zVAD, a pan caspase inhibitor, whereas, it was efficiently suppressed by addition of 3-methyladenine, an autophagy inhibitor. These results suggest that the selective MMP-2 inhibitor, ARP101, induces autophagy and autophagy-associated cell death. PMID:21187062

  1. Nuclear localization of catalytically active MMP-2 in endothelial cells and neurons

    PubMed Central

    Sinha, Satyesh K; Asotra, Kamlesh; Uzui, Hiroyasu; Nagwani, Santosh; Mishra, Vivek; Rajavashisth, Tripathi B

    2014-01-01

    From microscopic organelles and sub-cellular domains to the level of whole tissues, organs, and body parts, living organisms must continuously maintain and renovate structural components. Matrix metalloproteinases (MMPs) comprise a family of over two dozen Zn-dependent endopeptidases thought to be primary effectors of extracellular tissue renewal and remodeling processes. Endogenous inhibitors, particularly the tissue inhibitors of MMPs (TIMPs), counteract MMP-2 proteolytic activity, but also participate in conversion of several pro-MMPs to proteolytically active forms. Numerous pathologies are characterized by imbalances in activities of MMPs relative to TIMPs. MMPs are synthesized and stored in cytoplasmic domains prior to secretion or expression in cell surface-associated form. Several proteases have been identified in cell nuclei, but their functions, regulation, and substrates remain largely unknown. Here we showed that the catalytically active gelatinase MMP-2 is expressed in nuclei of endothelial cells and neurons, but not in glial or Schwannoma cell lines, in a pattern resembling nuclear speckles, and colocalizes with TIMP-1. PMID:24489995

  2. Stomach Cancer: Interconnection between the Redox State, Activity of MMP-2, MMP-9 and Stage of Tumor Growth.

    PubMed

    Burlaka, Anatoly P; Ganusevich, Irina I; Gafurov, Marat R; Lukin, Sergey M; Sidorik, Evgeny P

    2016-04-01

    High levels of reactive oxygen (ROS) and nitrogen (RNS) species can lead to the destruction of extracellular matrix facilitating tumor progression. ROS can activate matrix metalloproteinases (MMP), damage DNA and RNA. Therefore, the levels of MMP, ROS and RNS can serve as additional prognostic markers and for the estimation of the effectiveness of tumor therapy. Concerning gastric cancer, the prognostic role of MMP, its connection with the cancer staging remains controversial and correlations between the activity of MMP with the ROS and RNS levels are insufficiently confirmed. Superoxide generation rates, nitric oxide (NO) levels, concentrations of active forms of matrix metalloproteinases MMP-2 and MMP-9 in tumor and adjacent tissues of patients with stomach cancer at different disease stages were measured by electron spin resonance (ESR) including spin-trapping and polyacrylamide gel zymography. It is shown that the activity of MMP-2 and MMP-9 in tumor tissue correlate with the superoxide radicals generation rate and NO levels (r = 0.48÷0.67, p < 0.05). The activity of MMP-2 and MMP-9 in tumor tissues and superoxide radical generation rates correlate positively with the stage of regional dissemination (r = 0.45 and 0.37, correspondingly, p < 0.05), but MMP-2 and MMP-9 activity inversely depends on distant metastatic degree of stomach cancer (r = 0.58; p < 0.05). Additionally, the feasibility of ESR to locally determine oxidative stress is demonstrated. PMID:26905073

  3. Stomach Cancer: Interconnection between the Redox State, Activity of MMP-2, MMP-9 and Stage of Tumor Growth.

    PubMed

    Burlaka, Anatoly P; Ganusevich, Irina I; Gafurov, Marat R; Lukin, Sergey M; Sidorik, Evgeny P

    2016-04-01

    High levels of reactive oxygen (ROS) and nitrogen (RNS) species can lead to the destruction of extracellular matrix facilitating tumor progression. ROS can activate matrix metalloproteinases (MMP), damage DNA and RNA. Therefore, the levels of MMP, ROS and RNS can serve as additional prognostic markers and for the estimation of the effectiveness of tumor therapy. Concerning gastric cancer, the prognostic role of MMP, its connection with the cancer staging remains controversial and correlations between the activity of MMP with the ROS and RNS levels are insufficiently confirmed. Superoxide generation rates, nitric oxide (NO) levels, concentrations of active forms of matrix metalloproteinases MMP-2 and MMP-9 in tumor and adjacent tissues of patients with stomach cancer at different disease stages were measured by electron spin resonance (ESR) including spin-trapping and polyacrylamide gel zymography. It is shown that the activity of MMP-2 and MMP-9 in tumor tissue correlate with the superoxide radicals generation rate and NO levels (r = 0.48÷0.67, p < 0.05). The activity of MMP-2 and MMP-9 in tumor tissues and superoxide radical generation rates correlate positively with the stage of regional dissemination (r = 0.45 and 0.37, correspondingly, p < 0.05), but MMP-2 and MMP-9 activity inversely depends on distant metastatic degree of stomach cancer (r = 0.58; p < 0.05). Additionally, the feasibility of ESR to locally determine oxidative stress is demonstrated.

  4. Cadmium exposure inhibits MMP2 and MMP9 activities in the prostate and testis.

    PubMed

    Lacorte, Livia M; Rinaldi, Jaqueline C; Justulin, Luis A; Delella, Flávia K; Moroz, Andrei; Felisbino, Sérgio L

    2015-02-20

    Matrix metalloproteinases (MMPs) are zinc (Zn(2+)) and calcium (Ca(2+)) dependant endopeptidases, capable of degradation of numerous components of the extracellular matrix. Cadmium (Cd(2+)) is a well known environmental contaminant which could impair the activity of MMPs. In this sense, this study was conducted to evaluate if Cd(2+) intake inhibits these endopeptidases activities at the rat prostate and testicles and if it directly inhibits the activity of MMP2 and MMP9 at gelatinolytic assays when present in the incubation buffer. To investigate this hypothesis, Wistar rats (5 weeks old), were given tap water (untreated, n = 9), or 15 ppm CdCl2 diluted in drinking water, during 10 weeks (n = 9) and 20 weeks (n = 9). The animals were euthanized and their ventral prostate, dorsal prostate, and testicles were removed. These tissue samples were processed for protein extraction and subjected to gelatin zymography evaluation. Additionally, we performed an experiment of gelatin zymography in which 5 μM or 2 mM cadmium chloride (CdCl2) was directly dissolved at the incubation buffer, using the prostatic tissue samples from untreated animals that exhibited the highest MMP2 and MMP9 activities in the previous experiment. We have found that CdCl2 intake in the drinking water led to the inhibition of 35% and 30% of MMP2 and MMP9 (p < 0.05) at the ventral prostate and testis, respectively, in Cd(2+) treated animals when compared to controls. Moreover, the activities of the referred enzymes were 80% and 100% inhibited by 5 μM and 2 mM of CdCl2, respectively, even in the presence of 10 mM of CaCl2 within the incubation buffer solution. These important findings demonstrate that environmental cadmium contamination may deregulate the natural balance in the extracellular matrix turnover, through MMPs downregulation, which could contribute to the toxic effects observed in prostatic and testicular tissue after its exposure. PMID:25600809

  5. The Impact of Matrix Metalloproteinase 2 on Prognosis and Clinicopathology of Breast Cancer Patients: A Systematic Meta-Analysis

    PubMed Central

    Chen, Yiping; Wang, Xiaochen; Chen, Guodi; Dong, Caixia; Zhang, Depu

    2015-01-01

    Backgrounds Matrix metalloproteinase 2 (MMP-2) plays a crucial role in the progression of breast cancer (BC). The prognostic role of MMP-2 expression in BC patients has been widely reported, but the results were inconsistent. Thus, a meta-analysis was conducted to gain a better insight into the impact of MMP-2 expression on survival and clinicopathological features of BC patients. Methods Identical search strategies were used to search relevant literatures in electronic databases update to August 1, 2014. Individual hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were extracted and pooled to evaluate the strength of the association between positive MMP-2 expression and survival results and clinicopathological features of BC patients. Begg’s tests, Egger’s tests and funnel plots were used to evaluate publication bias. Heterogeneity and sensitivity analysis were also assessed. All the work was completed using STATA. Results Pooled HRs and 95% CIs suggested that MMP-2 expression had an unfavorable impact on both OS (HR: 1.53, 95% CI: 1.29–1.82) and DFS/RFS/DDFS (HR: 1.41, 95% CI: 1.07–1.86) in BC patients. Furthermore, MMP-2 expression was significantly associated with lymph node metastasis (positive vs negative: OR 1.91, 95% CI 1.17–3.12). Conclusion In conclusion, positive MMP-2 expression might be a significant predictive factor for poor prognosis in patients with BC. PMID:25816052

  6. The YY1/MMP2 axis promotes trophoblast invasion at the maternal–fetal interface

    PubMed Central

    Tian, Fu‐Ju; Cheng, Yan‐Xiang; Li, Xiao‐Cui; Wang, Fa; Qin, Chuan‐Mei; Ma, Xiao‐Ling

    2016-01-01

    Abstract YY1 is a sequence‐specific DNA‐binding transcription factor that has many important biological roles. However, its function in trophoblasts at the maternal–fetal interface remains to be elucidated. In this study, we used an mRNA microarray and reverse transcription qPCR and compared the YY1 mRNA expression level in trophoblasts between patients with recurrent miscarriage (RM) and healthy control subjects. Our results revealed that YY1 mRNA expression was significantly lower in the trophoblasts of the RM group compared with the healthy control group. Furthermore, immunofluorescence and immunohistochemical data showed that YY1 was highly expressed in human placental villi during early pregnancy, especially in cytotrophoblast cells and invasive extravillous trophoblasts, and it was expressed at a much lower level in the placental villi of term pregnancy. YY1 overexpression enhanced, and knockdown repressed, the invasion and proliferation of trophoblasts. Antibody array screening revealed that YY1 significantly promoted MMP2 expression in trophoblasts. Bioinformatics analysis identified three YY1‐binding sites in the MMP2 promoter region, and chromatin immunoprecipitation analysis verified that YY1 binds directly to its promoter region. Importantly, inhibition of YY1 by siRNA clearly decreased trophoblast invasion in an ex vivo explant culture model. Overall, our findings revealed a new regulatory pathway of YY1/MMP2 in trophoblast cell invasion during early pregnancy and indicated that YY1 may be involved in the pathogenesis of RM. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:27071480

  7. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

    PubMed Central

    Wiseman, Bryony S.; Sternlicht, Mark D.; Lund, Leif R.; Alexander, Caroline M.; Mott, Joni; Bissell, Mina J.; Soloway, Paul; Itohara, Shigeyoshi; Werb, Zena

    2003-01-01

    During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis. PMID:12975354

  8. Factor Analysis of the Image Correlation Matrix.

    ERIC Educational Resources Information Center

    Kaiser, Henry F.; Cerny, Barbara A.

    1979-01-01

    Whether to factor the image correlation matrix or to use a new model with an alpha factor analysis of it is mentioned, with particular reference to the determinacy problem. It is pointed out that the distribution of the images is sensibly multivariate normal, making for "better" factor analyses. (Author/CTM)

  9. Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

    PubMed Central

    Bramhall, S. R.; Stamp, G. W.; Dunn, J.; Lemoine, N. R.; Neoptolemos, J. P.

    1996-01-01

    It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8611434

  10. Activity of MMP-2, MMP-8 and MMP-9 in serum as a marker of progression of alcoholic liver disease in people from Lublin Region, eastern Poland.

    PubMed

    Prystupa, Andrzej; Boguszewska-Czubara, Anna; Bojarska-Junak, Agnieszka; Toruń-Jurkowska, Anna; Roliński, Jacek; Załuska, Wociech

    2015-01-01

    In alcoholic liver cirrhosis, normal liver cells are replaced by scar tissue (fibrosis). Liver fibrosis is a dynamic process in which activated hepatic stellate cells are involved in the synthesis of matrix proteins and the regulation of matrix degeneration. The aim of the presented study was to assess the usefulness of MMP-2, MMP-8 and MMP-9 as diagnostic markers of alcoholic liver disease. Sixty patients with alcoholic liver cirrhosis were randomly enrolled during hospitalization in departments of hospitals from the Lublin Region in eastern Poland. The stage of cirrhosis was estimated according to Child-Turcotte-Pugh criteria (Child-Pugh score) as P- Ch A, P-Ch B, P-Ch C. The control group consisted of 10 healthy persons without liver disease, who did not drink alcohol. Additionally, a group of alcoholics without liver cirrhosis was included in the study. Blood sample were obtained, and after centrifuge, serum was collected for further analysis. The activity of MMP-2, MMP-8 and MMP-9 in the blood plasma of the patients and the control group were measured by using the sandwich enzyme immunoassay technique with commercially available quantitative ELISA test kits. Activity of MMP-2, MMP-8 and MMP-9 in patients with liver cirrhosis were increased gradually according to Child-Pugh stages. The activity of MMP-2, MMP-8, MMP-9 were the highest in patients with liver cirrhosis stage C. MMP-2, MMP-8, MMP-9 concentrations in the people with liver cirrhosis (stage C) were significantly increased compared to controls. A significant difference were observed between activity MMP-2 in control group, alcoholics without liver cirrhosis, and those with liver cirrhosis (stages A, B, C according Child-Pugh score). MMP-2, MMP-8 and MMP-9 may be markers of alcoholic liver cirrhosis in the alcoholics. Elevated levels of MMP-2, MMP-8 and MMP-9 in the alcoholic patients indicated that cirrhosis has developed. The most sensitive is MMP-2, because the activity of this parameter is increased

  11. Relationship between Vitreous Levels of Matrix Metalloproteinases and Vascular Endothelial Growth Factor in Proliferative Diabetic Retinopathy

    PubMed Central

    Abu El-Asrar, Ahmed M.; Mohammad, Ghulam; Nawaz, Mohd. Imtiaz; Siddiquei, Mohammad Mairaj; Van den Eynde, Kathleen; Mousa, Ahmed; De Hertogh, Gert; Opdenakker, Ghislain

    2013-01-01

    To investigate which matrix metalloproteinases (MMPs) are more likely to be involved in the angiogenic process in proliferative diabetic retinopathy (PDR), we measured the levels of MMPs in the vitreous fluid from patients with PDR and controls and correlated these levels with the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 32 PDR and 24 nondiabetic patients were studied by mosaic multiplex MMPs enzyme-linked immunosorbent assay (ELISA), single ELISA, Western blot and zymography analysis. Epiretinal membranes from 11 patients with PDR were studied by immunohistochemistry. MMP-8 and MMP-13 were not detected. ELISA, Western blot and gelatin ymography assays revealed significant increases in the expression levels of MMP-1, MMP-7, MMP-9 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls, whereas MMP-2 and MMP-3 were not upregulated in vitreous samples from PDR patients. Significant correlations existed between ELISA and zymography assays for the quantitation of MMP-2 (r=0.407; p=0.039) and MMP-9 (r=0.711; p<0.001). Significant correlations were observed between levels of VEGF and levels of MMP-1 (r=0.845; P<0.001) and MMP-9 (r=0.775; p<0.001), and between levels of MMP-1 and MMP-9 (r=0.857; p<0.001). In epiretinal membranes, cytoplasmic immunoreactivity for MMP-9 was present in vascular endothelial cells and stromal monocytes/macrophages and neutrophils. Our findings suggest that among the MMPs measured, MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR. PMID:24392031

  12. Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

    PubMed Central

    Ammazzalorso, Alessandra; De Filippis, Barbara; Campestre, Cristina; Laghezza, Antonio; Marrone, Alessandro; Amoroso, Rosa; Tortorella, Paolo; Agamennone, Mariangela

    2016-01-01

    Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data. PMID:27782083

  13. E6/E7 oncoproteins of high risk HPV-16 upregulate MT1-MMP, MMP-2 and MMP-9 and promote the migration of cervical cancer cells

    PubMed Central

    Zhu, Dingjun; Ye, Mei; Zhang, Wei

    2015-01-01

    Background: E6 and E7 of high risk human papillomavirus 16 (HPV16) were reported to correlate with the cervical cancer (CC). And the presence of matrix metalloproteinases (MMPs) has also been indicated to be associated with CC. Methods: The present study investigated the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) in CC cells with HPV16-E6/E7 oncoprotein(s) negative or positive, and then determined the regulation of HPV16-E6/E7 oncoproteins on the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) and the migration of cervical cancer Caski and SiHa cells with RNAi technology. Results: It was demonstrated that the overexpression or the knockdown of HPV16-E6/E7 promoted or reduced MT1-MMP, MMP-2 and MMP-9 in CC cells. And the HPV16-E6, -E7 or -E6E7 influenced the migration of CC cells. The overexpression or the knockdown of them promoted or inhibited the migration of C33A or Caski/SiHa cells. Moreover, the chemical inhibition of MMP-2 or MMP-9 significantly reduced the migration of CC Caski or SiHa cells. Conclusions: Our results demonstrated that the E6-HPV16 or E7-HPV16 promoted the activity of MMP-2/9, and contributed to the migration of cervical cells. PMID:26191191

  14. 4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways

    PubMed Central

    Cao, Yuanfei; Wang, Xiaolong; Xu, Chang; Gao, Zhengyan; Zhou, Haihong; Wang, Yongzhi; Cao, Rui; Liu, Tao; Liu, Tongzu

    2016-01-01

    In order to identify the anti-invasive and anti-metastatic effect of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on the human bladder cancer EJ cell line, and to study its impact on the expression of wingless-type mouse mammary tumor virus integration site family, member 5a (Wnt5a), the phosphorylation of c-Jun N-terminal kinase (JNK), the expression levels of matrix metalloproteinase-2 (MMP-2), and the migration and invasion of EJ cells, migration and Matrigel invasion assays, as well as western blot analyses, were used in the present study. The results of the migration and Matrigel invasion assays indicated that the inhibitor of JNK SP600125 could inhibit the effect of 4-HPR on EJ cells. The expression of Wnt5a and MMP-2, and the phosphorylation of JNK, were analyzed by western blotting. The data revealed that 4-HPR inhibited the migration and invasion of bladder cancer cells through stimulating Wnt5a activation, causing the downregulation of MMP-2 expression and enhancing the phosphorylation of JNK in these cells. However, JNK signaling did not appear to have a direct effect on the expression of MMP-2. The present study demonstrated that 4-HPR may be a potent anti-invasive and anti-metastatic agent that functions via the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways. PMID:27602114

  15. 4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways

    PubMed Central

    Cao, Yuanfei; Wang, Xiaolong; Xu, Chang; Gao, Zhengyan; Zhou, Haihong; Wang, Yongzhi; Cao, Rui; Liu, Tao; Liu, Tongzu

    2016-01-01

    In order to identify the anti-invasive and anti-metastatic effect of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on the human bladder cancer EJ cell line, and to study its impact on the expression of wingless-type mouse mammary tumor virus integration site family, member 5a (Wnt5a), the phosphorylation of c-Jun N-terminal kinase (JNK), the expression levels of matrix metalloproteinase-2 (MMP-2), and the migration and invasion of EJ cells, migration and Matrigel invasion assays, as well as western blot analyses, were used in the present study. The results of the migration and Matrigel invasion assays indicated that the inhibitor of JNK SP600125 could inhibit the effect of 4-HPR on EJ cells. The expression of Wnt5a and MMP-2, and the phosphorylation of JNK, were analyzed by western blotting. The data revealed that 4-HPR inhibited the migration and invasion of bladder cancer cells through stimulating Wnt5a activation, causing the downregulation of MMP-2 expression and enhancing the phosphorylation of JNK in these cells. However, JNK signaling did not appear to have a direct effect on the expression of MMP-2. The present study demonstrated that 4-HPR may be a potent anti-invasive and anti-metastatic agent that functions via the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways.

  16. Vascular endothelial growth factor, matrix metalloproteinases, and cyclooxygenase-2 influence prognosis of uterine cervical cancer in young women.

    PubMed

    Noriyuki, Maiko; Sumi, Toshiyuki; Zhi, Xu; Misugi, Fumiko; Nobeyama, Hiroyuki; Yoshida, Hiroyuki; Matsumoto, Yoshinari; Yasui, Tomoyo; Honda, Ken-Ichi; Ishiko, Osamu

    2007-09-01

    Recent changes in the lifestyle of young women have led to an increase in the rate of uterine cervical cancer. We investigated the clinicopathological characteristics of uterine cervical cancer in young women, and examined the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Tumor samples from 439 patients with uterine cervical cancer, who were initially treated at Osaka City University Medical School Hospital, Japan between 1995 and 2004, were stained immunohistochemically. The patients were classified into two groups according to age at onset: group Y included women aged < or =35 years, and group O included women aged > or =36 years. Group Y had more cases of squamous cell carcinoma, while group O had more advanced cases (P<0.05). Advanced cases (beyond stage Ib2) had a significantly worse prognosis in group Y than in group O (P<0.05). There were no differences between the two groups in the expressions of VEGF, MMP-2 and COX-2. However, in advanced cases (beyond stage Ib2), the expression of VEGF, MMP-2 and COX-2 was significantly greater in group Y than in group O (P<0.05). The above findings suggest that the expression of VEGF, MMPs and COX-2 is related to a worse prognosis for advanced uterine cervical cancer in young women.

  17. Curcumin inhibits lung cancer invasion and metastasis by attenuating GLUT1/MT1-MMP/MMP2 pathway

    PubMed Central

    Liao, Hehe; Wang, Zhouquan; Deng, Zhiping; Ren, Hong; Li, Xiaojun

    2015-01-01

    Glucose transporter (GLUT) 1 is found highly expressed in malignant tumors and considered a mediator inducing cancer metastasis. Curcumin is a natural product which exerts anti-invasion and metastasis effects in cancer. This study aimed at evaluating whether attenuating GLUT1 was involved in curcumin’s anti-invasion and metastasis effects. In the in vitro part, constricted pcDNA3.1-GLUT1 vector was transfected into A549 cells. MTT assay was used to assess the curcumin’s effects on proliferation in lung cancer A549 cells. Transwell assay was used to evaluate the anti-invasion effect of curcumin on A549 cells. Real-time PCR and Western-blotting were employed to examine the expression levels of GLUT1, membrane type 1-MMP (MT1-MMP) and matrix metalloproteinase (MMP) 2 in curcumin- incubated A549 cells. In the in vivo part, tumor weight and metastatic rate were assessed in nude mice bearing untransfected, empty vector transfected and pcDNA3.1-GLUT1 transfected A549 cells originated tumors. In this study, we found that curcumin began to show significant cytotoxicity against proliferation effect at 45 μmol/L. Curcumin inhibited invasion and expressions of GLUT1, MT1-MMP and MMP2 untransfected A549 cells in a concentration-dependent manner. pcDNA3.1-GLUT1 transfected A549 cells exhibited resistance to curcumin’s anti-invasion effect by up-regulating expressions of GLUT2, MT1-MMP and MMP2. Furthermore, curcumin failed to decrease the metastatic rate in nude mice bearing pcDNA3.1-GLUT1 transfected A549 cells originated tumors. These results suggested that curcumin inhibit lung cancer invasion and metastasis by attenuating GLUT1/MT1-MMP/MMP2 pathway. PMID:26309547

  18. Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells1

    PubMed Central

    Lockwood, Charles J.; Oner, Ceyda; Uz, Yesim H.; Kayisli, Umit A.; Huang, S. Joseph; Buchwalder, Lynn F.; Murk, William; Funai, Edmund F.; Schatz, Frederick

    2011-01-01

    Extravillous trophoblasts (EVTs) invade human decidua via sequential integrin-mediated binding and proteolysis of basement membrane proteins in the extracellular matrix (ECM). In preeclampsia, shallow EVT invasion impairs spiral artery and arteriole remodeling to reduce uteroplacental blood flow. Excess decidual cell-expressed matrix metalloproteinases (MMPs) 2 and 9, in response to preeclampsia-related interleukin 1 beta (IL1B) and tumor necrosis factor alpha (TNF), may inappropriately degrade these basement membrane proteins and impede EVT invasion. This study found significantly higher immunohistochemical MMP9 levels in decidual cells and adjacent interstitial trophoblasts in placental sections of preeclamptic versus gestational age-matched control women. In contrast, immunostaining for MMP2 and tissue inhibitor of matrix metalloproteinases 1 and 2 (TIMP1 and TIMP2) were similar in preeclamptic and control groups. First-trimester decidual cells were incubated with estradiol (E2) or E2 + medroxyprogesterone acetate (MPA), with or without TNF or IL1B. As measured by ELISA, both cytokines elicited concentration-dependent increases in secreted MMP9 levels that were unaffected by MPA. In contrast, secreted levels of MMP2, TIMP1, and TIMP2 were unchanged in all treatment groups. Substrate gel zymography and Western blotting confirmed that each cytokine increased secreted levels of MMP9 but not MMP2. Similarly, quantitative RT-PCR found that TNF and IL1B enhanced MMP9, but not MMP2, mRNA levels. At the implantation site, inflammatory cytokine-enhanced MMP9 may promote preeclampsia by disrupting the decidual ECM to interfere with normal stepwise EVT invasion. PMID:18276934

  19. Sequence motifs of tissue inhibitor of metalloproteinases 2 (TIMP-2) determining progelatinase A (proMMP-2) binding and activation by membrane-type metalloproteinase 1 (MT1-MMP).

    PubMed Central

    Worley, Joanna R; Thompkins, Philip B; Lee, Meng H; Hutton, Mike; Soloway, Paul; Edwards, Dylan R; Murphy, Gillian; Knäuper, Vera

    2003-01-01

    Fundamental cellular processes including angiogenesis and cell migration require a proteolytic cascade driven by interactions of membrane-type matrix metalloproteinase 1 (MT1-MMP) and progelatinase A (proMMP-2) that are dependent on the presence of tissue inhibitor of metalloproteinases 2 (TIMP-2). There are unique interactions between TIMP-2 and MT1-MMP, which we have previously defined, and here we identify TIMP-2 sequence motifs specific for proMMP-2 binding in the context of its activation by MT1-MMP. A TIMP-2 mutant encoding the C-terminal domain of TIMP-4 showed loss of proMMP-2 activation, indicating that the C-terminal domain of TIMP-2 is important in establishing the trimolecular complex between MT1-MMP, TIMP-2 and proMMP-2. This was confirmed by analysis of a TIMP-4 mutant encoding the C-terminal domain of TIMP-2, which formed a trimolecular complex and promoted proMMP-2 processing to the intermediate form. Mutants encoding TIMP-4 from Cys(1) to Leu(185) and partial tail sequence of TIMP-2 showed some gain of activating capability relative to TIMP-4. The identified residues were subsequently mutated in TIMP-2 (E(192)-D(193) to I(192)-Q(193)) and this inhibitor showed a significantly reduced ability to facilitate proMMP-2 processing by MT1-MMP. Furthermore, the tail-deletion mutant Delta(186-194)TIMP-2 was completely incapable of promoting proMMP-2 activation by MT1-MMP. Thus the C-terminal tail residues of TIMP-2 are important determinants for stable trimolecular complex formation between TIMP-2, proMMP-2 and MT1-MMP and play an important role in MT1-MMP-mediated processing to the intermediate and final active forms of MMP-2 at the cell surface. PMID:12630911

  20. Matrix factorization on a hypercube multiprocessor

    SciTech Connect

    Geist, G.A.; Heath, M.T.

    1985-08-01

    This paper is concerned with parallel algorithms for matrix factorization on distributed-memory, message-passing multiprocessors, with special emphasis on the hypercube. Both Cholesky factorization of symmetric positive definite matrices and LU factorization of nonsymmetric matrices using partial pivoting are considered. The use of the resulting triangular factors to solve systems of linear equations by forward and back substitutions is also considered. Efficiencies of various parallel computational approaches are compared in terms of empirical results obtained on an Intel iPSC hypercube. 19 refs., 6 figs., 2 tabs.

  1. Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway.

    PubMed

    Ahn, Ji-Hye; Choi, Youn Seok; Choi, Jung-Hye

    2015-10-01

    Despite evidence that leptin may play a role in the pathogenesis of endometriosis, the specific function of leptin in the migration and invasion of endometriotic cells is not well characterized. In this study, we investigated the effect of leptin on the migration, invasion and matrix metalloproteinase (MMP) expression levels of human endometriotic cells. We found that leptin stimulated the migration and invasion of endometriotic cells (11Z, 12Z and 22B) in a dose-dependent manner. Leptin receptor (ObR) siRNA significantly inhibited the migration and invasion induced by leptin in 11Z and 12Z cells. Leptin-induced migration and invasion were significantly attenuated by pretreatment with SB-3CT, a specific gelatinase (MMP-2 and MMP-9) inhibitor. In addition, leptin-induced increases in the mRNA and protein expression and enzyme activity of MMP-2 in 11Z and 12Z cells. Selectively inhibiting MMP-2 using siRNA and an inhibitor (GM6003), impaired the ability of leptin to stimulate the migration and invasion of endometriotic cells, suggesting that MMP-2 plays an essential role in leptin-induced migration and invasion. Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) inhibitor (AG490) significantly inhibited the migration, invasion and MMP-2 expression induced by leptin in endometriotic cells. Furthermore, the Extracellular signal-Regulated Kinase inhibitor PD98059 neutralized the migration and invasion promoting effects of leptin. Taken together, these results suggest that leptin may contribute to the migration and invasion abilities of endometriotic cells via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway.

  2. Functional Promoter Polymorphisms of MMP-2 C-735T and MMP-9 C-1562T and Their Synergism with MMP-7 A-181G in Multiple Sclerosis.

    PubMed

    Rahimi, Zohreh; Abdan, Zahra; Rahimi, Ziba; Razazian, Nazanin; Shiri, Hadis; Vaisi-Raygani, Asad; Shakiba, Ebrahim; Vessal, Mahmood; Moradi, Mohammad-Taher

    2016-08-01

    Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Matrix metalloproteinases (MMPs) play an important role in breakdown of blood-brain barrier, transmigration, and invasion of immune cells and formation of MS lesions. The aim of present study was to investigate the influence of MMP-2 C-735T and MMP-9 C-1562T variants and their synergism with MMP-7 A-181G on susceptibility to MS. In a case-control study 125 MS patients and 235 healthy individuals from Western Iran were investigated. The various genotypes of MMP-2, MMP-9, and MMP-7 were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In females the presence of MMP-2 C allele was associated with an increased risk of MS (OR = 1.69, p = 0.041). No significant difference was detected between the frequency of MMP-9 T allele in MS patients (8.2%) and controls (12.8%, p = 0.068). The concomitant presence of both MMP-2 C and MMP-7 G alleles was associated with 1.82-fold increased risk of MS (p = 0.002). Also, a synergism was detected between MMP-9 C and MMP-7 G alleles that elevated the risk of MS by 1.5-times (p = 0.035). The presence of haplotype MMP-9 T, MMP-7 G, and MMP-2 C (TGC) compared to haplotype CAG increased the risk of MS by 3.13-fold (p = 0.16). The present study suggests that gene-gene interactions and variants of more genes instead of single gene might play a role in susceptibility to MS. We indicated that synergism between variants of MMP-2, MMP-7, and MMP-9 genes might increase the risk of MS.

  3. Expression of MMP-2 and TIMP-1 in Renal Tissue of Patients with Chronic Active Antibody-mediated Renal Graft Rejection

    PubMed Central

    2012-01-01

    Objective To investigate the expression of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metallopropteinase-1 (TIMP-1) in the renal allografts of patients with chronic active antibody-mediated rejection (AMR), and to explore their role in the pathogenesis of AMR. Methods Immunohistochemistry assay and computer-assisted image analysis were used to detect the expression of MMP-2 and TIMP-1 in the renal allografts with interstitial fibrosis and tubular atrophy (IF/TA) in 46 transplant recipients and 15 normal renal tissue specimens as the controls. The association of the expression level of either MMP-2 or TIMP-1 with the pathological grade of IF/TA in AMR was analyzed. Results The expression of either MMP-2 or TIMP-1 was significantly increased in the renal allografts of the recipients as compared with the normal renal tissue (P < 0.05). MMP-2 expression tended to decrease, while TIMP-1 and serum creatinine increased along with the increase of pathological grade of IF/TA (P < 0.05). In IF/TA groups, the expression of TIMP-1 was positively correlated to serum creatinine level (r = 0.718, P < 0.05). Conclusions It is suggested by the results that abnormal expressions of MMP-2 and TIMP-1 might play roles in the development of renal fibrosis in chronic AMR. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1128474926172838 PMID:23057632

  4. Effect of ulinastatin on the expression of iNOS, MMP-2, and MMP-3 in degenerated nucleus pulposus cells of rabbits.

    PubMed

    Hua, Guo; Haiping, Zhang; Baorong, He; Dingjun, Hao

    2013-01-01

    We examined the effects of ulinastatin on the expression of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-3 (MMP-3) in degenerated nucleus pulposus (NP) cells of rabbits induced by interleukin (IL)-1β in vitro. An in vitro NP cell culture model was set up with enzyme digestion. NP cells from adult white rabbits were divided into six groups: the normal control group, the ulinastatin control group (320 U/mL ulinastatin), the induced group (10 ng/mL IL-1β), and three inhibition groups (IL-1β followed by 160, 320, or 640 U/mL ulinastatin). After a 2-day culture, the NP cells were collected for immunohistochemical staining for MMP-2 and MMP-3 and spectrophotometric analysis of the amount of iNOS. Immunohistochemical staining showed that the expression of MMP-2 and MMP-3 proteins in NP cells decreased in the inhibition groups compared with the induced group, which was in inverse proportion to the ulinastatin concentration. Spectrophotometric results showed that, compared with the induced group, the iNOS content in each inhibition group decreased, most significantly in the 320 U/mL group. Ulinastatin effectively inhibited the increased expression of MMP-2, MMP-3, and iNOS in degenerated NP cells induced by IL-1β in vitro. It suggests that ulinastatin may potentially be useful for clinical therapy of intervertebral disc degeneration.

  5. Prognostic significance of TIMP-2, MMP-2, and MMP-9 on high-grade serous ovarian carcinoma using digital image analysis.

    PubMed

    Desmeules, Patrice; Trudel, Dominique; Turcotte, Stéphane; Sirois, Jennifer; Plante, Marie; Grégoire, Jean; Renaud, Marie-Claude; Orain, Michèle; Têtu, Bernard; Bairati, Isabelle

    2015-05-01

    The objective of this cohort study was to evaluate whether the immunohistochemical expression of tissue inhibitor of metalloprotease 2, matrix metalloproteinase (MMP) 2, and MMP-9 could predict the occurrence of death and progression in women with ovarian high-grade serous carcinoma (HGSC). A total of 100 women with primary HGSC who were treated by cytoreductive surgery and adjuvant chemotherapy at the Centre Hospitalier Universitaire de Québec (Canada) were included. Biomarker expression was evaluated by immunohistochemistry on tissue microarrays constructed from primary tumors. Immunostaining quantification was performed using digital image analysis, from algorithms created with Calopix software, and continuous H-score data were obtained. The cancer antigen-125 and/or the Response Evaluation Criteria In Solid Tumors criteria were used to define progression. Dates of death were obtained by record linkage with the Québec mortality files. Hazard ratios (HRs) of death and progression with their 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. Overall, a low variability of expression was observed for each marker. No association was found between the level of expression and standard prognostic factors. When assessed as a continuous variable, increased MMP-9 expression (10 units of H-score) was associated with death (HR, 1.08; 95% CI, 1.01-1.16; P = .02), but not with progression (HR, 1.03; 95% CI, 0.97-1.10; P = .29). There was no association between the expression of MMP-2 or tissue inhibitor of metalloprotease 2 and death or progression. In conclusion, in a homogeneous cohort of women with HGSC, increased MMP-9 tissue expression, as assessed by automated immunostaining quantification, was associated with a higher risk of death.

  6. Osthole ameliorates acute myocardial infarction in rats by decreasing the expression of inflammatory-related cytokines, diminishing MMP-2 expression and activating p-ERK.

    PubMed

    Duan, Juan; Yang, Yu; Liu, Hong; Dou, Peng-Cheng; Tan, Sheng-Yu

    2016-01-01

    Osthole, the active constituent of Cnidium monnieri extracts, has been shown to have a diverse range of pharmacological properties. In the present study, we aimed to evaluate the cardioprotective effects of osthole in a rat model of acute myocardial infarction (AMI). The rats with AMI were treated with 1, 3 and 10 mg/kg of osthole or the vehicle for 4 weeks. The infarct size of the rats with AMI was measured, and casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) activities in the rats with AMI were analyzed using commercially available kits. The nuclear factor-κB (NF-κB), tumor necrosis factor‑α (TNF-α), interleukin (IL)-1β and IL-6 levels in whole blood from rats with AMI were also detected using commercially available kits. The levels of Toll-like receptors 2/4 (TLR2/4) and nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) were also detected by RT-qPCR. Moreover, the protein expression levels of endothelial nitric oxide synthase (eNOS) and mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, cyclooxygenase-2 (COX-2), as well as matrix metalloproteinase-2 (MMP-2) were all assayed by western blot analysis. Our results revealed that osthole markedly reduced the infarct size, and the levels of CK, CK-MB, LDH and cTnT in the rats with AMI, and that these cardioprotective effects may be associated with the inhibition of inflammatory reactions, the reduction in MMP-2 activity and the activation of MAPK cascades.

  7. CCL2-CCR2 axis promotes metastasis of nasopharyngeal carcinoma by activating ERK1/2-MMP2/9 pathway

    PubMed Central

    Xie, Changqing; Xia, Weixiong; Jiang, Chen; Zeng, Tingting; Ye, Yanfang; Ke, Liangru; Yu, Yahui; Liang, Hu; Guan, Xin-Yuan; Guo, Xiang; Xiang, Yanqun

    2016-01-01

    Distant metastasis remains the major failure of nasopharyngeal carcinoma (NPC). In this study, the roles of chemokine C-C motif ligand 2 (CCL2), and its receptor chemokine C-C motif receptor type 2 (CCR2) on NPC metastasis were investigated. Serum CCL2 and CCL2/CCR2 expression level were remarkably increased in NPC patients compared to non-tumor patients by ELISA and IHC analyses. High expressions of CCL2/CCR2 were significantly associated with NPC metastasis and poor overall survival (OS). High expression of CCR2 is an independent adverse prognostic factor of OS and distant metastasis free survival (DMFS). Overexpressions of CCL2 and CCR2 were detected in high-metastatic NPC cell lines. Upregulating CCL2 and CCR2 respectively in low-metastatic NPC cell lines could promote cell migration and invasion, and exogenous CCL2 enhanced the motility in CCR2-overexpressing cells. On the other hand, downregulating CCL2 and CCR2 respectively in high-metastatic NPC cell lines by shRNA could decrease cell migration and invasion. However, exogenous CCL2 could not rescue the weaken ability of motility of CCR2-silencing cells. In nude mouse model, distant metastasis was significantly facilitated in either CCL2-overexpressing or CCR2-overexpressing groups, which was more obvious in CCR2-overexpressing group. Also, distant metastasis was considerably inhibited in either CCL2-silencing or CCR2-silencing groups. Dual overexpression of CCL2/CCR2 could activate extracellular signal-regulated kinase (ERK1/2) signaling pathway, which sequentially induced matrix metalloproteinase (MMP) 2 and 9 upregulations in the downstream. In conclusion, CCL2-CCR2 axis could promote NPC metastasis by activating ERK1/2-MMP2/9 pathway. This study helps to develop novel therapeutic targets for distant metastasis in NPC. PMID:26701209

  8. Raf kinase inhibitor protein suppresses nuclear factor-κB-dependent cancer cell invasion at the level of matrix metalloproteinase expression but not cell migration

    PubMed Central

    Beshir, Anwar B.; Ren, Gang; Magpusao, Anniefer N.; Barone, Lauren M.; Yeung, Kam C.; Fenteany, Gabriel

    2010-01-01

    Accumulating evidence suggests that Raf kinase inhibitor protein (RKIP), which negatively regulates multiple signaling cascades including the Raf and nuclear factor κB (NF-κB) pathways, functions as a metastasis suppressor. However, the basis for this activity is not clear. We investigated this question in a panel of breast cancer, colon cancer and melanoma cell lines. We found that RKIP negatively regulated the invasion of the different cancer cells through three-dimensional extracellular matrix barriers by controlling the expression of matrix metalloproteinases (MMPs), particularly, MMP-1 and MMP-2. Silencing of RKIP expression resulted in a highly invasive phenotype and dramatically increased levels of MMP-1 and MMP-2 expression, while overexpression of RKIP decreased cancer cell invasion in vitro and metastasis in vivo of murine tumor allografts. Knockdown of MMP-1 or MMP-2 in RKIP-knockdown cells reverted their invasiveness to normal. In contrast, when examining migration of the different cancer cells in a two-dimensional, barrier-less environment, we found that RKIP had either a positive regulatory activity or no activity, but in no case a negative one (as would be expected if RKIP suppressed metastasis at the level of cell migration itself). Therefore, RKIP’s function as a metastasis suppressor appears to arise from its ability to negatively regulate expression of specific MMPs, and thus invasion through barriers, and not from a direct effect on the raw capacity of cells to move. The NF-κB pathway, but not the Raf pathway, appeared to positively control the invasion of breast cancer cells. A regulatory loop involving an opposing relationship between RKIP and the NF-κB pathway may control the level of MMP expression and cell invasion. PMID:20855151

  9. Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells

    PubMed Central

    Kang, Young-Mi; Hong, Seong-Hwan; Yang, Jae-Ho; Oh, Jin-Cheol; Park, Jin-Oh; Lee, Byung Ho; Lee, Sang-Yoon; Kim, Hak-Sun; Lee, Hwan-Mo

    2016-01-01

    Background N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. Methods Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10-12, 10-10, 10-8, and 10-6 M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. Results Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. Conclusions Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression.

  10. Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells

    PubMed Central

    Kang, Young-Mi; Hong, Seong-Hwan; Yang, Jae-Ho; Oh, Jin-Cheol; Park, Jin-Oh; Lee, Byung Ho; Lee, Sang-Yoon; Kim, Hak-Sun; Lee, Hwan-Mo

    2016-01-01

    Background N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. Methods Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10-12, 10-10, 10-8, and 10-6 M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. Results Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. Conclusions Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression. PMID:27622181

  11. Immunolocalization and activity of the MMP-9 and MMP-2 in odontogenic region of the rat incisor tooth after post shortening procedure.

    PubMed

    Gomes, Jose Rosa; Omar, Nádia Fayez; dos Santos Neves, Juliana; Narvaes, Eliene Aparecida Orsini; Novaes, Pedro Duarte

    2011-04-01

    MMP-9 and MMP-2 are metalloproteinases which degrade the denatured collagen fibers. However, there is no report about roles of these MMPs in the odontogenic region of the adult rat incisor tooth under different eruption conditions. Male Wistar rats were divided in a normofunctional group (NF) in which their lower teeth remained in a normal eruption. In a hypofunctional group (HP) rats underwent shortening of their lower left incisor tooth every 2 days during 12 days. The eruption rate as well as the expression and activities of MMP-9 and MMP-2 were evaluated using imunohistochemistry and zymography. Although the shortening increased the eruption rate, no changes in the MMP-9 and MMP-2 were observed. We conclude that in adult rats, in opposite to development of tooth, the MMP-9 and MMP-2 present in the odontogenic region does not seem to play a direct role in the remodeling matrix, even after post-shortening procedures which to lead an acceleration of the eruption process in the incisor.

  12. Ginsenoside Rg3 inhibition of vasculogenic mimicry in pancreatic cancer through downregulation of VE‑cadherin/EphA2/MMP9/MMP2 expression.

    PubMed

    Guo, Jing-Qiang; Zheng, Qing-Hui; Chen, Hui; Chen, Liang; Xu, Jin-Bo; Chen, Min-Yuan; Lu, Dian; Wang, Zhao-Hong; Tong, Hong-Fei; Lin, Shengzhang

    2014-09-01

    Ginsenoside Rg3 (Rg3), a trace tetracyclic triterpenoid saponin, is extracted from ginseng and shown to have anticancer activity against several types of cancers. This study explored the effect of Rg3 on pancreatic cancer vasculogenic mimicry. Altered vasculogenic mimicry formation was assessed using immunohistochemistry and PAS staining and associated with the expression of vascular endothelial-cadherin (VE-cadherin), epithelial cell kinase (EphA2), matrix metalloproteinase (MMP)-2 and MMP-9. The effect of Rg3 on the regulation of pancreatic cancer vasculogenic mimicry was evaluated in vitro and in vivo. The data showed vasculogenic mimicry in pancreatic cancer tissues. In addition, the expression of VE-cadherin, EphA2, MMP-2 and MMP-9 proteins associated with formation of pancreatic cancer vasculogenic mimicry. Rg3 treatment reduced the levels of vasculogenic mimicry in nude mouse xenografts in vitro and in vivo, while the expression of VE-cadherin, EphA2, MMP-2 and MMP-9 mRNA and proteins was downregulated by Rg3 treatment in vitro and in tumor xenografts. In conclusion, ginsenoside Rg3 effectively inhibited the formation of pancreatic cancer vasculogenic mimicry by downregulating the expression of VE-cadherin, EphA2, MMP9 and MMP2. Further studies are required to evaluate ginsenoside Rg3 as an agent to control pancreatic cancer.

  13. Exogenous coenzyme Q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model

    PubMed Central

    2010-01-01

    Background/Aims Matrix Metalloproteinases 2 is a key molecule in cellular invasion and metastasis. Mitochondrial ROS has been established as a mediator of MMP activity. Coenzyme Q10 contributes to intracellular ROS regulation. Coenzyme Q10 beneficial effects on cancer are still in controversy but there are indications of Coenzyme Q10 complementing effect on tamoxifen receiving breast cancer patients. Methods In this study we aimed to investigate the correlation of the effects of co-incubation of coenzyme Q10 and N-acetyl-L-cysteine (NAC) on intracellular H2O2 content and Matrix Metalloproteinase 2 (MMP-2) activity in MCF-7 cell line. Results and Discussion Our experiment was designed to assess the effect in a time and dose related manner. Gelatin zymography and Flowcytometric measurement of H2O2 by 2'7',-dichlorofluorescin-diacetate probe were employed. The results showed that both coenzyme Q10 and N-acetyl-L-cysteine reduce MMP-2 activity along with the pro-oxidant capacity of the MCF-7 cell in a dose proportionate manner. Conclusions Collectively, the present study highlights the significance of Coenzyme Q10 effect on the cell invasion/metastasis effecter molecules. PMID:21118526

  14. Granulocyte-Macrophage Colony-Stimulating Factor- and Tumor Necrosis Factor Alpha-Mediated Matrix Metalloproteinase Production by Human Osteoblasts and Monocytes after Infection with Brucella abortus ▿

    PubMed Central

    Scian, Romina; Barrionuevo, Paula; Giambartolomei, Guillermo H.; Fossati, Carlos A.; Baldi, Pablo C.; Delpino, M. Victoria

    2011-01-01

    Osteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. Since matrix metalloproteinases (MMPs) are involved in joint and bone damage in inflammatory and infectious diseases, we investigated the production of MMPs by human osteoblasts and monocytes, either upon Brucella abortus infection or upon reciprocal stimulation with factors produced by each infected cell type. B. abortus infection of the normal human osteoblastic cell line hFOB 1.19 triggered a significant release of MMP-2, which was mediated in part by granulocyte-macrophage colony-stimulating factor (GM-CSF) acting on these same cells. Supernatants from infected osteoblasts exhibited increased levels of monocyte chemoattractant protein 1 and induced the migration of human monocytes (THP-1 cell line). Infection with B. abortus induced a high MMP-9 secretion in monocytes, which was also induced by heat-killed B. abortus and by the Omp19 lipoprotein from B. abortus. These effects were mediated by Toll-like receptor 2 and by the action of tumor necrosis factor alpha (TNF-α) produced by these same cells. Supernatants from B. abortus-infected monocytes induced MMP-2 secretion in uninfected osteoblasts, and this effect was mediated by TNF-α. Similarly, supernatants from infected osteoblasts induced MMP-9 secretion in uninfected monocytes. This effect was mediated by GM-CSF, which induced TNF-α production by monocytes, which in turn induced MMP-9 in these cells. These results suggest that MMPs could be potentially involved in the tissue damage observed in osteoarticular brucellosis. PMID:20956574

  15. Epb41l3 suppresses esophageal squamous cell carcinoma invasion and inhibits MMP2 and MMP9 expression.

    PubMed

    Zeng, Rong; Huang, Jun-Peng; Li, Xu Feng; Xiong, Wei-Bin; Wu, Gang; Jiang, Zhao-Jing; Song, Shu-Jie; Li, Ji-Qiang; Zheng, Yan-Fang; Zhang, Ji-Ren

    2016-04-01

    EPB41L3 may play a role as a metastasis suppressor by supporting regular arrangements of actin stress fibres and alleviating the increase in cell motility associated with enhanced metastatic potential. Downregulation of epb41l3 has been observed in many cancers, but the role of this gene in esophageal squamous cell carcinoma (ESCC) remains unclear. Our study aimed to determine the effect of epb41l3 on ESCC cell migration and invasion. We investigated epb41l3 protein expression in tumour and non-tumour tissues by immunohistochemical staining. Expression in the non-neoplastic human esophageal cell line Het-1a and four ESCC cell lines - Kyse150, Kyse510, Kyse450 and Caes17 - was assessed by quantitative Polymerase Chain Reaction (qPCR) and Western blotting. Furthermore, an EPB41L3 overexpression plasmid and EPB41L3-specific small interfering RNA were used to upregulate EPB41L3 expression in Kyse150 cells and to downregulate EPB41L3 expression in Kyse450 cells, respectively. Cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The expression levels of p-AKT, matrix metalloproteinase (MMP)2 and MMP9 were evaluated. Expression of epb41l3 was significantly lower in tumour tissues than in non-tumour tissues and in ESCC cell lines compared with the Het-1a cell line. Kyse450 and Caes17 cells exhibited higher expression of epb41l3 than Kyse150 and Kyse510 cells. Overexpressing epb41l3 decreased Kyse150 cell migration and invasion, whereas EPB41L3-specific small interfering RNA silencing increased these functions in Kyse450 cells. Furthermore, overexpressing epb41l3 led to downregulation of MMP2 and MMP9 in Kyse150 and Kyse510 cells. Our findings reveal that EPB41L3 suppresses tumour cell invasion and inhibits MMP2 and MMP9 expression in ESCC cells.

  16. Quercetin metabolites inhibit MMP-2 expression in A549 lung cancer cells by PPAR-γ associated mechanisms.

    PubMed

    Chuang, Cheng-Hung; Yeh, Chiao-Lin; Yeh, Shu-Lan; Lin, En-Shyh; Wang, Li-Yu; Wang, Ying-Hsuna

    2016-07-01

    Our previous study demonstrated that quercetin-metabolite-enriched plasma (QP) but not quercetin itself upregulates peroxisome proliferator-activated receptor gamma (PPAR-γ) expression to induce G2/M arrest in A549 cells. In the present study, we incubated A549 cells with QP as well as quercetin-3-glucuronide (Q3G) and quercetin-3'-sulfate (Q3'S), two major metabolites of quercetin, to investigate the effects of quercetin metabolites on cell invasion and migration, the possible mechanisms and the role of PPAR-γ. We also compared the effects of QP with those of quercetin and troglitazone (TGZ), a PPAR-γ ligand. The results showed that QP significantly suppressed cell invasion and migration, as well as matrix metalloproteinases (MMPs)-2 activity and expression in a dose-dependent manner. The effects of 10% QP on those parameters were similar to those of 10μM quercetin and 20μM TGZ. However, QP and TGZ rather than quercetin itself increased the expressions of nm23-H1 and tissue inhibitor of metalloproteinase (TIMP-2). Furthermore, we demonstrated that Q3G and Q3'S also inhibited the protein expression of MMP-2. GW9662, a PPAR-γ antagonist, significantly diminished such an effect of Q3G and Q3'S. Silencing PPAR-γ expression in A549 cells also significantly diminished the suppression effect of Q3G and Q3'S on MMP-2 expression. Taken together, our study demonstrated that QP inhibited cell invasion and migration through nm23-H1/TIMP-2/MMP-2 associated mechanisms. The upregulation of PPAR-γ by quercetin metabolites such as Q3G and Q3'S could play an important role in the effects of QP. PMID:27260467

  17. Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in the hair cycle

    PubMed Central

    HOU, CHUN; MIAO, YONG; WANG, XUE; CHEN, CHAOYUE; LIN, BOJIE; HU, ZHIQI

    2016-01-01

    According to the growth state of hair follicles, the hair cycle is divided into the anagen, catagen and telogen phases. A number of biological factors have been shown to synchronize with the hair cycle. As an important component of the hair follicle, the extracellular matrix is regulated by matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of matrix metalloproteinases; TIMPs). It has been reported that MMP-2, MMP-9 and TIMP-1 are associated with the hair cycle; however, their expression levels during the hair cycle have not been fully elucidated. Reverse transcription-polymerase chain reaction and ELISA analysis in the present study demonstrated that, during the hair cycle in mice, mRNA and protein expression levels of MMP-2 and MMP-9 were elevated in the anagen phase, and decreased during the catagen and telogen phases. Furthermore, SDS-PAGE gelatin zymography demonstrated that their activities fluctuated in the hair cycle. Additionally, it was observed that the mRNA and protein expression levels of TIMP-1 and TIMP-2 were negatively correlated with MMP-9 and MMP-2, respectively. Immunohistochemical examination demonstrated that MMP-2 and TIMP-2 were present in all structures of the hair follicle. However, MMP-9 and TIMP-1 were locally expressed in certain areas of the hair follicle, such as in the sebaceous gland at the anagen, catagen and telogen phases, and in the inner root sheath at the catagen phase. These results suggested that MMP-2 and MMP-9 may serve an important role in the hair growth cycle. PMID:27429651

  18. Genetic polymorphisms in MMP 2, 3, 7, and 9 genes and the susceptibility and clinical outcome of cervical cancer in a Chinese Han population.

    PubMed

    Xie, Beibei; Zhang, Zhen; Wang, Hui; Chen, Zhaojie; Wang, Yongsheng; Liang, Huazheng; Yang, Gaoyuan; Yang, Xingsheng; Zhang, Haiyan

    2016-04-01

    Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumor progression, including the invasion and metastasis. However, there are no data about the role of MMP polymorphism in the development of cervical cancer. A hospital-based case-control study was conducted in 230 patients with cervical cancer and 230 healthy controls to investigate the possible association between the MMP2 rs243865, MMP3 rs3025058, MMP7 rs11568818, and MMP9 rs3918242 polymorphisms, respectively, and the risk of cervical cancer. Our results suggested that the MMP2 rs243865-1306 C/T was significantly associated with an increased risk of cervical cancer (CT vs. CC, OR = 1.46; 95 % CI 1.18-3.55; P = 0.032; TT vs. CC, OR = 1.72; 95 % CI 1.28-4.02; P = 0.031; CT + TT vs. CC, OR = 1.43; 95 % CI 1.21-3.44; P = 0.029). Similarly, the MMP7 rs11568818-181A/G genotypes can also elevate the risk of cervical cancer in all genetic models. However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms in cervical cancer patients were not significantly different from controls. Further analysis showed MMP2 rs243865 and MMP7 rs11568818 genotypes were associated with advanced tumor stages of cervical cancer patients. More interestingly, the MMP2 rs243865 and MMP7 rs11568818 genotype was statistically significantly associated with a poor survival in cervical cancer patients. Our results showed that the MMP2 rs243865 and MMP7 rs11568818 genotypes e were associated with increased susceptibility and development of cervical cancer in Chinese Han population.

  19. Salinomycin causes migration and invasion of human fibrosarcoma cells by inducing MMP-2 expression via PI3-kinase, ERK-1/2 and p38 kinase pathways.

    PubMed

    Yu, Seon-Mi; Kim, Song Ja

    2016-06-01

    Salinomycin (SAL) is a polyether ionophore antibiotic that has recently been shown to regulate a variety of cellular responses in various human cancer cells. However, the effects of SAL on metastatic capacity of HT1080 human fibrosarcoma cells have not been elucidated. We investigated the effect of SAL on migration and invasion, with emphasis on the expression and activation of matrix metalloproteinase (MMP)-2 in HT1080 human fibrosarcoma cells. Treatment of SAL promoted the expression and activation of MMP-2 in a dose- and time-dependent manner, as detected by western blot analysis, gelatin zymography, and real-time polymerase chain reaction. SAL also increased metastatic capacities, as determined by an increase in the migration and invasion of cells using the wound healing assay and the invasion assay, respectively. To confirm the detailed molecular mechanisms of these effects, we measured the activation of phosphoinositide 3 kinase (PI3-kinase) and mitogen-activated protein kinase (MAPK)s (ERK-1/2 and p38 kinase), as detected by the phosphorylated proteins through western blot analysis. SAL treatment increased the phosphorylation of Akt and MAPKs. Inhibition of PI3-kinase, ERK-1/2, and p38 kinase with LY294002, PD98059, and SB203580, respectively, in the presence of SAL suppressed the metastatic capacity by reducing MMP-2 expression, as determined by gelatin zymography. Our results indicate that the PI3-kinase and MAPK signaling pathways are involved in migration and invasion of HT1080 through induction of MMP-2 expression and activation. In conclusion, SAL significantly increases the metastatic capacity of HT1080 cells by inducing MMP-2 expression via PI3-kinase and MAPK pathways. Our results suggest that SAL may be a potential agent for the study of cancer metastatic capacities.

  20. Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway.

    PubMed

    Wang, Cheng; Wen, Jianyan; Zhou, Yun; Li, Li; Cui, Xiaobing; Wang, Jinyu; Pan, Lin; Ye, Zhidong; Liu, Peng; Wu, Liling

    2015-12-01

    Apelin is an adipokine that has a critical role in the development of atherosclerosis, which may offer potential for therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs, apelin dose- and time-dependently promoted VSMC migration. Apelin increased the phosphorylation of Akt, whereas LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and an Akt1/2 kinase inhibitor blocked the apelin-induced VSMC migration. Apelin dose-dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by LY294002 and Akt1/2 kinase inhibitor. Furthermore, apelin increased matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed apelin-induced VSMC migration. Moreover, the levels of apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the apelin-induced MMP-2 activation and VSMC migration.

  1. Andrographolide Exerts Chondroprotective Activity in Equine Cartilage Explant and Suppresses Interleukin-1β-Induced MMP-2 Expression in Equine Chondrocyte Culture

    PubMed Central

    Kongtawelert, Prachya

    2014-01-01

    Cartilage erosion in degenerative joint diseases leads to lameness in affected horses. It has been reported that andrographolide from Andrographis paniculata inhibited cartilage matrix-degrading enzymes. This study aimed to explore whether this compound protects equine cartilage degradation in the explant culture model and to determine its effect on matrix metalloproteinase-2 (MMP-2) expression, a matrix-degrading enzyme, in equine chondrocyte culture. Equine articular cartilage explant culture was induced by 25 ng/mL interleukin-1β, a key inducer of cartilage degeneration, in cultures with or without andrographolide ranging from 10 to 50 μM. After 3–21 days, they were analyzed for the markers of cartilage degradation. It was found that interleukin-1β increased the release of sulfated glycosaminoglycans and hyaluronan from the explants into the culture media consistently with the decrease in uronic acid and collagen content in the cartilage explants. These catabolic effects were inhibited when cotreated with interleukin-1β and andrographolide. In primary equine chondrocytes, andrographolide suppressed interleukin-1β-induced MMP-2 mRNA expression and MMP-2 activity in the culture medium. These results confirmed the in vitro potent chondroprotective activities of this compound which were performed in cartilage explants and on a cellular level. These may indicate the application of andrographolide for therapeutic use in equine degenerative joint diseases. PMID:27379277

  2. Predicting structure in nonsymmetric sparse matrix factorizations

    SciTech Connect

    Gilbert, J.R.; Ng, E.G.

    1992-10-01

    Many computations on sparse matrices have a phase that predicts the nonzero structure of the output, followed by a phase that actually performs the numerical computation. We study structure prediction for computations that involve nonsymmetric row and column permutations and nonsymmetric or non-square matrices. Our tools are bipartite graphs, matchings, and alternating paths. Our main new result concerns LU factorization with partial pivoting. We show that if a square matrix A has the strong Hall property (i.e., is fully indecomposable) then an upper bound due to George and Ng on the nonzero structure of L + U is as tight as possible. To show this, we prove a crucial result about alternating paths in strong Hall graphs. The alternating-paths theorem seems to be of independent interest: it can also be used to prove related results about structure prediction for QR factorization that are due to Coleman, Edenbrandt, Gilbert, Hare, Johnson, Olesky, Pothen, and van den Driessche.

  3. An MMP-2 Responsive Liposome Integrating Antifibrosis and Chemotherapeutic Drugs for Enhanced Drug Perfusion and Efficacy in Pancreatic Cancer.

    PubMed

    Ji, Tianjiao; Li, Suping; Zhang, Yinlong; Lang, Jiayan; Ding, Yanping; Zhao, Xiao; Zhao, Ruifang; Li, Yiye; Shi, Jian; Hao, Jihui; Zhao, Ying; Nie, Guangjun

    2016-02-10

    Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a β-cyclodextrin (β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the β-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-β in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified-liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy. PMID:26759926

  4. Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety.

    PubMed

    Zhu, Lin; Wang, Tao; Perche, Federico; Taigind, Anton; Torchilin, Vladimir P

    2013-10-15

    In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor-targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2)-sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2-sensitive moiety), transactivating transcriptional activator peptide-PEG1000-phosphoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart, free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells. PMID:24062440

  5. Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety

    PubMed Central

    Zhu, Lin; Wang, Tao; Perche, Federico; Taigind, Anton; Torchilin, Vladimir P.

    2013-01-01

    In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor-targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2)-sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2-sensitive moiety), transactivating transcriptional activator peptide-PEG1000-phosphoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart, free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells. PMID:24062440

  6. Ageing related down-regulation of myocardial connexin-43 and up-regulation of MMP-2 may predict propensity to atrial fibrillation in experimental animals.

    PubMed

    Nagibin, V; Egan Benova, T; Viczenczova, C; Szeiffova Bacova, B; Dovinova, I; Barancik, M; Tribulova, N

    2016-09-19

    Mechanisms underlying atrial fibrillation (AF), the most common cardiac arrhythmia, particularly in aged population, are not fully elucidated. We have previously shown an increased propensity of old guinea pigs (GPs) heart to inducible AF when comparing to young animals. This study aimed to verify our hypothesis that susceptibility of aged heart to AF may be attributed to abnormalities in myocardial connexin-43 (Cx43) and extracellular matrix that affect cardiac electrical properties. Experiments were conducted on male and female 4-week-old and 24-week-old GPs. Atrial tissue was processed for analysis of Cx43 topology using immunohistochemistry, expression of Cx43 protein using immunobloting, and expression of mRNA of Cx43 and extracellular matrix metalloproteinase-2 (MMP-2) using real time PCR. Immunohistochemistry revealed uniform Cx43 distribution predominantly on lateral sides of the cardiomyocytes of young male and female GP atria. In contrast, non-uniform distribution, mislocalization and reduced immunolabeling of Cx43 were detected in atria of old GPs. In parallel, the atrial tissue levels of Cx43 mRNA were significantly decreased, while mRNA expression of MMP-2 was significantly increased in old versus young GPs. The changes were more pronounced in old GPs males comparing to females. Findings indicate that age-related down-regulation of atrial Cx43 and up-regulation of MMP-2 as well as disordered Cx43 distribution can facilitate development of AF in old guinea pig hearts. PMID:27643943

  7. MMP-2 and MMP-9 Activities and TIMP-1 and TIMP-2 Expression in the Prostatic Tissue of Two Ethanol-Preferring Rat Models

    PubMed Central

    Fioruci-Fontanelli, Beatriz Aparecida; Chuffa, Luiz Gustavo A.; Mendes, Leonardo O.; Pinheiro, Patricia Fernanda F.; Delella, Flávia Karina; Kurokawa, Cilmery S.; Felisbino, Sérgio Luis; Martinez, Francisco Eduardo

    2015-01-01

    We investigated whether chronic ethanol intake is capable of altering the MMP-2 and MMP-9 activities and TIMP-2 and TIMP-1 expression in the dorsal and lateral prostatic lobes of low (UChA) and high (UChB) ethanol-preferring rats. MMP-2 and MMP-9 activities and TIMP-1 and TIMP-2 expression were significantly reduced in the lateral prostatic lobe of the ethanol drinking animals. Dorsal prostatic lobe was less affected showing no significant alterations in these proteins, except for a reduction in the TIMP-1 expression in UChA rats. These important findings demonstrate that chronic ethanol intake impairs the physiological balance of the prostate extracellular matrix turnover, through downregulation of MMPs, which may contribute to the development of prostatic diseases. Furthermore, since these proteins are also components of prostate secretion, the negative impact of chronic ethanol intake on fertility may also involve reduction of MMPs and TIMPs in the seminal fluid. PMID:26258010

  8. The anti-fibrotic effect of liver growth factor is associated with decreased intrahepatic levels of matrix metalloproteinases 2 and 9 and transforming growth factor beta 1 in bile duct-ligated rats.

    PubMed

    Díaz-Gil, Juan J; García-Monzón, Carmelo; Rúa, Carmen; Martín-Sanz, Paloma; Cereceda, Rosa M; Miquilena-Colina, María E; Machín, Celia; Fernández-Martínez, Amalia; García-Cañero, Rarael

    2008-05-01

    Liver growth factor (LGF), a mitogen for liver cells, behaves as an anti-fibrotic agent even in extrahepatic sites, but its mechanistic basis is unknown. We aimed to determine the intrahepatic expression pattern of key modulators of liver fibrosis in bile duct-ligated rats (BDL) after injection of LGF. BDL rats received either LGF (4.5 microg/ratXdose, two doses/week, at time 0 or 2 or 5w after operation, depending on the group (BDL+LGF groups, n=20) or saline (BDL+S groups, n=20). Groups were compared in terms of fibrosis (histomorphometry), liver function (aminopyrine breath test), matrix metalloproteinases MMP-2 and MMP-9, transforming growth factor beta 1 (TGF-beta1) and liver endoglin content (Western blotting), and serum tissue inhibitor of metalloproteinases 1 (TIMP-1) levels (ELISA). In BDL+LGF rats, the fibrotic index was significantly lower at 5w, p=0.006, and at 8w, p=0.04, than in BDL+S rats. Liver function values in BDL+LGF rats were higher than those obtained in BDL+S rats (80% at 5w and 79% at 8w, versus 38% and 29%, p<0.01, taking healthy controls as 100%). Notably, in BDL+LGF rats the intrahepatic expression levels of both MMPs were lower at 2w (MMP-2, p=0.03; MMP-9, p=0.05) and 5w (MMP-2, p=0.05, MMP-9, p=0.04). In addition, the hepatic TGF-beta1 level in BDL+LGF rats was lower at 2w (36%, p=0.008), 5w (50%) and 8wk (37%), whereas intrahepatic endoglin expression remained constant in all BDL rats studied. LGF ameliorates liver fibrosis and improves liver function in BDL rats. The LGF-induced anti-fibrotic effect is associated with a decreased hepatic level of MMP-2, MMP-9 and TGF-beta1 in fibrotic rats.

  9. Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction

    PubMed Central

    Tveitarås, Maria K.; Skogstrand, Trude; Leh, Sabine; Helle, Frank; Chatziantoniou, Christos; Reed, Rolf K.; Hultström, Michael

    2015-01-01

    Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis

  10. The activation of TLR7 regulates the expression of VEGF, TIMP1, MMP2, IL-6, and IL-15 in Hela cells.

    PubMed

    Li, Lei; Cheng, Feng-Wei; Wang, Fang; Jia, Bo; Luo, Xin; Zhang, Sheng-Quan

    2014-04-01

    Toll-like receptors (TLRs) play important roles in activation of immunoreaction and tumor development. Toll-like receptor 7 (TLR7), one of the TLRs binding with single-stranded RNA, activates intracellular pathways and stimulates the release of proinflammatory cytokines, chemokines. In this study, we investigated the impact of the TLR7-signaling pathway on the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 1 (TIMP1), interleukin 6 (IL-6), and interleukin 15 (IL-15), which have been testified to refer to the immunomodulating and tumor progression. We confirmed that the TLR7 was expressed by Hela cells, despite the abundance was weak. Gardiquimod, one of the TLR7 ligands, can promote these five genes expression in varying degrees. After stimulating with gardiquimod, the expression of the IL-15V1, 3 increased about 4.5 times on RNA level, the other expression was only up-regulated about 2 times. We also discovered that gardiquimod could activate the MAPK/ERK- and PI3K/AKT-signaling pathways, and the specific inhibitors studies indicate that, the effect of gardiquimod on these genes expression is mainly or partially dependent on the activation of these two signaling pathways. To sum up, the activation of TLR7 signaling pathway may modulate some genes expression in Hela cells and may contribute to the pathogenesis of the cervical cancer.

  11. Low-Rank Matrix Factorization With Adaptive Graph Regularizer.

    PubMed

    Lu, Gui-Fu; Wang, Yong; Zou, Jian

    2016-05-01

    In this paper, we present a novel low-rank matrix factorization algorithm with adaptive graph regularizer (LMFAGR). We extend the recently proposed low-rank matrix with manifold regularization (MMF) method with an adaptive regularizer. Different from MMF, which constructs an affinity graph in advance, LMFAGR can simultaneously seek graph weight matrix and low-dimensional representations of data. That is, graph construction and low-rank matrix factorization are incorporated into a unified framework, which results in an automatically updated graph rather than a predefined one. The experimental results on some data sets demonstrate that the proposed algorithm outperforms the state-of-the-art low-rank matrix factorization methods.

  12. The Effect of Autologous Platelet-Rich Gel on the Dynamic Changes of the Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinase-2 Expression in the Diabetic Chronic Refractory Cutaneous Ulcers

    PubMed Central

    Li, Lan; Chen, Dawei; Wang, Chun; Liu, Guanjian; Ran, Xingwu

    2015-01-01

    Aim. To investigate the dynamic changes on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in the diabetic chronic refractory cutaneous ulcers after the autologous platelet-rich gel (APG) treatment. Methods. The study was developed at the Diabetic Foot Care Centre, West China Hospital. The granulation tissues from the target wounds were taken before and within 15 days after APG application. The expression of MMP-2 and TIMP-2 as well as transforming growth factor-β1 (TGF-β1) in the granulation tissue was detected by q TR-PCR and IHC. The relationship between the expression level of MMP-2 and TIMP-2 and their ratio and that of TGF-β1 was analyzed. Results. The expression of MMP-2 (P < 0.05) was suppressed, and the expression of TIMP-2 (P < 0.05) was promoted, while the ratio of MMP-2/TIMP-2 (P < 0.05) was decreased after APG treatments. The expression of TGF-β1 had negative correlation with the ratio of MMP-2/TIMP-2 (P < 0.05) and positive correlation with the expression of TIMP-2 (P < 0.05). Conclusions. APG treatment may suppress the expression of MMP-2, promoting that of the TIMP-2 in the diabetic chronic refractory cutaneous wounds. TGF-β1 may be related to these effects. PMID:26221614

  13. The need of MMP-2 on the sperm surface for Xenopus fertilization: its role in a fast electrical block to polyspermy.

    PubMed

    Iwao, Yasuhiro; Shiga, Keiko; Shiroshita, Ayumi; Yoshikawa, Tomoyasu; Sakiie, Maho; Ueno, Tomoyo; Ueno, Shuichi; Ijiri, Takashi W; Sato, Ken-ichi

    2014-11-01

    Monospermic fertilization in the frog, Xenopus laevis, is ensured by a fast-rising, positive fertilization potential to prevent polyspermy on the fertilized egg, followed by a slow block with the formation of a fertilization envelope over the egg surface. In this paper, we found that not only the enzymatic activity of sperm matrix metalloproteinase-2 (MMP-2) was necessary for a sperm to bind and/or pass through the extracellular coat of vitelline envelope, but also the hemopexin (HPX) domain of MMP-2 on the sperm surface was involved in binding and membrane fusion between the sperm and eggs. A peptide with a partial amino acid sequence of the HPX domain caused egg activation accompanied by an increase in [Ca(2+)]i in a voltage-dependent manner, similar to that in fertilization. The membrane microdomain (MD) of unfertilized eggs bound the HPX peptide, and this was inhibited by ganglioside GM1 distributed in the MD. The treatment of sperm with GM1 or anti-MMP-2 HPX antibody allows the sperm to fertilize an egg clamped at 0 mV, which untreated sperm cannot achieve. We propose a model accounting for the mechanism of voltage-dependent fertilization based on an interaction between the positively charged HPX domain in the sperm membrane and negatively-charged GM1 in the egg plasma membrane.

  14. Sodium fluoride inhibits MMP-2 and MMP-9.

    PubMed

    Kato, M T; Bolanho, A; Zarella, B L; Salo, T; Tjäderhane, L; Buzalaf, M A R

    2014-01-01

    The importance of fluoride (F) in preventing dental caries by favorably interfering in the demineralization-remineralization processes is well-established, but its ability to inhibit matrix metalloproteinases (MMPs), which could also help to prevent dentin caries, has not been investigated. This study assessed the ability of F to inhibit salivary and purified human gelatinases MMPs-2 and -9. Saliva was collected from 10 healthy individuals. Pooled saliva was centrifuged, and supernatants were incubated for 1 hr at 37°C and subjected to zymography. Sodium fluoride (50-275 ppm F) was added to the incubation buffer. The reversibility of the inhibition of MMPs-2 and -9 by NaF was tested by the addition of NaF (250-5,000 ppm F) to the incubation buffer, after which an additional incubation was performed in the absence of F. F decreased the activities of pro- and active forms of salivary and purified human MMPs in a dose-response manner. Purified gelatinases were completely inhibited by 200 ppm F (IC50 = 100 and 75 ppm F for MMPs-2 and -9, respectively), and salivary MMP-9 by 275 ppm F (IC50 = 200 ppm F). Inhibition was partially reversible at 250-1,500 ppm F, but was irreversible at 5,000 ppm F. This is the first study to describe the ability of NaF to inhibit MMPs completely.

  15. Expression of matrix metalloproteinase and its tissue inhibitor in haemangioma.

    PubMed

    Zhong, Shan; Yang, Guohua; Xia, Cong; Duanlian, Zhang; Shan, Shengguo

    2009-10-01

    The action mechanism of matrix metalloproteinases-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in the genesis, development and degeneration of haemangioma was investigated by detecting their expression in the tissue of haemangioma in different phases by using the immunohistochemistry. Fifty paraffin-embedded specimens of skin capillary haemangioma were collected, which were documented in the Department of Pathology, Renmin Hospital of Wuhan University from 2000 to 2006. All samples were stained by regular HE method, and proliferative cell nuclear antigen (PCNA) was tested by immunohistochemical S-P method. The samples were classified according to the Mulliken criteria and the expression pattern of PCNA. Immunohistochemical S-P method was applied to detect the expression of MMP-2 and TIMP-2 in proliferative and degenerative phases of cutaneous capillary haemangioma, and in normal skin tissues. In combination with the detection of the expression of factor VIII-related antigen, it was verified that in haemangioma tissues, the cells expressing MMP-2 and TIMP-2 were vascular endothelial cells. The MMP-2 and TIMP-2 expression was quantitatively analyzed by image analysis system (HPIAS-1000), and one-way ANOVA(107) and SNK(q) test were done to analyze average absorbance (A) and positive area rate of immunohistochemically positive particles by using SPSS11.5. The results showed: (1) Among 50 samples of haemangioma, there were 26 proliferative haemangiomas, and 24 degenerative haemangiomas, respectively; (2) The expression of MMP-2 was weak in normal vascular endothelial cells, cytoplasm of connective tissues and extracellular matrix around blood vessels. The expression of MMP-2 in proliferative group was significantly higher than in degenerative group and control group (normal skin) (P<0.05), but there was no statistically significant difference between the latter two groups; (3) TIMP-2 was highly expressed in normal tissues, degenerative vascular

  16. Paris saponin VII suppresses osteosarcoma cell migration and invasion by inhibiting MMP-2/9 production via the p38 MAPK signaling pathway

    PubMed Central

    Cheng, Gong; Gao, Fengguang; Sun, Xiujiang; Bi, Haiyong; Zhu, Yonglin

    2016-01-01

    Metastasis is the primary cause of mortality in osteosarcoma. Targeting metastasis is a major strategy in osteosarcoma treatment. As a traditional Chinese medicine, Trillium tschonoskii Maxim has been widely used in the therapy of various diseases, including cancer. However, currently there is no evidence regarding the anti-metastasic effect of Paris saponin VII (PS VII), which is extracted from Trillium tschonoskii Maxim, on osteosarcoma cells and its underling mechanisms. The present study aimed to examine the effect of PS VII on the migration and invasion of osteosarcoma cells. Viability and proliferation of osteosarcoma cells were examined by MTT assay. Migration and invasion of osteosarcoma cells was then detected using scratch wound healing assays and Transwell assays, respectively. Additionally, the expression of matrix metalloproteinase (MMP)-2 and -9 was determined at the mRNA and protein level following treatment with PS VII. Mitogen-activated protein kinase (MAPK) expression was also detected by western blot analysis. Finally, an inhibitor of p38 MAPK was used to verify the effect of PS VII on the expression of MMP-2 and -9, as well as the migration and invasion osteosarcoma cells. This demonstrated that the proliferation, migration and invasion of the osteosarcoma cells were suppressed following treatment with PS VII. PS VII downregulated the expression of MMP-2 and -9 in a dose- and time-dependent manner. PS VII also exerted its ability to downregulate the phosphorylation of p38 MAPKs. Furthermore, by using a p38 inhibitor, SB203580, the role of PS VII in MMP-2 and -9 expression and osteosarcoma cell invasion was revealed. Taken together, these results demonstrated that PS VII suppresses the migration and invasion of osteosarcoma cells via the p38 MAPK signaling pathway. PMID:27572907

  17. Matrix metalloproteinase-9 activity is associated with poor prognosis in T3-T4 node-negative colorectal cancer.

    PubMed

    Cho, Yong Beom; Lee, Woo Yong; Song, Sang Yong; Shin, Hee Jung; Yun, Seong Hyeon; Chun, Ho-Kyung

    2007-11-01

    Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase (MMP) inhibitor. RECK, MMP-2, and MMP-9 are believed to play crucial roles in tumor progression. This study was designed to examine the prognostic value of RECK, MMP-2, and MMP-9 in conjunction with other clinicopathologic factors in patients of T3-T4 node-negative colorectal cancer. RECK and MMP expression was observed using immunohistochemical analysis of the primary tumor from 89 patients with curatively resected T3-4 N0 colorectal cancer retrospectively. High RECK expression was observed in 51 cases, whereas expression was low in the other 38 cases. MMP-2 and MMP-9 expression was positive in cancer cells in 24 and 33 cases, respectively. RECK and MMP-2 expression was not significantly associated with any clinicopathologic factors. However, expression of MMP-9 was correlated with tumor location. A statistically significant inverse correlation was found between RECK and MMP-2 expression, and a statistically significant correlation was found between MMP-2 and MMP-9 expression. However, no association between RECK and MMP-9 expression was observed. Univariate analysis demonstrated that rectal tumor location, preoperative carcinoembryonic antigen more than 5 ng/mL, positive lymphatic invasion, less than 12 dissected lymph nodes, and positive MMP-9 expression were poor prognostic factors of disease-free survival. A multivariate analysis confirmed that enhanced MMP-9 expression was an independent and significant factor for prediction of a poor prognosis. In addition, positive lymphatic invasion and less than 12 dissected lymph nodes were significant negative prognostic factors. In conclusion, MMP-9 status represents a novel prognostic factor in evaluation of T3-T4 node-negative colorectal cancer.

  18. Diosmetin inhibits the metastasis of hepatocellular carcinoma cells by downregulating the expression levels of MMP-2 and MMP-9

    PubMed Central

    LIU, JIE; WEN, XIAOJUN; LIU, BIN; ZHANG, QINGYU; ZHANG, JINGJING; MIAO, HUILAI; ZHU, RUNZHI

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most malignant types of tumor worldwide with a high rate of mortality. Diosmetin (DIOS) exhibits various activities, including anticancer activities. However, the role of DIOS in the metastasis of HCC, and its underlying molecular mechanism, remain to be fully elucidated. In the present study, the antimetastatic effects of DIOS were investigated in SK-HEP-1 and MHcc97H HCC cell lines. Cell proliferation, wound healing, motility, invasion and adhesion capacities were examined to evaluate the inhibitory effect of DIOS on the metastasis of HCC cells. Cell viability was detected using an MTT assay in order to verify the inhibitory effect of DIOS on the proliferation of HCC cells. Cell migration was assessed using would healing and motility assays in order to verify the inhibitory effect of DIOS on the migration of HCC cells. Cell invasion and adhesion assays were performed in order to verify the inhibitory effect of DIOS on the invasion and adhesion of HCC cells. Matrix metalloproteinase (MMP)-2/9, proteins of the mitogen-activated protein kinase (MAPK) pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase and p38 MAPK) and protein kinase C-δ were detected in order to verify the potential molecular mechanisms of DIOS in the inhibition of the metastasis of HCC cells. DIOS was observed to inhibit the metastasis of SK-HEP-1 and MHcc97H cells by downregulating the expression of MMP-2/9 via the PKC/MAPK/MMP pathways. DIOS also inhibited the migration and invasion of the HCC cells, and may serve as a potential candidate agent for the prevention of HCC metastasis. PMID:26847170

  19. MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor.

    PubMed

    Dai, Zhi; Yao, Qing; Zhu, Lin

    2016-05-25

    Low tumor targetability and multidrug resistance (MDR) are two major impediments to the success of cancer treatments. Nanomaterials which possess high tumor targetability and the ability to reverse the MDR are rare. This report describes a new type of self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) which showed both the matrix metalloproteinase 2 (MMP2)-sensitive tumor-targeted drug delivery and ability to inhibit the P-glycoprotein (P-gp)-mediated drug efflux. In this study, we synthesized a series of the homologous analogues of PEG-pp-PE copolymers and investigated the influence of their structures, including PEG lengths and peptide linkers, on the drug efflux, and identified the underlying mechanisms. We found that the whole structure (PEG-peptide-lipid) rather than any parts of the copolymers was key for the P-gp inhibition and a delicate balance between the hydrophilic and lipophilic segments of the PEG-pp-PE copolymers was needed for better modulating the P-gp-mediated drug efflux. The best copolymer, PEG2k-pp-PE, showed even higher P-gp inhibition effect than the d-α-tocopherol polyethylene glycol 1000 succinate (TPGS1k). We also found that the P-gp inhibition capability of PEG-pp-PE copolymers was highly associated with the P-gp down-regulation, the increase in the plasma membrane fluidity, and the inhibition of the P-gp ATPase activity. Besides, the excellent physicochemical properties, high drug loading, MMP2-dependent drug release, and improved drug efficacy in the MDR cancer cells suggested that the PEG-pp-PE copolymers might have great potential for building tumor-targeted drug delivery systems for treating drug-resistant cancers.

  20. Ras-association domain family 10 acts as a novel tumor suppressor through modulating MMP2 in hepatocarcinoma

    PubMed Central

    Liu, W; Wang, J; Wang, L; Qian, C; Qian, Y; Xuan, H; Zhuo, W; Li, X; Yu, J; Si, J

    2016-01-01

    Ras-Association Domain Family 10 (RASSF10) is the last identified member of the RASSF family. The functional characteristics of this new gene in human cancers remain largely unclear. Here, we examined RASSF10 for the biological functions and related molecular mechanisms in hepatocellular carcinoma (HCC). We found that RASSF10 is expressed in normal human liver tissue, but is silenced or down-regulated in 62.5% (5/8) of HCC cell lines. The mean expression level of RASSF10 was significantly lower in primary HCCs compared with their adjacent normal tissues (P<0.005, n=52). The promoter methylation contributes to the inactivation of RASSF10 as demonstrated by bisulfite genomic sequencing and demethylation treatment analyses. Transgenic expression of RASSF10 in silenced HCC cell lines suppressed cell viability, colony formation and inhibited tumor growth in nude mice (QGY7703, P<0.01; HepG2, P<0.05). Furthermore, RASSF10 was shown to induce the cell accumulation in G1 phase with the increase of p27, as well as the decrease of cyclinD1 and CDK2/CDK4. Over-expression of RASSF10 also inhibited HCC cells migration (P<0.01) or invasion (P<0.05). Adhesion genes array revealed that Matrix Metalloproteinase 2 (MMP2) was a downstream effector of RASSF10. RASSF10 acting as a tumor suppressor to inhibit HCC invasion partially mediated by Focal Adhesion Kinase or p38 MAPK to decrease the accumulation of MMP2. Our study suggests that RASSF10 acts as a tumor suppressor for HCC. PMID:27348267

  1. MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor.

    PubMed

    Dai, Zhi; Yao, Qing; Zhu, Lin

    2016-05-25

    Low tumor targetability and multidrug resistance (MDR) are two major impediments to the success of cancer treatments. Nanomaterials which possess high tumor targetability and the ability to reverse the MDR are rare. This report describes a new type of self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) which showed both the matrix metalloproteinase 2 (MMP2)-sensitive tumor-targeted drug delivery and ability to inhibit the P-glycoprotein (P-gp)-mediated drug efflux. In this study, we synthesized a series of the homologous analogues of PEG-pp-PE copolymers and investigated the influence of their structures, including PEG lengths and peptide linkers, on the drug efflux, and identified the underlying mechanisms. We found that the whole structure (PEG-peptide-lipid) rather than any parts of the copolymers was key for the P-gp inhibition and a delicate balance between the hydrophilic and lipophilic segments of the PEG-pp-PE copolymers was needed for better modulating the P-gp-mediated drug efflux. The best copolymer, PEG2k-pp-PE, showed even higher P-gp inhibition effect than the d-α-tocopherol polyethylene glycol 1000 succinate (TPGS1k). We also found that the P-gp inhibition capability of PEG-pp-PE copolymers was highly associated with the P-gp down-regulation, the increase in the plasma membrane fluidity, and the inhibition of the P-gp ATPase activity. Besides, the excellent physicochemical properties, high drug loading, MMP2-dependent drug release, and improved drug efficacy in the MDR cancer cells suggested that the PEG-pp-PE copolymers might have great potential for building tumor-targeted drug delivery systems for treating drug-resistant cancers. PMID:27145021

  2. H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: a role for MMP-2 in the H-ras-induced invasive phenotype.

    PubMed

    Moon, A; Kim, M S; Kim, T G; Kim, S H; Kim, H E; Chen, Y Q; Kim, H R

    2000-01-15

    Elevated p21ras expression is associated with tumor aggressiveness in breast cancer including the extent of invasion into fat tissues, infiltration into lymphatic vessels and tumor recurrence. In the present study, we have examined the roles of H-ras and N-ras, members of the human ras gene family, in the pathogenesis of breast cancer. We show that H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells (MCF10A) as determined by the Matrigel invasion assay, whereas both H-ras and N-ras induce anchorage-independent growth, as shown by soft agar assay. We examined the effects of H-ras and N-ras activation on the expression of MMP-2 and MMP-9, which can degrade type IV collagen, the major structural collagen of the basement membrane. We show that MMP-2 is efficiently induced by H-ras, whereas MMP-9 induction is more prominent in N-ras-activated MCF10A cells. We also show that H-ras-mediated invasiveness is significantly inhibited when the expression of MMP-2 is down-regulated, using an oligodeoxyribonucleotide complementary to the MMP-2 mRNA, or when MMP-2 activity is blocked by its inhibitor TIMP-2 (tissue inhibitors of matrix metalloproteinase-2). Our results show that the H-ras-induced invasive phenotype is associated more closely with the expression of MMP-2 in human breast epithelial cells, rather than the induction of MMP-9 expression, as shown previously for rat embryonic fibroblasts.

  3. Effect of Qingguangan on the expressions of MMP-2 and MMP-9 in filtering bleb after trabeculectomy in rabbits

    PubMed Central

    Li, Wen-Juan; Peng, Qing-Hua; Tan, Han-Yu; Liu, Yan

    2012-01-01

    AIM To explore the effect of Qingguangan on the expressions of MMP-2 and MMP-9 in filtering bleb scarring area after trabeculectomy in rabbit model. METHODS Thirty-two New Zealand rabbits were randomized into four groups: control group, experimental group, MMC group (ocular trabeculectomy in combination with MMC), and Qingguangan group. Trabeculectomy was performed on both eyes in each group except control group. Qingguangan group was mouth-fed with Qingguangan (solution). On postoperative day 14, the appearances of MMP-2 and MMP-9 on filtrating blebs were observed by immunohistochemistry. RESULTS Statistical differences of the expressions of MMP-2 and MMP-9 were noted among groups on day 14 following surgery. Histology immunohistochemistry showed significant differences on the expressions of MMP-2 and MMP-9 between each group (P<0.05). CONCLUSION Qingguangan can promote the expressions of MMP-2 and MMP-9. PMID:23275898

  4. Targeting TGF-β1 inhibits invasion of anaplastic thyroid carcinoma cell through SMAD2-dependent S100A4-MMP-2/9 signalling

    PubMed Central

    Zhang, Kejun; Liu, Xiaoli; Hao, Fengyun; Dong, Anbing; Chen, Dong

    2016-01-01

    Objective: Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. However, the molecular mechanisms of ATC invasion are poorly understood. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in promoting tumor metastasis. TGF-β1 was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeted down-regulation of TGF-β1 inhibits invasion of ATC cells. Methods: Effects of TGF-β1 stimulation or TGF-β1 sliencing by small interfering RNA (TGF-β1 siRNA) on invasion in 8505C and SW1736 cells in vitro was detected. Using siRNAs and inhibitors to examine the TGF-β1 signaling pathway. Results: TGF-β1 siRNA inhibits cell migration and invasion in vitro, followed by inactivation of pSMAD2, S100A4 and MMP-2/9. TGF-β stimulation activated pSMAD2-dependent S100A4 and MMP-2/9 expression, and increased cell migration and invasion. The depletion of pSMAD2 or S100A4 or MMP-2/9 expression inhibited TGF-β signaling pathway. Moreover, it significantly weakened the proinvasive effects of TGF-β on ATC cells. Conclusions: Therapies targeting the TGF-β1 inhibits invasion of ATC cells by impeding the SMAD2-dependent S100A4-MMP-2/9 signalling in vitro. PMID:27347327

  5. Effect of antisense TIMP-1 cDNA on the expression of TIMP-1 and MMP-2 in lung tissue with pulmonary fibrosis induced by bleomycin.

    PubMed

    Tang, Haiying; Mao, Jingwei; Gao, Lili; Liu, Jia; Wu, Taihua

    2013-01-01

    The aim of this study was to observe the effect of antisense tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) cDNA on the concentration of hydroxyproline (HYP) and the expression of TIMP-1 and matrix metalloproteinase-2 (MMP-2) in the lung tissue of rats with bleomycin (BLM)‑induced pulmonary fibrosis. Sprague-Dawley rats were randomly divided into 5 groups: the control, pulmonary fibrosis model, sense TIMP-1 transfection, antisense TIMP-1 transfection and empty vector transfection groups. For the transfection groups, following the intratracheal injection of BLM on days 1, 3, 7, 14, 28 and 60, the rats were treated with retroviral vectors and sacrificed on day 28. The control and pulmonary fibrosis groups were treated with normal saline at the same time‑points. The concentration of HYP and the expression levels of TIMP-1 and MMP-2 in the lung tissue were detected. The HYP concentration and lung tissue TIMP-1 expression levels of the antisense TIMP-1 group decreased significantly on days 1 and 3 compared with those of the empty vector and pulmonary fibrosis groups at the same time-points (P<0.01), but increased significantly in the sense TIMP-1 group (P<0.01). No significant differences were observed in the HYP concentration and TIMP-1 expression levels in the antisense TIMP-1, sense TIMP-1, empty vector and pulmonary fibrosis groups on days 7, 14, 28 and 60. The lung expression levels of MMP-2 in all groups, with the exception of the control group, had no significant differences at all time-points (P>0.05). Antisense TIMP-1 cDNA retroviral vectors are able to suppress the development of pulmonary fibrosis in the early stages.

  6. Expression of survivin and matrix metalloproteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix.

    PubMed

    Yoshida, Hiroyuki; Sumi, Toshiyuki; Hyun, Yooji; Nakagawa, Eri; Hattori, Kanae; Yasui, Tomoyo; Morimura, Mina; Honda, Ken-Ichi; Nakatani, Tatsuya; Ishiko, Osamu

    2003-01-01

    Cervical cancer can be classified into two histological types: squamous cell carcinoma (SCA) and adenocarcinoma (ACA). Reportedly ACA has poorer prognoses, metastasizes more easily to lymph nodes, and is more resistant to radiotherapy than SCA. To clarify the cause of characteristic differences between these histological types, we examined the expressions of apoptosis inhibiting and tumor-invasion related factors in both histological types. We reviewed the 34 cases of cervical cancer (17 ACA, 17 SCA) that had surgery as their initial treatment at Osaka City University Medical School Hospital between 1996 and 2001. The differences of survivin, and matrix metalloproteinase (MMP-2, and MMP-7) expressions between both histological types were immunohistochemically assayed, and the correlation between the expression of each protein and clinicopathological characteristics was analyzed. Survivin was expressed significantly stronger in ACA cases (p=0.035). The number of patients who expressed MMP-2 and MMP-7 simultaneously was significantly higher in SCA cases (p=0.039). MMP-2 and MMP-7 had tendencies to be expressed stronger in SCA (p=0.057 and p=0.084, respectively). These results suggest that the differences of the expression of survivin (an apoptosis inhibiting factor), MMP-2, and MMP-7 (tumor-invasion related factors) between ACA and SCA were causes of the characteristic differences between the two histological types.

  7. Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma.

    PubMed

    Wu, Xiao; Liu, Bao-Jun; Ji, Shumeng; Wu, Jing-Feng; Xu, Chang-Qing; Du, Yi-Jie; You, Xiao-Fang; Li, Bei; Le, Jing-Jing; Xu, Hai-Lin; Duan, Xiao-Hong; Dong, Jing-Cheng

    2015-07-01

    Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal-regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor-stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression. PMID:25824133

  8. Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2

    PubMed Central

    Chumanevich, Alena; Wedman, Piper; Oskeritzian, Carole A.

    2016-01-01

    Mast cells (MC) are present in most vascularized tissues around the vasculature likely exerting immunomodulatory functions. Endowed with diverse mediators, resident MC represent first-line fine-tuners of local microenvironment. Sphingosine-1-phosphate (S1P) functions as a pluripotent signaling sphingolipid metabolite in health and disease. S1P formation occurs at low levels in resting MC and is upregulated upon activation. Its export can result in type 2 S1P receptor- (S1PR2-) mediated stimulation of MC, further fueling inflammation. However, the role of S1PR2 ligation in proangiogenic vascular endothelial growth factor- (VEGF-) A and matrix metalloproteinase- (MMP-) 2 release from MC is unknown. Using a preclinical MC-dependent model of acute allergic responses and in vitro stimulated primary mouse bone marrow-derived MC (BMMC) or human primary skin MC, we report that S1P signaling resulted in substantial amount of VEGF-A release. Similar experiments using S1pr2-deficient mice or BMMC or selective S1P receptor agonists or antagonists demonstrated that S1P/S1PR2 ligation on MC is important for VEGF-A secretion. Further, we show that S1P stimulation triggered transcriptional upregulation of VEGF-A and MMP-2 mRNA in human but not in mouse MC. S1P exposure also triggered MMP-2 secretion from human MC. These studies identify a novel proangiogenic axis encompassing MC/S1P/S1PR2 likely relevant to inflammation. PMID:26884643

  9. Toxicity reduction and MMP-2 stimulation of papain and bromelain loaded in elastic niosomes.

    PubMed

    Manosroi, Aranya; Chankhampan, Charinya; Manosroi, Worapaka; Manosroi, Jiradej

    2012-10-01

    The elastic niosomes (Tween 61/cholesterol/sodium cholate at 1:1:0.1 molar ratio) loaded with the protease enzymes (papain and bromelain) gave the vesicular sizes of 109.5 to 143.9 nm with the negative zeta potential of -14.7 to -30.1 mv. The elastic niosomes loaded with the standard papain (PS), extracted papain (PE), standard bromelain (BS) and extracted bromelain (BE) showed deformability index (DI values) of 1.35, 1.81, 1.22 and 1.61 times higher than their corresponding non-elastic niosomes, respectively. The elastic niosomes did not only improve the entrapment efficiency of the enzymes over the non-elastic niosomes of about 1.35 times, but also reduced the toxicity on skin human fibroblasts by SRB assay of the PS, PE, BS and BE at 1.68, 2.10, 1.56 and 1.52 times, respectively. The relative MMP-2 stimulation of PS, PE, BS and BE loaded in elastic niosomes were 1.26 +/- 0.14, 1.34 +/- 0.15, 1.09 +/- 0.09 and 1.20 +/- 0.04 for the pro MMP-2 and 1.26 +/- 0.12, 1.41 +/- 0.23, 1.01 +/- 0.08 and 1.03 +/- 0.12 for the active MMP-2, respectively in comparing to the control which were similar activity to their free enzymes. The PE loaded in elastic niosomes gave superior characteristics (low cytotoxicity and high MMP-2 stimulation) to other enzymes. The elastic niosomes can enhance the chemical stability of PE, which exhibited higher remaining contents than the free PE of 1.36 times when kept at 27 +/- 2 degrees C after 8 weeks. Therefore, the extracted papain loaded in elastic niosomes appeared to have potential to be developed as a topical product for scar treatment.

  10. Wound-healing effects of low-level laser therapy in diabetic rats involve the modulation of MMP-2 and MMP-9 and the redistribution of collagen types I and III.

    PubMed

    Aparecida Da Silva, Andreia; Leal-Junior, Ernesto Cesar Pinto; Alves, Ana Carolina Araruna; Rambo, Caroline Sobral; Dos Santos, Solange Almeida; Vieira, Rodolfo P; De Carvalho, Paulo De Tarso Camillo

    2013-08-01

    The present study aimed to determine if LLLT restores the balance between mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9) and also the balance between collagen types I and III during the healing process of diabetic wounds. One hundred and twenty male Wistar rats were distributed in Control (untreated non-diabetic rats: UND); Laser (laser treated in non-diabetic rats: LTND); Diabetic (diabetic rats non-laser treated rats: UD); and Diabetic+ Laser (diabetic rats laser treated: DLT) groups. The diabetes model using streptozotocin efficiently induced diabetes, as demonstrated through increased levels of blood glucose. Diode laser (50 mW, 660 nm, 4 J/cm(2), 80 s) was applied a single time after scare induction. Twenty-four hours after LLLT application, rats were euthanized, the scarred areas were collected for MMP-2 and MMP-9 mRNA analysis and also for histological analysis (inflammation and types I and III collagen). The results demonstrated that scare in untreated diabetic rats significantly increased the MMP-2 and MMP-9 expression compared with that in non-diabetic rats (p < 0.05), while LLLT significantly reduced MMP-2 and MMP-9 expression compared with that in untreated diabetic rats (p < 0.05). To conclude, the results also showed that LLLT was able to alter the expression of MMP-9 as well as accelerate the production of collagen and increase the total percentage of collagen type III in diabetic animals.

  11. Factored-matrix representation of distributed fast transforms. Master's thesis

    SciTech Connect

    Bainbridge, R.L.

    1987-03-01

    Parallel implementations of Fast Fourier Transforms (FFTs) and other fast transforms are represented using factored, partitioned matrices. The factored matrix description of a distributed FFT is introduced using a decimation in time (DIT) FFT algorithm suitable for implementation on a distributed-signal processor. The heart of the matrix representation of distributed fast transforms is the use of permutations of an NxN identity matrix to describe the required interprocessor data transfers on the Butterfly Network. The properties of these transfer matrices and the resulting output ordering are discussed in detail. The factored matrix representation is then used to show that the Fast Hartley Transform (FHT) and the Walsh Hadamard Transform (WHT) are supported by the Butterfly Network.

  12. Baicalein inhibits pulmonary carcinogenesis-associated inflammation and interferes with COX-2, MMP-2 and MMP-9 expressions in-vivo

    SciTech Connect

    Chandrashekar, Naveenkumar; Selvamani, Asokkumar; Subramanian, Raghunandhakumar; Pandi, Anandakumar; Thiruvengadam, Devaki

    2012-05-15

    The objective of the present study is to investigate the therapeutic efficacy of baicalein (BE) on inflammatory cytokines, which is in line with tumor invasion factors and antioxidant defensive system during benzo(a)pyrene [B(a)P] (50 mg/kg body weight) induced pulmonary carcinogenesis in Swiss albino mice. After experimental period, increased levels of total and differential cell count in bronchoalveolar lavage fluid were observed. Accompanied by marked increase in immature mast cell by toluidine blue staining and mature mast cell by safranin–alcian blue staining in B(a)P-induced lung cancer bearing animals. Protein expression levels studied by immunohistochemistry and immunoblot analysis of cytokines such as tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were also found to be significantly increased in lung cancer bearing animals. B(a)P-exposed mice lung exhibits activated expression of nuclear transcription factor kappa-B as confirmed by immunofluorescence and immunoblot analysis. Administration of BE (12 mg/kg body weight) significantly counteracted all the above deleterious changes. Moreover, assessment of tumor invasion factors on protein levels by immunoblot and mRNA expression levels by RT-PCR revealed that BE treatment effectively negates B(a)P-induced upregulated expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and cyclo-oxygenase-2. Further analysis of lipid peroxidation markers such as thiobarbituric acid reactive substances, hydro-peroxides and antioxidants such as glutathione-S-transferase and reduced glutathione in lung tissue was carried out to substantiate the antioxidant effect of BE. The chemotherapeutic effect observed in the present study is attributed to the potent anti-inflammatory and antioxidant potential by BE against pulmonary carcinogenesis. -- Highlights: ► BE treatment protects from inflammatory cells and mast-cells accumulation in lungs. ► BE altered the expressions of TNF

  13. Sparse matrix orderings for factorized inverse preconditioners

    SciTech Connect

    Benzi, M.; Tuama, M.

    1998-09-01

    The effect of reorderings on the performance of factorized sparse approximate inverse preconditioners is considered. It is shown that certain reorderings can be very beneficial both in the preconditioner construction phase and in terms of the rate of convergence of the preconditioned iteration.

  14. Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension.

    PubMed

    Belo, V A; Guimarães, Danielle A; Castro, Michele Mazzaron

    2015-01-01

    For vascular remodeling in hypertension, it is essential that vascular smooth muscle cells (VSMCs) reshape in order to proliferate and migrate. The extracellular matrix (ECM) needs to be degraded to favor VSMC migration. Many proteases, including matrix metalloproteinases (MMPs), contribute to ECM proteolysis and VSMC migration. Bioactive peptides, hemodynamic forces and reactive oxygen-nitrogen species regulate MMP-2 expression and activity. Increased MMP-2 activity contributes to hypertension-induced maladaptive arterial changes and sustained hypertension. New ECM is synthesized to supply VSMCs with bioactive mediators, which stimulate hypertrophy. MMP-2 stimulates the interaction of VSMCs with newly formed ECM, which triggers intracellular signaling via integrins to induce a phenotypic switch and persistent migration. VSMCs switch from a contractile to a synthetic phenotype in order to migrate and contribute to vascular remodeling in hypertension. MMPs also disrupt growth factors bound to ECM, thus contributing to their capacity to regulate VSMC migration. This review sheds light on the proteolytic effects of MMP-2 on ECM and non-ECM substrates in the vasculature and how these effects contribute to VSMC migration in hypertension. The inhibition of MMP activity as a therapeutic target may make it possible to reduce arterial maladaptation caused by hypertension and prevent the resulting fatal cardiovascular events. PMID:26731549

  15. Role of matrix metalloproteinases in radiation-induced lung injury in alveolar epithelial cells of Bama minipigs

    PubMed Central

    YUE, HAIYING; HU, KAI; LIU, WENQI; JIANG, JIE; CHEN, YUHUA; WANG, RENSHENG

    2015-01-01

    Radiation-induced lung injury (RILI) is a common complication associated with thoracic radiotherapy. The aim of the present study was to investigate the effects of a single 15-Gy dose of right-thoracic lung irradiation on the expression levels of matrix metalloproteinases (MMPs) and other proteins in the alveolar epithelial type II (AE2) cells of Bama minipigs. All minipigs received either right-thoracic irradiation or sham irradiation under anesthesia, and were sacrificed at 4, 8, 12 or 24 weeks after irradiation. Collagen deposition was measured using Massons trichrome staining. Surfactant protein A (SP-A), transforming growth factor β1 (TGFβ1), MMP2, MMP9, vimentin and E-cadherin protein expression levels were evaluated using western blot analysis, and the MMP2 and MMP9 gelatinase activities were tested using gelatin zymography. SP-A and α-smooth muscle actin (α-SMA) co-localization was visualized using double immunofluorescence staining. At each time-point following irradiation, a significant increase in TGFβ1, α-SMA, MMP2, MMP9 and vimentin protein expression levels and MMP2 and MMP9 gelatinase activity were observed in the irradiated lungs compared with the sham-irradiated controls. By contrast, SP-A and E-cadherin protein expression levels decreased in a time-dependent manner post-irradiation. SP-A and α-SMA co-localization was observed in irradiated alveolar epithelial cells. These data demonstrate that E-cadherin, SP-A, MMP2 and MMP9 may function as sensitive predictors of RILI. Epithelial-mesenchymal transition (EMT) occurs in the irradiated lungs of Bama minipigs, and MMP2 and MMP9 may contribute to EMT in AE2 cells by regulating TGFβ1. Therefore, EMT may serve a crucial function in the development of RILI. PMID:26622503

  16. The G12 family proteins upregulate matrix metalloproteinase-2 via p53 leading to human breast cell invasion.

    PubMed

    Kim, Eun-Sook; Jeong, Jae-Boon; Kim, Seonhoe; Lee, Kyung-Min; Ko, Eunyoung; Noh, Dong-Young; Hwang, Ki-Tae; Ha, Ji Hee; Lee, Chang Ho; Kim, Sang Geon; Moon, Aree

    2010-11-01

    Although mounting evidence suggests a role for G(12) proteins, G(α12) and G(α13), in tumor progression, a direct role of G(12) proteins has not been determined. This study aims to elucidate the molecular mechanism for a tumorigenic and invasive potential of G(α12) and G(α13) in MCF10A human breast epithelial cells. Here, we report, for the first time, that G(α12) and G(α13) induce upregulation of matrix metalloproteinase (MMP)-2 leading to the invasive and migratory phenotypes in MCF10A cells. We further show that p53 is an important transcription factor for induction of MMP-2 transcriptional activation by G(α12/13). G(α12/13)-induced MMP-2 upregulation, invasion, and migration are dependent on the activation of Ras, Rac1, MKK3/6, p38, and Akt. Using human breast tissue samples, we demonstrate that the expression levels of G(α12) and MMP-2 are strongly correlated with the pathogenically diagnosed cancer (P < 0.0001). Moreover, the expression of G(α12) shows a strong correlation with that of MMP-2 in human breast cancer tissues, implicating the in vivo tumorigenic potential of G(α12). Taken together, this study elucidated the role of G(12) proteins in regulating processes for MMP-2 expression and malignant phenotypic conversion of MCF10A human breast epithelial cells, providing a molecular basis for the promoting role of G(α12) and G(α13) in breast cell invasion.

  17. Sparse nonnegative matrix factorization with ℓ0-constraints

    PubMed Central

    Peharz, Robert; Pernkopf, Franz

    2012-01-01

    Although nonnegative matrix factorization (NMF) favors a sparse and part-based representation of nonnegative data, there is no guarantee for this behavior. Several authors proposed NMF methods which enforce sparseness by constraining or penalizing the ℓ1-norm of the factor matrices. On the other hand, little work has been done using a more natural sparseness measure, the ℓ0-pseudo-norm. In this paper, we propose a framework for approximate NMF which constrains the ℓ0-norm of the basis matrix, or the coefficient matrix, respectively. For this purpose, techniques for unconstrained NMF can be easily incorporated, such as multiplicative update rules, or the alternating nonnegative least-squares scheme. In experiments we demonstrate the benefits of our methods, which compare to, or outperform existing approaches. PMID:22505792

  18. Associations of MMP1, MMP2 and MMP3 Genes Polymorphism with Coal Workers' Pneumoconiosis in Chinese Han Population.

    PubMed

    Ji, Xiaoming; Wang, Lijuan; Wu, Baiqun; Han, Ruhui; Han, Lei; Wang, Ting; Yang, Jingjin; Ni, Chunhui

    2015-10-30

    Coal workers' pneumoconiosis (CWP) has been associated with abnormalities in the extracellular matrix remodeling, as well as aberrant matrix metalloproteinases (MMPs) in lung tissues. We investigated the association of three functional polymorphisms in MMP gene promoters (MMP1 rs1799750, MMP2 rs2285053 and MMP3 rs522616) with the risk of CWP. A total of 693 CWP cases and 690 controls were included in a case-control study. Genotype analysis was performed by the TaqMan method. Statistically significant differences were found in distributions of MMP3 rs522616 under a recessive model (p = 0.047) between CWP cases and controls. In the stratification analysis, individuals with MMP3 rs522616 GG genotype decreased the risk of CWP (adjusted OR = 0.72, 95% CI = 0.52-0.99) compared to those with AA/AG genotype obviously, particularly among subgroups of no smokers (adjusted OR = 0.64, 95% CI = 0.41-1.00). Furthermore, serum MMP3 protein levels measured with enzyme-linked immune-sorbent assay in the control group was significantly lower than that in the CWP groups (p = 0.02). Extremely lower MMP3 among subjects with the rs522616 GG or AG genotype compared with the AA genotype carriers (p < 0.05, p < 0.01 respectively) in the normal serum. These findings indicate that the MMP3 rs522616 polymorphism may contribute to the etiology of CWP in the Chinese population and MMP3 might be a potential diagnostic biomarker for CWP, additional independent studies are warranted to validate our findings in different populations as well as in a larger series.

  19. Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP-2 and -12 as Antineoplastic Agents.

    PubMed

    Rane, Rajesh A; Naphade, Shital S; Bangalore, Pavan Kumar; Palkar, Mahesh B; Patel, Harun M; Shaikh, Mahamadhanif S; Alwan, Wesam S; Karpoormath, Rajshekhar

    2015-08-01

    Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50  = 0.03 μm), 5t (IC50  = 0.03 μm), 4s (IC50  = 0.07 μm), and 5n (IC50  = 0.01 μm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50  = 1.8 μm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50  = 83.1 to 231.8 μm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.

  20. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2.

    PubMed

    Deshane, Jessy; Garner, Craig C; Sontheimer, Harald

    2003-02-01

    Primary brain tumors (gliomas) have the unusual ability to diffusely infiltrate the normal brain thereby evading surgical treatment. Chlorotoxin is a scorpion toxin that specifically binds to the surface of glioma cells and impairs their ability to invade. Using a recombinant His-Cltx we isolated and identified the principal Cltx receptor on the surface of glioma cells as matrix metalloproteinase-2 (MMP-2). MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain. We demonstrate that Cltx specifically and selectively interacts with MMP-2 isoforms, but not with MMP-1, -3, and -9, which are also expressed in malignant glioma cells. Importantly, we show that the anti-invasive effect of Cltx on glioma cells can be explained by its interactions with MMP-2. Cltx exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. These findings suggest that Cltx is a specific MMP-2 inhibitor with significant therapeutic potential for gliomas and other diseases that invoke the activity of MMP-2.

  1. Constructing the S-matrix With Complex Factorization

    SciTech Connect

    Schuster, Philip C.; Toro, Natalia; /Stanford U., ITP

    2009-06-19

    A remarkable connection between BCFW recursion relations and constraints on the S-matrix was made by Benincasa and Cachazo in 0705.4305, who noted that mutual consistency of different BCFW constructions of four-particle amplitudes generates nontrivial (but familiar) constraints on three-particle coupling constants - these include gauge invariance, the equivalence principle, and the lack of non-trivial couplings for spins > 2. These constraints can also be derived with weaker assumptions, by demanding the existence of four-point amplitudes that factorize properly in all unitarity limits with complex momenta. From this starting point, we show that the BCFW prescription can be interpreted as an algorithm for fully constructing a tree-level S-matrix, and that complex factorization of general BCFW amplitudes follows from the factorization of four-particle amplitudes. The allowed set of BCFW deformations is identified, formulated entirely as a statement on the three-particle sector, and using only complex factorization as a guide. Consequently, our analysis based on the physical consistency of the S-matrix is entirely independent of field theory. We analyze the case of pure Yang-Mills, and outline a proof for gravity. For Yang-Mills, we also show that the well-known scaling behavior of BCFW-deformed amplitudes at large z is a simple consequence of factorization. For gravity, factorization in certain channels requires asymptotic behavior {approx} 1/z{sup 2}.

  2. Blind spectral unmixing in terahertz domain using nonnegative matrix factorization

    NASA Astrophysics Data System (ADS)

    Li, Xian; Huang, Ping J.; Ma, Ye H.; Hou, Di B.; Zhang, Guangxin

    2015-11-01

    Recovering component spectra from terahertz measurements of unknown mixtures has been studied in this paper using nonnegative matrix factorization (NMF). NMF mathematically decomposes the spectra data into two nonnegative matrixes which describe the component spectra and the corresponding fractional abundance. Two basic algorithms in the class of this method, NMF and NMF with smoothness constraint (cNMF), were adopted to resolve the terahertz absorption spectra matrix obtained from a ternary mixture with varying compositions of Nitrofurantoin, L-Leucine and D-Tyrosine. The quality of the decomposition results was evaluated. The performance of the two algorithms on extracting component terahertz spectra was compared. The optimal result reached by cNMF in this study implies the capability of the NMF method for blind terahertz spectral unmixing. The attempt made in our work helps to further investigate unknown mixtures by terahertz spectroscopy.

  3. Robust Collaborative Nonnegative Matrix Factorization for Hyperspectral Unmixing

    NASA Astrophysics Data System (ADS)

    Li, Jun; Bioucas-Dias, Jose M.; Plaza, Antonio; Liu, Lin

    2016-10-01

    The recently introduced collaborative nonnegative matrix factorization (CoNMF) algorithm was conceived to simultaneously estimate the number of endmembers, the mixing matrix, and the fractional abundances from hyperspectral linear mixtures. This paper introduces R-CoNMF, which is a robust version of CoNMF. The robustness has been added by a) including a volume regularizer which penalizes the distance to a mixing matrix inferred by a pure pixel algorithm; and by b) introducing a new proximal alternating optimization (PAO) algorithm for which convergence to a critical point is guaranteed. Our experimental results indicate that R-CoNMF provides effective estimates both when the number of endmembers are unknown and when they are known.

  4. BNP, NTproBNP, CMBK, and MMP-2 predict mortality in severe Chagas cardiomyopathy

    PubMed Central

    Sherbuk, Jacqueline E.; Okamoto, Emi E.; Marks, Morgan A.; Fortuny, Enzo; Clark, Eva H.; Galdos-Cardenas, Gerson; Vasquez-Villar, Angel; Fernandez, Antonio B.; Crawford, Thomas C.; Do, Rose Q.; Flores-Franco, Jorge Luis; Colanzi, Rony; Gilman, Robert H.; Bern, Caryn

    2015-01-01

    Background Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival. Objectives Our study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital. Methods The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, ECG findings, medications, and serum cardiac biomarker levels (BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP-9, TIMP-1, TIMP-2, TGFb1, and TGFb2) were ascertained. Echocardiograms were preferentially performed on those with cardiac symptoms or electrocardiogram abnormalities. Participants were contacted by phone approximately 1 year after initial evaluation; deaths were reported by family members. Receiver operating characteristic curves were used to optimize cut-off values for each marker. For markers with area under curve > 0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality. Results The median follow-up time was 14.1 months (interquartile range 12.5- 16.7 months). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy, 20 (40%) had died. Higher baseline levels of BNP (HR[95% CI]:3.1 [1.2, 8.4]), NTproBNP (4.4[1.8,11.0]), CKMB (3.3[1.3, 8.0]), and MMP-2 (4.2[1.5, 11.8]) were significantly associated with subsequent mortality. Conclusions Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NTproBNP, CKMB and MMP2 have added predictive value for mortality, even in the presence of

  5. Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna.

    PubMed

    Rajaram, Shailja; Murawala, Hiral; Buch, Pranav; Patel, Sonam; Balakrishnan, Suresh

    2016-04-01

    The tail fin of teleost fish responds to amputation by expressing few putative factors that promote scar-free wound healing, which paves the way for restoration of the lost part. Among the factors playing a role in this initial response, bone morphogenetic proteins (BMPs) are crucial. In the current study, we have analyzed the effect of BMP inhibition on wound healing in sailfin molly Poecilia latipinna. The study involved histological assessment of wound epithelium formation, an expression profile of proteins, and gelatinase activity as well as expression in response to BMP signal inhibition. LDN193189, a pharmacological inhibitor of BMP receptor, was administered to experimental fish. Our observations include incomplete wound healing and a significant reduction in the expression of a number of proteins as a result of LDN treatment at 24 h post-amputation. A pronounced effect was also seen on the gelatinases MMP-9 and MMP-2, which showed significantly reduced activities on a zymogram. Reduced expression of these MMPs after inhibitor treatment was also confirmed by western blot and real-time PCR analyses. In view of these results, we confirm that BMP signaling has a definitive role in the early stages of fin regeneration in P. latipinna. The effect of BMP inhibition is especially seen on the expression of MMP-9 and MMP-2, which are very important effectors of tissue remodeling immediately following amputation.

  6. Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna.

    PubMed

    Rajaram, Shailja; Murawala, Hiral; Buch, Pranav; Patel, Sonam; Balakrishnan, Suresh

    2016-04-01

    The tail fin of teleost fish responds to amputation by expressing few putative factors that promote scar-free wound healing, which paves the way for restoration of the lost part. Among the factors playing a role in this initial response, bone morphogenetic proteins (BMPs) are crucial. In the current study, we have analyzed the effect of BMP inhibition on wound healing in sailfin molly Poecilia latipinna. The study involved histological assessment of wound epithelium formation, an expression profile of proteins, and gelatinase activity as well as expression in response to BMP signal inhibition. LDN193189, a pharmacological inhibitor of BMP receptor, was administered to experimental fish. Our observations include incomplete wound healing and a significant reduction in the expression of a number of proteins as a result of LDN treatment at 24 h post-amputation. A pronounced effect was also seen on the gelatinases MMP-9 and MMP-2, which showed significantly reduced activities on a zymogram. Reduced expression of these MMPs after inhibitor treatment was also confirmed by western blot and real-time PCR analyses. In view of these results, we confirm that BMP signaling has a definitive role in the early stages of fin regeneration in P. latipinna. The effect of BMP inhibition is especially seen on the expression of MMP-9 and MMP-2, which are very important effectors of tissue remodeling immediately following amputation. PMID:26614502

  7. Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction.

    PubMed

    Mohammad, Ghulam; Kowluru, Renu A

    2010-09-01

    In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional resulting in accelerated apoptosis of its capillary cells. Matrix metalloproteinase-2 (MMP2) is considered critical in cell integrity and cell survival, and diabetes activates MMP2 in the retina and its capillary cells. This study aims at elucidating the mechanism by which MMP2 contributes to the development of diabetic retinopathy. Using isolated bovine retinal endothelial cells, the effect of regulation of MMP2 (by its siRNA and pharmacological inhibitor) on superoxide accumulation and mitochondrial dysfunction was evaluated. The effect of inhibiting diabetes-induced retinal superoxide accumulation on MMP2 and its regulators was investigated in diabetic mice overexpressing mitochondrial superoxide dismutase (MnSOD). Inhibition of MMP2 ameliorated glucose-induced increase in mitochondrial superoxide and membrane permeability, prevented cytochrome c leakage from the mitochondria, and inhibited capillary cell apoptosis. Overexpression of MnSOD protected the retina from diabetes-induced increase in MMP2 and its membrane activator (MT1-MMP), and decrease in its tissue inhibitor (TIMP-2). These results implicate that, in diabetes, MMP2 activates apoptosis of retinal capillary cells by mitochondrial dysfunction increasing their membrane permeability. Understanding the role of MMP2 in the pathogenesis of diabetic retinopathy should help lay ground for MMP2-targeted therapy to retard the development of retinopathy in diabetic patients.

  8. Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells.

    PubMed

    Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G

    2000-10-31

    We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.

  9. Associations of MMP-2, BAX, and Bcl-2 mRNA and Protein Expressions with Development of Atrial Fibrillation

    PubMed Central

    Diao, Shu-Ling; Xu, Hui-Pu; Zhang, Bei; Ma, Bao-Xin; Liu, Xian-Liang

    2016-01-01

    Background To examine changes of mRNA and protein expressions of MMP-2, Bcl-2, and BAX in atrial fibrillation (AF) patients, and investigate the correlations among these 3 biomarkers. Material/Methods Rheumatic heart disease patients (n=158) undergoing cardiac surgical procedures for mitral valve repair or replacement were included as the AF group (n=123), containing paroxysmal AF (n=42), persistent AF (n=36), and permanent AF (n=45). Rheumatic heart disease patients with sinus rhythm (SR) (n=35) were enrolled as the SR group (control group). Immunohistochemistry, Western blot, and real-time polymerase chain reaction (PCR) were applied to detect the protein and mRNA expression levels of MMP-2, Bcl-2, and BAX. Apoptosis was observed with light and electron microscopes and detected by TdT-mediated dUTP nick-end labeling (TUNEL). Results Compared with the SR group, the left atrial diameters (LADs), protein and mRNA expression levels of MMP-2 and BAX, apoptotic index (AI), and Bcl-2/BAX ratio were evidently increased in the 3 AF groups, but protein and mRNA expression levels of Bcl-2 decreased in the AF groups (all P<0.05). Correlation analysis found that MMP-2 protein expression levels was positively correlated with BAX expression, but negatively correlated with Bcl-2 expression levels. Conclusions Our study results suggest that elevated MMP-2 expression and disturbance balance of Bcl-2/BAX expressions may be associated with the development and maintenance of AF. MMP-2 may be involved in the development of AF through promoting BAX expressions and inhibiting Bcl-2. PMID:27141955

  10. Distribution and activity levels of matrix metalloproteinase 2 and 9 in canine and feline osteosarcoma.

    PubMed

    Gebhard, Christiane; Fuchs-Baumgartinger, Andrea; Razzazi-Fazeli, Ebrahim; Miller, Ingrid; Walter, Ingrid

    2016-01-01

    Overexpression of matrix metalloproteinases (MMPs) has been associated with increased tumor aggressiveness and metastasis dissemination. We investigated whether the contrasting metastatic behavior of feline and canine osteosarcoma is related to levels and activities of MMP2 and MMP9. Zymography and immunohistochemistry were used to determine expression levels of MMP2 and MMP9 in canine and feline osteosarcoma. Using immunohistochemistry, increased MMP9 levels were identified in most canine osteosarcomas, whereas cat samples more often displayed moderate levels. High levels of pro-MMP9, pro-MMP2, and active MMP2 were detected by gelatin zymography in both species, with significantly higher values for active MMP2 in canine osteosarcoma. These findings indicate that MMP2 is probably involved in canine and feline osteosarcoma and their expression and activity could be associated with the different metastatic behavior of canine and feline osteosarcoma. PMID:26733734

  11. Topical application of Gallic acid suppresses the 7,12-DMBA/Croton oil induced two-step skin carcinogenesis by modulating anti-oxidants and MMP-2/MMP-9 in Swiss albino mice.

    PubMed

    Subramanian, Vimala; Venkatesan, Balaji; Tumala, Anusha; Vellaichamy, Elangovan

    2014-04-01

    Gallic acid (GA - 3,4,5-trihydroxybenzoic acid), a dietary anti-oxidant has been shown to inhibit cancer cell growth in in vitro. Herein, we investigated the in vivo chemo preventive activity of GA on 7,12-Dimethylbenz[a]anthracene (DMBA)/Croton oil induced two-step skin carcinogenesis in Swiss albino mice. Skin tumor incidence and tumor volume were recorded during the 16 weeks of experimental period. In addition, LDH-isozyme shift, skin collagen content, activities of matrix metalloproteinases (MMP-2/MMP-9) enzymes and enzymatic and non-enzymatic antioxidant were studied in the skin and serum of experimental mice. Tumor incidence was significantly increased in the DMBA/Croton oil induced mice (100%; p<0.001) when compared to GA co-treated mice (60%; p<0.01) and 5-FU treated mice (50%; p<0.01). Skin collagen content, MMPs activities, LDH-isoenzymes and MMP-2/-9 expressions were increased in DMBA/Croton oil induced skin while decreased levels of enzymatic (GST, SOD, CAT & GPx) and non-enzymatic anti-oxidant (GSH) were noticed. On the other hand, GA co-treatment exhibited a significant protection by reverting back the altered levels of LDH-isoenzymes, antioxidants, collagen and MMP-2/MMP-9 activities. The results of this study indicate that topical application of GA inhibits DMBA/Croton oil induced two-stage skin carcinogenic process by modulating the antioxidants and MMPs (-2 & -9) in the mouse skin.

  12. Manifold regularized non-negative matrix factorization with label information

    NASA Astrophysics Data System (ADS)

    Li, Huirong; Zhang, Jiangshe; Wang, Changpeng; Liu, Junmin

    2016-03-01

    Non-negative matrix factorization (NMF) as a popular technique for finding parts-based, linear representations of non-negative data has been successfully applied in a wide range of applications, such as feature learning, dictionary learning, and dimensionality reduction. However, both the local manifold regularization of data and the discriminative information of the available label have not been taken into account together in NMF. We propose a new semisupervised matrix decomposition method, called manifold regularized non-negative matrix factorization (MRNMF) with label information, which incorporates the manifold regularization and the label information into the NMF to improve the performance of NMF in clustering tasks. We encode the local geometrical structure of the data space by constructing a nearest neighbor graph and enhance the discriminative ability of different classes by effectively using the label information. Experimental comparisons with the state-of-the-art methods on theCOIL20, PIE, Extended Yale B, and MNIST databases demonstrate the effectiveness of MRNMF.

  13. Medical image fusion based on non-negative matrix factorization

    NASA Astrophysics Data System (ADS)

    Zhang, Daoming; Zhang, Xianda

    2009-10-01

    Medical image fusion is a process of obtaining a new composite image from two or more source images which are from different modalities. In this paper, we proposed a novel medical image fusion scheme based on the non-negative matrix factorization (NMF) algorithm, the only resulted basis image is just the fused image. Since the CT and MRI images have a lot of pixels which are zeros, the NMF algorithm can not be employed directly. To overcome this difficulty, we first add a positive bias to the original data matrix and remove the bias from the resulted fusion image after the NMF procedure. The experiment results show that the proposed approach outperforms the existing wavelet-based methods and Laplacian pyramid-based methods.

  14. Regulation of Matrix Metalloproteinase Expression in Endothelial Cells by Heat-Inactivated Streptococcus pneumoniae

    PubMed Central

    Michel, Uwe; Zobotke, Rita; Mäder, Michael; Nau, Roland

    2001-01-01

    Matrix metalloproteinases (MMPs) may contribute to an impaired endothelial layer in several diseases. We examined the effect of heat-inactivated Streptococcus pneumoniae R6 on MMP-2 and MMP-9 release by cultured aortic and brain capillary endothelial cells. Treatment with heat-inactivated S. pneumoniae caused an increased release of MMP-2 by both cell types. PMID:11179373

  15. Increased expression of angiogenic factors in cultured human brain arteriovenous malformation endothelial cells.

    PubMed

    Xu, Ming; Xu, Hongzhi; Qin, Zhiyong; Zhang, Jie; Yang, Xiaoyu; Xu, Feng

    2014-09-01

    To compare the mRNA level of angiogenic factor vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2, and MMP-9 in cultured human brain arteriovenous malformation (AVM) endothelial cells (ECs) and normal brain endothelial cells (BECs). Tissue explants both from deformed vessels of AVM and normal microvessel were put into culture for endothelial cells. After the monolayer adherent ECs reached confluence, they were tested with endothelial specific marker CD34 and von Willebrand factor (vWF) by immunochemical assay. mRNA levels of VEGF-A, MMP-2, and MMP-9 in AVM endothelial cells (AVMECs) and BECs were measured by PCR. Immunostaining confirmed that more than 95 % of the cultured cells were CD34 (Fig. 1b) and/or vWF positive. Expression levels of VEGF-A and MMP-2 mRNAs were significantly higher in AVMECs than in BECs. The MMP-9 level was also increased in AVMECs, but the difference was not statistically significant. Vascular tissue explants adherent method is a better approach for isolation and culture of AVMECs. Cultured AVMECs expressed higher angiogenic factors (VEGF, MMP-2) than the controlled BECs, implicating angiogenesis plays an important role in the pathogenesis of AVM.

  16. Cross-talk between macrophages, smooth muscle cells, and endothelial cells in response to cigarette smoke: the effects on MMP2 and 9.

    PubMed

    Ghosh, Abhijit; Pechota, L V T Angela; Upchurch, Gilbert R; Eliason, Jonathan L

    2015-12-01

    We hypothesized that matrix metalloproteinase secretion in response to cigarette smoke is modulated by cross-talk between resident cells within the aorta, namely, aortic smooth muscles, endothelial cells, and infiltrating macrophages, and this may be crucial for in vivo formation/progression of abdominal aortic aneurysm (AAA). Cigarette smoke extract (CSE) was applied to rat aortic smooth muscle (RASMC), endothelial (RAEC) or RAW cells, and conditioned media (CSE-CM) collected. Fresh cells were treated with CSE-CM for 24 h and then maintained in serum-free medium (SFM) for 72 h to analyze MMP2 and MMP9 in media by zymography and the ratio (pS/pJ) of phospho-Stat3 (pStat3) and phospho-Jak2 (pJak2) inside the cells by Western blot. We observed that CSE-CM from RAW and RAEC increased MMP9 by 200 and 17 %, respectively, in RASMC and also increased pS/pJ ratio (305 and 228 %, respectively) in RASMC. RAW cell-derived CSE-CM induced RAEC to produce moderate amounts of MMP2 (17 %), MMP9 (30 %), and a 137 % increase in pS/pJ. RAW cells receiving unstimulated CM from RASMC and RAEC produced significant amounts of MMP9 (128 and 155 %, respectively) and increased pS/pJ (45 and 1283 %, respectively). CSE-CM from RASMC and RAEC induced significant production of MMP9 from RAW cells (237 and 162 %, respectively) and increase in pS/pJ ratios (1348 and 1494 %, respectively). This is the first in vitro study demonstrating cigarette smoke extract-mediated differential interactions between resident cells in the aorta leads to altered modulation of signaling molecules that may be vital for AAA formation under in vivo conditions.

  17. Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression.

    PubMed

    Zhang, Jian; Zhu, Xiaobing; Li, Hengyuan; Li, Binghao; Sun, Lingling; Xie, Tao; Zhu, Ting; Zhou, Hong; Ye, Zhaoming

    2015-01-01

    The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cells. Piperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cells. Piperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cells, via increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma. PMID:25479727

  18. Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression.

    PubMed

    Zhang, Jian; Zhu, Xiaobing; Li, Hengyuan; Li, Binghao; Sun, Lingling; Xie, Tao; Zhu, Ting; Zhou, Hong; Ye, Zhaoming

    2015-01-01

    The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cells. Piperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cells. Piperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cells, via increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma.

  19. Matrix Metalloproteinases Contribute to Neuronal Dysfunction in Animal Models of Drug Dependence, Alzheimer's Disease, and Epilepsy

    PubMed Central

    Mizoguchi, Hiroyuki; Yamada, Kiyofumi; Nabeshima, Toshitaka

    2011-01-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy. PMID:22235372

  20. LPS Induces Occludin Dysregulation in Cerebral Microvascular Endothelial Cells via MAPK Signaling and Augmenting MMP-2 Levels

    PubMed Central

    Qin, Lan-hui; Huang, Wen; Mo, Xue-an; Chen, Yan-lan; Wu, Xiang-hong

    2015-01-01

    Disrupted blood-brain barrier (BBB) integrity contributes to cerebral edema during central nervous system infection. The current study explored the mechanism of lipopolysaccharide- (LPS-) induced dysregulation of tight junction (TJ) proteins. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to LPS, SB203580 (p38MAPK inhibitor), or SP600125 (JNK inhibitor), and cell vitality was determined by MTT assay. The proteins expressions of p38MAPK, JNK, and TJs (occludin and zonula occludens- (ZO-) 1) were determined by western blot. The mRNA levels of TJ components and MMP-2 were measured with quantitative real-time polymerase chain reaction (qRT-PCR), and MMP-2 protein levels were determined by enzyme-linked immunosorbent assay (ELISA). LPS, SB203580, and SP600125 under respective concentrations of 10, 7.69, or 0.22 µg/mL had no effects on cell vitality. Treatment with LPS decreased mRNA and protein levels of occludin and ZO-1 and enhanced p38MAPK and JNK phosphorylation and MMP-2 expression. These effects were attenuated by pretreatment with SB203580 or SP600125, but not in ZO-1 expression. Both doxycycline hyclate (a total MMP inhibitor) and SB-3CT (a specific MMP-2 inhibitor) partially attenuated the LPS-induced downregulation of occludin. These data suggest that MMP-2 overexpression and p38MAPK/JNK pathways are involved in the LPS-mediated alterations of occludin in hCMEC/D3; however, ZO-1 levels are not influenced by p38MAPK/JNK. PMID:26290681

  1. The cloning and expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase 2 in normal canine lymph nodes and in canine lymphoma.

    PubMed

    Newman, R G; Kitchell, B E; Wallig, M A; Paria, B

    2008-04-01

    Matrix metalloproteinase-2 (MMP-2) and its inhibitor, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), are known to be important in cancer. The purposes of this study were to determine the cDNA sequence of canine MMP-2 and to investigate the expression patterns of MMP-2 and TIMP2 in normal canine lymph nodes and spontaneously arising canine lymphomas. We cloned and sequenced a PCR product containing most (1901 base pairs) of the coding sequence of canine MMP-2 that translates into a 623 amino acid protein. The cDNA and deduced amino acid sequences are highly homologous to those of other mammalian species. Canine MMP-2 and TIMP2 mRNAs were detectable in the majority of normal lymph node and lymphomatous samples evaluated. No statistical difference was identified when comparing the expression of either gene with regard to normal versus neoplastic nodes, nodal versus extranodal lymphoma, lymphoma grade, or B versus T cell immunophenotype. PMID:17604063

  2. Extracellular matrix and growth factors in corneal wound healing.

    PubMed

    Nishida, T; Tanaka, T

    1996-08-01

    The crystal clear cornea has been challenged by refractive surgeries. The surgical outcome depends on the healing responses of the cornea. The factors responsible for the corneal wound healing have been characterized. The orchestrated action of extracellular matrix proteins, growth factors, cytokines, and their receptors have been investigated extensively over the past decade. The clinical results with refractive surgeries provide us various important information with regard to the physiology and pathology of the cornea. The role of basement membrane or Bowman's membrane is now challenged for the maintenance and repair of the epithelium. Furthermore, the interactions between epithelium and stroma is another field to be investigated. The regulatory mechanisms of the maintenance of stromal collagen by keratocytes is also studied. This review discusses the current advancement in the healing responses of the cornea to various injuries and refractive surgeries.

  3. A fast algorithm for nonnegative matrix factorization and its convergence.

    PubMed

    Li, Li-Xin; Wu, Lin; Zhang, Hui-Sheng; Wu, Fang-Xiang

    2014-10-01

    Nonnegative matrix factorization (NMF) has recently become a very popular unsupervised learning method because of its representational properties of factors and simple multiplicative update algorithms for solving the NMF. However, for the common NMF approach of minimizing the Euclidean distance between approximate and true values, the convergence of multiplicative update algorithms has not been well resolved. This paper first discusses the convergence of existing multiplicative update algorithms. We then propose a new multiplicative update algorithm for minimizing the Euclidean distance between approximate and true values. Based on the optimization principle and the auxiliary function method, we prove that our new algorithm not only converges to a stationary point, but also does faster than existing ones. To verify our theoretical results, the experiments on three data sets have been conducted by comparing our proposed algorithm with other existing methods.

  4. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases

    PubMed Central

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  5. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases.

    PubMed

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  6. Identification of sources of Phoenix aerosol by positive matrix factorization.

    PubMed

    Ramadan, Z; Song, X H; Hopke, P K

    2000-08-01

    Chemical composition data for fine and coarse particles collected in Phoenix, AZ, were analyzed using positive matrix factorization (PMF). The objective was to identify the possible aerosol sources at the sampling site. PMF uses estimates of the error in the data to provide optimum data point scaling and permits a better treatment of missing and below-detection-limit values. It also applies nonnegativity constraints to the factors. Two sets of fine particle samples were collected by different samplers. Each of the resulting fine particle data sets was analyzed separately. For each fine particle data set, eight factors were obtained, identified as (1) biomass burning characterized by high concentrations of organic carbon (OC), elemental carbon (EC), and K; (2) wood burning with high concentrations of Na, K, OC, and EC; (3) motor vehicles with high concentrations of OC and EC; (4) nonferrous smelting process characterized by Cu, Zn, As, and Pb; (5) heavy-duty diesel characterized by high EC, OC, and Mn; (6) sea-salt factor dominated by Na and Cl; (7) soil with high values for Al, Si, Ca, Ti, and Fe; and (8) secondary aerosol with SO4(-2) and OC that may represent coal-fired power plant emissions. For the coarse particle samples, a five-factor model gave source profiles that are attributed to be (1) sea salt, (2) soil, (3) Fe source/motor vehicle, (4) construction (high Ca), and (5) coal-fired power plant. Regression of the PM mass against the factor scores was performed to estimate the mass contributions of the resolved sources. The major sources for the fine particles were motor vehicles, vegetation burning factors (biomass and wood burning), and coal-fired power plants. These sources contributed most of the fine aerosol mass by emitting carbonaceous particles, and they have higher contributions in winter. For the coarse particles, the major source contributions were soil and construction (high Ca). These sources also peaked in winter.

  7. Matrix metalloproteinases-2/9-sensitive peptide-conjugated polymer micelles for site-specific release of drugs and enhancing tumor accumulation: preparation and in vitro and in vivo evaluation

    PubMed Central

    Zhang, Xiaoyan; Wang, Xiaofei; Zhong, Weitong; Ren, Xiaoqing; Sha, Xianyi; Fang, Xiaoling

    2016-01-01

    Since elevated expression of matrix metalloproteinase (MMP)-2 and MMP-9 is commonly observed in several malignant tumors, MMPs have been widely reported as key factors in the design of drug delivery systems. Several strategies have been proposed to develop MMPs-responsive nanoparticles to deliver chemotherapeutics to malignant solid tumors. A stimuli-responsive drug delivery system, which could be cleaved by MMPs, was proposed in this study. By inserting an MMP-2/9 cleavable oligopeptide GPVGLIGK-NH2 (GK8) as spacer between α-tocopherol succinate (α-TOS) and methoxy-polyethylene glycol molecular weight (MW 2000 Da) activated by N-hydroxysuccinimide (mPEG2K-NHS), mPEG2K-GK8-α-TOS (TGK) was synthesized as the primary ingredient for MMP-2/9-sensitive micelles composed of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and TGK (n:n =40:60, TGK micelles). mPEG2K-α-TOS (T2K) was similarly synthesized as nonsensitive control. The TGK micelles showed better stability than nonsensitive micelles composed of TPGS and T2K (n:n =40:60, T2K micelles) owing to the inserted peptide. Fluorescence resonance energy transfer results indicated that TGK micelles could be successfully cleaved by MMP-2/9. Effective drug release was demonstrated in the presence of collagenase type IV, a mixture of MMP-2 and MMP-9. Compared with nonsensitive micelles, docetaxel (DTX)-loaded TGK micelles showed a fold higher cellular uptake in HT1080 cells. While the half-maximal inhibitory concentration (IC50) of TGK and T2K micelles were similar (P>0.05) in MCF-7 cells (MMP-2/9 underexpression), the IC50 values of the aforementioned micelles were 0.064±0.006 and 0.122±0.009 μg/mL, respectively, in HT1080 cells (MMP-2/9 overexpression). The MMP-2/9-sensitive micelles also demonstrated desired tumor targeting and accumulation ability in vivo. The results of in vivo antitumor effect evaluation indicate that TGK micelles are potent against solid tumors while maintaining minimum systemic

  8. Source identifications of airborne fine particles using positive matrix factorization and U.S. Environmental Protection Agency positive matrix factorization.

    PubMed

    Kim, Eugene; Hopke, Philip K

    2007-07-01

    The widely used source apportionment model, positive matrix factorization (PMF2), has been applied to various air pollution data. Recently, U.S. Environmental Protection Agency (EPA) developed EPA positive matrix factorization (PMF), a version of PMF that will be freely distributed by EPA. The objectives of this study were to conduct source apportionment studies for particulate matter less than 2.5 microm in aerodynamic diameter (PM(2.5)) speciation data using PMF2 and EPA PMF (version 1.1) and to compare identified sources between the two models. In the present study, ambient PM(2.5) compositional datasets of 24-hr integrated samples collected at EPA Speciation Trends Network monitoring sites in Chicago, IL, and Portland, OR, were analyzed. Both PMF2 and EPA PMF extracted eight sources for the Chicago data and 10 sources for the Portland data. The model-resolved source profiles were similar between two models for both datasets. However, in several sources, the average contributions did not agree well and the time series contributions were not highly correlated. The differences between PMF2 and EPA PMF solutions were caused by the different least-square algorithm and the different nonnegativity constraints. Most of the average source contributions resolved by both models were within 5-95% uncertainty provided by EPA PMF, indicating that the sources resolved by both models were reproducible.

  9. Sparse Nonnegative Matrix Factorization Strategy for Cochlear Implants.

    PubMed

    Hu, Hongmei; Lutman, Mark E; Ewert, Stephan D; Li, Guoping; Bleeck, Stefan

    2015-01-01

    Current cochlear implant (CI) strategies carry speech information via the waveform envelope in frequency subbands. CIs require efficient speech processing to maximize information transfer to the brain, especially in background noise, where the speech envelope is not robust to noise interference. In such conditions, the envelope, after decomposition into frequency bands, may be enhanced by sparse transformations, such as nonnegative matrix factorization (NMF). Here, a novel CI processing algorithm is described, which works by applying NMF to the envelope matrix (envelopogram) of 22 frequency channels in order to improve performance in noisy environments. It is evaluated for speech in eight-talker babble noise. The critical sparsity constraint parameter was first tuned using objective measures and then evaluated with subjective speech perception experiments for both normal hearing and CI subjects. Results from vocoder simulations with 10 normal hearing subjects showed that the algorithm significantly enhances speech intelligibility with the selected sparsity constraints. Results from eight CI subjects showed no significant overall improvement compared with the standard advanced combination encoder algorithm, but a trend toward improvement of word identification of about 10 percentage points at +15 dB signal-to-noise ratio (SNR) was observed in the eight CI subjects. Additionally, a considerable reduction of the spread of speech perception performance from 40% to 93% for advanced combination encoder to 80% to 100% for the suggested NMF coding strategy was observed. PMID:26721919

  10. Sparse Nonnegative Matrix Factorization Strategy for Cochlear Implants

    PubMed Central

    Lutman, Mark E.; Ewert, Stephan D.; Li, Guoping; Bleeck, Stefan

    2015-01-01

    Current cochlear implant (CI) strategies carry speech information via the waveform envelope in frequency subbands. CIs require efficient speech processing to maximize information transfer to the brain, especially in background noise, where the speech envelope is not robust to noise interference. In such conditions, the envelope, after decomposition into frequency bands, may be enhanced by sparse transformations, such as nonnegative matrix factorization (NMF). Here, a novel CI processing algorithm is described, which works by applying NMF to the envelope matrix (envelopogram) of 22 frequency channels in order to improve performance in noisy environments. It is evaluated for speech in eight-talker babble noise. The critical sparsity constraint parameter was first tuned using objective measures and then evaluated with subjective speech perception experiments for both normal hearing and CI subjects. Results from vocoder simulations with 10 normal hearing subjects showed that the algorithm significantly enhances speech intelligibility with the selected sparsity constraints. Results from eight CI subjects showed no significant overall improvement compared with the standard advanced combination encoder algorithm, but a trend toward improvement of word identification of about 10 percentage points at +15 dB signal-to-noise ratio (SNR) was observed in the eight CI subjects. Additionally, a considerable reduction of the spread of speech perception performance from 40% to 93% for advanced combination encoder to 80% to 100% for the suggested NMF coding strategy was observed. PMID:26721919

  11. Sparse Nonnegative Matrix Factorization Strategy for Cochlear Implants.

    PubMed

    Hu, Hongmei; Lutman, Mark E; Ewert, Stephan D; Li, Guoping; Bleeck, Stefan

    2015-12-30

    Current cochlear implant (CI) strategies carry speech information via the waveform envelope in frequency subbands. CIs require efficient speech processing to maximize information transfer to the brain, especially in background noise, where the speech envelope is not robust to noise interference. In such conditions, the envelope, after decomposition into frequency bands, may be enhanced by sparse transformations, such as nonnegative matrix factorization (NMF). Here, a novel CI processing algorithm is described, which works by applying NMF to the envelope matrix (envelopogram) of 22 frequency channels in order to improve performance in noisy environments. It is evaluated for speech in eight-talker babble noise. The critical sparsity constraint parameter was first tuned using objective measures and then evaluated with subjective speech perception experiments for both normal hearing and CI subjects. Results from vocoder simulations with 10 normal hearing subjects showed that the algorithm significantly enhances speech intelligibility with the selected sparsity constraints. Results from eight CI subjects showed no significant overall improvement compared with the standard advanced combination encoder algorithm, but a trend toward improvement of word identification of about 10 percentage points at +15 dB signal-to-noise ratio (SNR) was observed in the eight CI subjects. Additionally, a considerable reduction of the spread of speech perception performance from 40% to 93% for advanced combination encoder to 80% to 100% for the suggested NMF coding strategy was observed.

  12. Differential Expression of Matrix Metalloproteinase-2 Expression in Disseminated Tumor Cells and Micrometastasis in Bone Marrow of Patients with Nonmetastatic and Metastatic Prostate Cancer: Theoretical Considerations and Clinical Implications—An Immunocytochemical Study

    PubMed Central

    Murray, Nigel P.; Reyes, Eduardo; Tapia, Pablo; Badínez, Leonardo; Orellana, Nelson

    2012-01-01

    Matrix metalloproteinase-2 (MMP-2) is important in the dissemination and invasion of tumor cells and activates angiogenesis. We present an immunocytochemical study of MMP-2 expression in circulating prostate cells (CPCs), disseminated tumor cells (DTCs), and micrometastasis (mM) in bone marrow of men with prostate cancer. Methods and Patients. Tumor cells were identified with anti-PSA immunocytochemistry. Positive samples underwent processing with anti-MMP-2, its expression was compared with Gleason score, concordance of expression, and metastatic and nonmetastatic disease. Results. 215 men participated, CPCs were detected in 62.7%, DTCs in 62.2%, and mM in 71.4% in nonmetastatic cancer; in metastatic cancer all had CPCs, DTCs, and mM detected. All CPCs and DTCs expressed MMP-2; in mM MMP-2 expression was positively associated with increasing Gleason score. MMP-2 expression in CPCs and DTCs showed concordance. In low grade tumors, mM and surrounding stromal cells were MMP-2 negative, with variable expression in high grade tumors; in metastatic disease, both mM and stromal cells were MMP-2 positive. Conclusions. CPCs and DTCs are different from mM, with inhibition of MMP-2 expression in mM of low grade tumors. With disease progression, MMP-2 expression increases in both mM and surrounding stromal cells, with implications for the use of bisphosphonates or MMP-2 inhibitors. PMID:23227342

  13. Efficient multitasking of Choleski matrix factorization on CRAY supercomputers

    NASA Technical Reports Server (NTRS)

    Overman, Andrea L.; Poole, Eugene L.

    1991-01-01

    A Choleski method is described and used to solve linear systems of equations that arise in large scale structural analysis. The method uses a novel variable-band storage scheme and is structured to exploit fast local memory caches while minimizing data access delays between main memory and vector registers. Several parallel implementations of this method are described for the CRAY-2 and CRAY Y-MP computers demonstrating the use of microtasking and autotasking directives. A portable parallel language, FORCE, is used for comparison with the microtasked and autotasked implementations. Results are presented comparing the matrix factorization times for three representative structural analysis problems from runs made in both dedicated and multi-user modes on both computers. CPU and wall clock timings are given for the parallel implementations and are compared to single processor timings of the same algorithm.

  14. Symmetric nonnegative matrix factorization: algorithms and applications to probabilistic clustering.

    PubMed

    He, Zhaoshui; Xie, Shengli; Zdunek, Rafal; Zhou, Guoxu; Cichocki, Andrzej

    2011-12-01

    Nonnegative matrix factorization (NMF) is an unsupervised learning method useful in various applications including image processing and semantic analysis of documents. This paper focuses on symmetric NMF (SNMF), which is a special case of NMF decomposition. Three parallel multiplicative update algorithms using level 3 basic linear algebra subprograms directly are developed for this problem. First, by minimizing the Euclidean distance, a multiplicative update algorithm is proposed, and its convergence under mild conditions is proved. Based on it, we further propose another two fast parallel methods: α-SNMF and β -SNMF algorithms. All of them are easy to implement. These algorithms are applied to probabilistic clustering. We demonstrate their effectiveness for facial image clustering, document categorization, and pattern clustering in gene expression.

  15. Neutrophil activator of matrix metalloproteinase-2 (NAM).

    PubMed

    Rollo, Ellen E; Hymowitz, Michelle; Schmidt, Cathleen E; Montana, Steve; Foda, Hussein; Zucker, Stanley

    2006-01-01

    We have isolated a novel soluble factor(s), neutrophil activator of matrix metalloproteinases (NAM), secreted by unstimulated normal human peripheral blood neutrophils that causes the activation of cell secreted promatrix metalloproteinase-2 (proMMP-2). Partially purified preparations of NAM have been isolated from the conditioned media of neutrophils employing gelatin-Sepharose chromatography and differential membrane filter centrifugation. NAM activity, as assessed by exposing primary human umbilical vein endothelial cells (HUVEC) or HT1080 cells to NAM followed by gelatin zymography, was seen within one hour. Tissue inhibitor of metalloproteinase-2 (TIMP-2) and hydroxamic acid derived inhibitors of MMPs (CT1746 and BB94) abrogated the activation of proMMP-2 by NAM, while inhibitors of serine and cysteine proteases showed no effect. NAM also produced an increase in TIMP-2 binding to HUVEC and HT1080 cell surfaces that was inhibited by TIMP-2, CT1746, and BB94. Time-dependent increases in MT1-MMP protein and mRNA were seen following the addition of NAM to cells. These data support a role for NAM in cancer dissemination.

  16. Immunohistochemical analysis of MMP-9, MMP-2 and TIMP-1, TIMP-2 expression in the central nervous system following infection with viral and bacterial meningitis.

    PubMed

    Sulik, Artur; Chyczewski, Lech

    2008-01-01

    Matrix metalloproteinases (MMPs) are capable of degrading components of the basal lamina of cerebral vessels, thereby disrupting the blood-brain barrier and inducing leukocyte recruitment. This study provides comprehensive information regarding the cell specificity of matrix metalloproteinases (MMP-2, MMP-9) and their binding tissue inhibitors (TIMP-1, TIMP-2) in the central nervous system during viral and bacterial meningitis. Specifically, we evaluated the immunoreactivity of MMPs and TIMPs in various cell types in brain parenchyma and meninges obtained from autopsy tissues. We found that a higher proportion of endothelial cells were positive for MMP-9 during meningitis when compared to controls. In addition, the immunoreactivity of MMP-9 decreased and the immunoreactivity of TIMP-1 increased in astrocytes upon infection. Furthermore, the results of this study revealed that mononuclear cells were highly immunoreactive for TIMP-1, TIMP-2 and MMP-9 during viral meningitis and that the expression of TIMPs in polymorphonuclear cells was even higher during bacterial meningitis. Taken together the results of this study indicated that the central nervous system resident cells and inflammatory infiltrates contribute to MMPs activity and that the expression patterns vary between cell types and in response to viral and bacterial meningitis.

  17. Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways.

    PubMed

    Qian, Liqiang; Liu, Yan; Xu, Yang; Ji, Weidan; Wu, Qiuye; Liu, Yongjing; Gao, Quangen; Su, Changqing

    2015-11-01

    Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo, and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment.

  18. Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways.

    PubMed

    Qian, Liqiang; Liu, Yan; Xu, Yang; Ji, Weidan; Wu, Qiuye; Liu, Yongjing; Gao, Quangen; Su, Changqing

    2015-11-01

    Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo, and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment. PMID:26259512

  19. EPA Positive Matrix Factorization (PMF) 3.0 Fundamentals & User Guide

    EPA Science Inventory

    Positive matrix factorization (PMF) is a multivariate factor analysis tool that decomposes a matrix of ambient data into two matrices - factor contributions and factor profiles - which then need to be interpreted by an analyst as to what source types are represented using measure...

  20. Efficient Nonnegative Matrix Factorization by DC Programming and DCA.

    PubMed

    Le Thi, Hoai An; Vo, Xuan Thanh; Dinh, Tao Pham

    2016-06-01

    In this letter, we consider the nonnegative matrix factorization (NMF) problem and several NMF variants. Two approaches based on DC (difference of convex functions) programming and DCA (DC algorithm) are developed. The first approach follows the alternating framework that requires solving, at each iteration, two nonnegativity-constrained least squares subproblems for which DCA-based schemes are investigated. The convergence property of the proposed algorithm is carefully studied. We show that with suitable DC decompositions, our algorithm generates most of the standard methods for the NMF problem. The second approach directly applies DCA on the whole NMF problem. Two algorithms-one computing all variables and one deploying a variable selection strategy-are proposed. The proposed methods are then adapted to solve various NMF variants, including the nonnegative factorization, the smooth regularization NMF, the sparse regularization NMF, the multilayer NMF, the convex/convex-hull NMF, and the symmetric NMF. We also show that our algorithms include several existing methods for these NMF variants as special versions. The efficiency of the proposed approaches is empirically demonstrated on both real-world and synthetic data sets. It turns out that our algorithms compete favorably with five state-of-the-art alternating nonnegative least squares algorithms. PMID:27136704

  1. Identifying Dust Sources by Positive Matrix Factorization (PMF)

    NASA Astrophysics Data System (ADS)

    Engelbrecht, Johann P.

    2010-05-01

    This presentation is on the source attribution by Positive Matrix Factorization (PMF) of aerosol samples collected in Iraq, a major source of mineral dust in the Middle East. Globally transported mineral dust from North Africa, the Middle East, China, and elsewhere are routinely being sampled at high elevation monitoring sites such as those on the Canary Islands and Hawaii, and many ambient monitoring sites worldwide. Chemical results of these filter samples reflect differences in sources impacting at each site, further complicated by the regional geomorphology and meteorology. Trace elements, isotopes, elemental ratios, and mineralogy are generally being used to pinpoint geological source regions of natural and anthropogenic dusts. A receptor site is seldom impacted by only one source at a time. Dust palls are continually being modified by added dust from soils across which they migrate, also by particle segregation in the dust plume, and precipitation of the coarser particles. The result is that dust is a mixture, with contributions from different sources, each with a different chemical and mineralogical signature. PMF is a non-negative factorization procedure that produces only positive factor scores and loadings, in contrast to classical factor analysis (FA) and Principal Components Analysis (PCA). PMF enables us to resolve factors (chemical signatures) for source types contributing to the ambient chemical data set, and also models the source-type contributions to individual ambient samples. The latter can often be related to specific source regions. PMF was applied separately to two ambient data sets collected in Iraq in 2006, the one on Teflon membrane filters and the other on quartz fiber. Each of the filter types were previously analyzed for different chemical species: Teflon membrane for elements, by XRF and ICP-MS, while quartz fiber filters were analyzed for ions and carbon. [Engelbrecht et al. 2009] A set of 392 Teflon filter samples analyzed for 25

  2. Online nonnegative matrix factorization with robust stochastic approximation.

    PubMed

    Guan, Naiyang; Tao, Dacheng; Luo, Zhigang; Yuan, Bo

    2012-07-01

    Nonnegative matrix factorization (NMF) has become a popular dimension-reduction method and has been widely applied to image processing and pattern recognition problems. However, conventional NMF learning methods require the entire dataset to reside in the memory and thus cannot be applied to large-scale or streaming datasets. In this paper, we propose an efficient online RSA-NMF algorithm (OR-NMF) that learns NMF in an incremental fashion and thus solves this problem. In particular, OR-NMF receives one sample or a chunk of samples per step and updates the bases via robust stochastic approximation. Benefitting from the smartly chosen learning rate and averaging technique, OR-NMF converges at the rate of in each update of the bases. Furthermore, we prove that OR-NMF almost surely converges to a local optimal solution by using the quasi-martingale. By using a buffering strategy, we keep both the time and space complexities of one step of the OR-NMF constant and make OR-NMF suitable for large-scale or streaming datasets. Preliminary experimental results on real-world datasets show that OR-NMF outperforms the existing online NMF (ONMF) algorithms in terms of efficiency. Experimental results of face recognition and image annotation on public datasets confirm the effectiveness of OR-NMF compared with the existing ONMF algorithms.

  3. Predicting Drug–Target Interactions Using Probabilistic Matrix Factorization

    PubMed Central

    2013-01-01

    Quantitative analysis of known drug–target interactions emerged in recent years as a useful approach for drug repurposing and assessing side effects. In the present study, we present a method that uses probabilistic matrix factorization (PMF) for this purpose, which is particularly useful for analyzing large interaction networks. DrugBank drugs clustered based on PMF latent variables show phenotypic similarity even in the absence of 3D shape similarity. Benchmarking computations show that the method outperforms those recently introduced provided that the input data set of known interactions is sufficiently large—which is the case for enzymes and ion channels, but not for G-protein coupled receptors (GPCRs) and nuclear receptors. Runs performed on DrugBank after hiding 70% of known interactions show that, on average, 88 of the top 100 predictions hit the hidden interactions. De novo predictions permit us to identify new potential interactions. Drug–target pairs implicated in neurobiological disorders are overrepresented among de novo predictions. PMID:24289468

  4. Online nonnegative matrix factorization with robust stochastic approximation.

    PubMed

    Guan, Naiyang; Tao, Dacheng; Luo, Zhigang; Yuan, Bo

    2012-07-01

    Nonnegative matrix factorization (NMF) has become a popular dimension-reduction method and has been widely applied to image processing and pattern recognition problems. However, conventional NMF learning methods require the entire dataset to reside in the memory and thus cannot be applied to large-scale or streaming datasets. In this paper, we propose an efficient online RSA-NMF algorithm (OR-NMF) that learns NMF in an incremental fashion and thus solves this problem. In particular, OR-NMF receives one sample or a chunk of samples per step and updates the bases via robust stochastic approximation. Benefitting from the smartly chosen learning rate and averaging technique, OR-NMF converges at the rate of in each update of the bases. Furthermore, we prove that OR-NMF almost surely converges to a local optimal solution by using the quasi-martingale. By using a buffering strategy, we keep both the time and space complexities of one step of the OR-NMF constant and make OR-NMF suitable for large-scale or streaming datasets. Preliminary experimental results on real-world datasets show that OR-NMF outperforms the existing online NMF (ONMF) algorithms in terms of efficiency. Experimental results of face recognition and image annotation on public datasets confirm the effectiveness of OR-NMF compared with the existing ONMF algorithms. PMID:24807135

  5. Wavelet Speech Enhancement Based on Nonnegative Matrix Factorization

    NASA Astrophysics Data System (ADS)

    Wang, Syu-Siang; Chern, Alan; Tsao, Yu; Hung, Jeih-weih; Lu, Xugang; Lai, Ying-Hui; Su, Borching

    2016-08-01

    For most of the state-of-the-art speech enhancement techniques, a spectrogram is usually preferred than the respective time-domain raw data since it reveals more compact presentation together with conspicuous temporal information over a long time span. However, the short-time Fourier transform (STFT) that creates the spectrogram in general distorts the original signal and thereby limits the capability of the associated speech enhancement techniques. In this study, we propose a novel speech enhancement method that adopts the algorithms of discrete wavelet packet transform (DWPT) and nonnegative matrix factorization (NMF) in order to conquer the aforementioned limitation. In brief, the DWPT is first applied to split a time-domain speech signal into a series of subband signals without introducing any distortion. Then we exploit NMF to highlight the speech component for each subband. Finally, the enhanced subband signals are joined together via the inverse DWPT to reconstruct a noise-reduced signal in time domain. We evaluate the proposed DWPT-NMF based speech enhancement method on the MHINT task. Experimental results show that this new method behaves very well in prompting speech quality and intelligibility and it outperforms the convnenitional STFT-NMF based method.

  6. Nonnegative Matrix Factorization for Efficient Hyperspectral Image Projection

    NASA Technical Reports Server (NTRS)

    Iacchetta, Alexander S.; Fienup, James R.; Leisawitz, David T.; Bolcar, Matthew R.

    2015-01-01

    Hyperspectral imaging for remote sensing has prompted development of hyperspectral image projectors that can be used to characterize hyperspectral imaging cameras and techniques in the lab. One such emerging astronomical hyperspectral imaging technique is wide-field double-Fourier interferometry. NASA's current, state-of-the-art, Wide-field Imaging Interferometry Testbed (WIIT) uses a Calibrated Hyperspectral Image Projector (CHIP) to generate test scenes and provide a more complete understanding of wide-field double-Fourier interferometry. Given enough time, the CHIP is capable of projecting scenes with astronomically realistic spatial and spectral complexity. However, this would require a very lengthy data collection process. For accurate but time-efficient projection of complicated hyperspectral images with the CHIP, the field must be decomposed both spectrally and spatially in a way that provides a favorable trade-off between accurately projecting the hyperspectral image and the time required for data collection. We apply nonnegative matrix factorization (NMF) to decompose hyperspectral astronomical datacubes into eigenspectra and eigenimages that allow time-efficient projection with the CHIP. Included is a brief analysis of NMF parameters that affect accuracy, including the number of eigenspectra and eigenimages used to approximate the hyperspectral image to be projected. For the chosen field, the normalized mean squared synthesis error is under 0.01 with just 8 eigenspectra. NMF of hyperspectral astronomical fields better utilizes the CHIP's capabilities, providing time-efficient and accurate representations of astronomical scenes to be imaged with the WIIT.

  7. Link community detection using generative model and nonnegative matrix factorization.

    PubMed

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities.

  8. Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation. Correlation with ischaemic events.

    PubMed

    Lenti, Massimo; Falcinelli, Emanuela; Pompili, Marcella; de Rango, Paola; Conti, Valentina; Guglielmini, Giuseppe; Momi, Stefania; Corazzi, Teresa; Giordano, Giuseppe; Gresele, Paolo

    2014-06-01

    Purified active matrix metalloproteinase-2 (MMP-2) is able to promote platelet aggregation. We aimed to assess the role of MMP-2 expressed in atherosclerotic plaques in the platelet-activating potential of human carotid plaques and its correlation with ischaemic events. Carotid plaques from 81 patients undergoing endarterectomy were tested for pro-MMP-2 and TIMP-2 content by zymography and ELISA. Plaque extracts were incubated with gel-filtered platelets from healthy volunteers for 2 minutes before the addition of a subthreshold concentration of thrombin receptor activating peptide-6 (TRAP-6) and aggregation was assessed. Moreover, platelet deposition on plaque extracts immobilised on plastic coverslips under high shear-rate flow conditions was measured. Forty-three plaque extracts (53%) potentiated platelet aggregation (+233 ± 26.8%), an effect prevented by three different specific MMP-2 inhibitors (inhibitor II, TIMP-2, moAb anti-MMP-2). The pro-MMP-2/TIMP-2 ratio of plaques potentiating platelet aggregation was significantly higher than that of plaques not potentiating it (3.67 ± 1.21 vs 1.01 ± 0.43, p<0.05). Moreover, the platelet aggregation-potentiating effect, the active-MMP-2 content and the active MMP-2/pro-MMP-2 ratio of plaque extracts were significantly higher in plaques from patients who developed a subsequent major cardiovascular event. In conclusion, atherosclerotic plaques exert a prothrombotic effect by potentiating platelet activation due to their content of MMP-2; an elevated MMP-2 activity in plaques is associated with a higher rate of subsequent ischaemic cerebrovascular events. PMID:24499865

  9. Prognostic significance of matrix metalloproteinases 2 and 9 in endometrial cancer.

    PubMed

    Puljiz, Mario; Puljiz, Zeljko; Vucemilo, Tiha; Ramić, Snjezana; Knezević, Fabijan; Culo, Branimir; Alvir, Ilija; Tomica, Darko; Danolić, Damir

    2012-12-01

    We investigated the prognostic significance of matrix metalloproteinases 2 (MMP 2) and 9 (MMP 9) in endometrial cancer (EC). The expression of MMP 2 and MMP 9 was analyzed immunohistochemically in 73 primary EC patients. In most cases, the gelatinases were predominantly localized to epithelial cell of tumor origin. In univariate analysis histological type, tumor grade, FIGO (1988) surgical stage and high stromal MMP 2 expression were identified as a significant determinant for EC recurrence, while epithelial MMP 2 expression and epithelial and stromal MMP 9 expression were not. Multivariate analysis revealed a subgroup of patient age > or = 63.6 years with endometrioid adenocarcinoma and papillary serous carcinoma, all FIGO (2009) stage I disease where strong staining of stromal MMP 2 increase risk of EC recurrence (p = 0.037).

  10. BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway

    PubMed Central

    WANG, YONG-HUI; SUI, XIAO-MEI; SUI, YA-NA; ZHU, QIN-WEI; YAN, KAI; WANG, LI-SHAN; WANG, FEI; ZHOU, JIA-HUA

    2015-01-01

    Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with poor prognosis, and HCC-associated mortality primarily occurs due to migration and invasion of HCC cells. The manipulation of epigenetic proteins, such as BRD4, has recently emerged as an alternative therapeutic strategy. The present study aimed to investigate the novel mechanism of BRD4 involvement in the migration and invasion of HCC cells. Reverse transcription-quantitative polymerase chain reaction was used to assess BRD4 mRNA expression levels in HCC cell lines. This analysis demonstrated that BRD4 was significantly overexpressed in HCC cell lines compared with a human immortalized normal liver cell line. A short hairpin RNA (shRNA) was then used to suppress BRD4 expression in HCC cells, and resulted in impaired HCC cell proliferation, migration and invasion. When the HepG2 HCC cell line was treated with recombinant human sonic hedgehog (SHH) peptide, the migration and invasion capabilities of HepG2 cells that were inhibited by BRD4 silencing were restored. BRD4 induced cell migration and invasion in HepG2 cells through the activation of matrix metalloproteinase (MMP)-2 and MMP-9, mediated by the SHH signaling pathway. Taken together, the results of the present study demonstrated the importance of BRD4 in HCC cell proliferation and metastasis. Thus, BRD4 is a potential novel target for the development of therapeutic approaches against HCC. PMID:26622824

  11. Angiogenic Type I Collagen Extracellular Matrix Integrated with Recombinant Bacteriophages Displaying Vascular Endothelial Growth Factors.

    PubMed

    Yoon, Junghyo; Korkmaz Zirpel, Nuriye; Park, Hyun-Ji; Han, Sewoon; Hwang, Kyung Hoon; Shin, Jisoo; Cho, Seung-Woo; Nam, Chang-Hoon; Chung, Seok

    2016-01-21

    Here, a growth-factor-integrated natural extracellular matrix of type I collagen is presented that induces angiogenesis. The developed matrix adapts type I collagen nanofibers integrated with synthetic colloidal particles of recombinant bacteriophages that display vascular endothelial growth factor (VEGF). The integration is achieved during or after gelation of the type I collagen and the matrix enables spatial delivery of VEGF into a desired region. Endothelial cells that contact the VEGF are found to invade into the matrix to form tube-like structures both in vitro and in vivo, proving the angiogenic potential of the matrix.

  12. Synthesis and discovery of (I-3,II-3)-biacacetin as a novel non-zinc binding inhibitor of MMP-2 and MMP-9.

    PubMed

    Nanjan, Pandurangan; Nambiar, Jyotsna; Nair, Bipin G; Banerji, Asoke

    2015-07-01

    Eleven biflavones (7a-b and 9a-i) were synthesised by a simple and efficient protocol and screened for MMP-2 and MMP-9 inhibitory activities. Amongst them, a natural product-like analog, (I-3,II-3)-biacacetin (9h) was found to be the most potent inhibitor. Molecular docking studies suggest that unlike most of the known inhibitors, 9h inhibits MMP-2 and MMP-9 through non-zinc binding interactions.

  13. Function of all-trans retinoic acid observation on similar myopia changes in cultivated rabbit retinal pigment epithelium and relation with myopia relevant factors.

    PubMed

    Xing, Bin

    2016-03-01

    To observe the role of all-trans retinoic acid (ATRA) during the similar myopia changes of cultured rabbit retinal pigment epithelium (RPE) cells, as well as the variation changes and relationships with myopic correlation factors such as hepatocyte growth factor (HGF) and matrix metalloprateinase-2 (MMP-2). Rabbit RPE cells of primary generation were selected and cultured to fifth generation by subculture. Then the morphology of RPE cells were observed and cell vitality was analyzed by using the Trypan blue reject test. The expressions of HGF and MMP-2 in RPE cells were tested by using an immunobistochemistry method. The HGF concentration in RPE cell culture fluid was detected by applying enzyme-linked immunosorbnent assay (ELISA). As the ATRA concentration enhanced and action time prolonged, the survival rate of RPE cells was reduced, but the expressions of HGF and MMP-2 increased, so did the secretion of HGF. ATRA concentration with no less than 5 nM/ml was able to induce the growth inhibition of RPE cells and the decrease in survival rate, which was similar to the changes in RPE cells in myopia. With the actin of ATRA, the expressions of HGF and MMP-2 increased in RPE cells, with more distinct in HGF increase.

  14. Function of all-trans retinoic acid observation on similar myopia changes in cultivated rabbit retinal pigment epithelium and relation with myopia relevant factors.

    PubMed

    Xing, Bin

    2016-03-01

    To observe the role of all-trans retinoic acid (ATRA) during the similar myopia changes of cultured rabbit retinal pigment epithelium (RPE) cells, as well as the variation changes and relationships with myopic correlation factors such as hepatocyte growth factor (HGF) and matrix metalloprateinase-2 (MMP-2). Rabbit RPE cells of primary generation were selected and cultured to fifth generation by subculture. Then the morphology of RPE cells were observed and cell vitality was analyzed by using the Trypan blue reject test. The expressions of HGF and MMP-2 in RPE cells were tested by using an immunobistochemistry method. The HGF concentration in RPE cell culture fluid was detected by applying enzyme-linked immunosorbnent assay (ELISA). As the ATRA concentration enhanced and action time prolonged, the survival rate of RPE cells was reduced, but the expressions of HGF and MMP-2 increased, so did the secretion of HGF. ATRA concentration with no less than 5 nM/ml was able to induce the growth inhibition of RPE cells and the decrease in survival rate, which was similar to the changes in RPE cells in myopia. With the actin of ATRA, the expressions of HGF and MMP-2 increased in RPE cells, with more distinct in HGF increase. PMID:27113312

  15. Fast iterative image reconstruction using sparse matrix factorization with GPU acceleration

    NASA Astrophysics Data System (ADS)

    Zhou, Jian; Qi, Jinyi

    2011-03-01

    Statistically based iterative approaches for image reconstruction have gained much attention in medical imaging. An accurate system matrix that defines the mapping from the image space to the data space is the key to high-resolution image reconstruction. However, an accurate system matrix is often associated with high computational cost and huge storage requirement. Here we present a method to address this problem by using sparse matrix factorization and parallel computing on a graphic processing unit (GPU).We factor the accurate system matrix into three sparse matrices: a sinogram blurring matrix, a geometric projection matrix, and an image blurring matrix. The sinogram blurring matrix models the detector response. The geometric projection matrix is based on a simple line integral model. The image blurring matrix is to compensate for the line-of-response (LOR) degradation due to the simplified geometric projection matrix. The geometric projection matrix is precomputed, while the sinogram and image blurring matrices are estimated by minimizing the difference between the factored system matrix and the original system matrix. The resulting factored system matrix has much less number of nonzero elements than the original system matrix and thus substantially reduces the storage and computation cost. The smaller size also allows an efficient implement of the forward and back projectors on GPUs, which have limited amount of memory. Our simulation studies show that the proposed method can dramatically reduce the computation cost of high-resolution iterative image reconstruction. The proposed technique is applicable to image reconstruction for different imaging modalities, including x-ray CT, PET, and SPECT.

  16. Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo

    PubMed Central

    Momi, Stefania; Falcinelli, Emanuela; Giannini, Silvia; Ruggeri, Loredana; Cecchetti, Luca; Corazzi, Teresa; Libert, Claude

    2009-01-01

    Platelet activation at a site of vascular injury is essential for the arrest of bleeding; however, excessive platelet activation at a site of arterial damage can result in the unwarranted formation of arterial thrombi, precipitating acute myocardial infarction, or ischemic stroke. Activation of platelets beyond the purpose of hemostasis may occur when substances facilitating thrombus growth and stability accumulate. Human platelets contain matrix metalloproteinase 2 (MMP-2) and release it upon activation. Active MMP-2 amplifies the platelet aggregation response to several agonists by potentiating phosphatidylinositol 3-kinase activation. Using several in vivo thrombosis models, we show that the inactivation of the MMP-2 gene prevented thrombosis induced by weak, but not strong, stimuli in mice but produced only a moderate prolongation of the bleeding time. Moreover, using cross-transfusion experiments and wild-type/MMP-2−/− chimeric mice, we show that it is platelet-derived MMP-2 that facilitates thrombus formation. Finally, we show that platelets activated by a mild vascular damage induce thrombus formation at a downstream arterial injury site by releasing MMP-2. Thus, platelet-derived MMP-2 plays a crucial role in thrombus formation by amplifying the response of platelets to weak activating stimuli. These findings open new possibilities for the prevention of thrombosis by the development of MMP-2 inhibitors. PMID:19808257

  17. Development of in-cell imaging assay systems for MMP-2 and MMP-9 based on trans-localizing molecular beacon proteins.

    PubMed

    Lee, Min Jun; Cho, Young-Ah; Hwang, Hyun Jin; Kim, Jeong Hee

    2015-06-01

    A sensitive in-cell imaging MMP-2 and MMP-9 detection systems that enables direct fluorescence detection of a target protease and its inhibition inside living cells has been developed. This in-cell imaging system utilizes the concept of fluorescent molecular beacon reporter (MBR) protein comprising a masking protein, a mitochondrial targeting sequence, a protease specific cleavage sequence and a fluorescent marker sequence, green fluorescent protein (GFP). The MBR protein is designed to change its intracellular location upon cleavage by either MMP-2 or MMP-9 from cytosol to mitochondria. Full and partial MMP-2 and MMP-9 were tested for optimal expression and activity in the cell. The activity of MMP-2 and MMP-9 was approximately 65-71%. Among MMP clones, MMP-2 catalytic domain and MMP-9 clone containing pro, catalytic and hemopexin domain were most active. Both MMP-2 and MMP-9 required divalent ions Ca and Zn for its activity and MMP-9 was more active at higher Ca/Zn ratio. With the in-cell imaging assay the protease activity can be measured in cellular environment and cellular toxicity of candidate molecules can be monitored at the same time. These are great advantage when compared to other currently used in vitro biochemical assays. The in-cell imaging assay developed in this study can be modified for other MMPs and can be used in various life science and drug discovery researches including the high throughput screening and high contents screening applications.

  18. Factors affecting the release of flavor encapsulated in carbohydrate matrixes.

    PubMed

    Gunning, Y M; Gunning, P A; Kemsley, E K; Parker, R; Ring, S G; Wilson, R H; Blake, A

    1999-12-01

    The effects of water content and temperature variation on the release of flavor components into the headspace over flavors, encapsulated by an extrusion process, in low water content carbohydrate matrixes is studied. The largest amounts of release occurred when the matrix was above its glass transition temperature, whether this was due to increased water content or elevated temperature. Under these conditions up to 70% of the sucrose in the matrix crystallized over a period of 10 days, as quantified using Fourier transform Raman spectroscopy. Smaller amounts of headspace release occurred when the water content of the encapsulated flavor system was decreased from 3. 5 to 3.1% w/w. Small amounts of release occurred from the "as prepared" materials, which were associated with the presence of small amounts of unencapsulated flavor oil with direct access to the headspace. It was concluded that release due to matrix permeability was relatively slow as compared with the above mechanisms.

  19. Acetylsalicylic acid regulates MMP-2 activity and inhibits colorectal invasion of murine B16F0 melanoma cells in C57BL/6J mice: effects of prostaglandin F(2)alpha.

    PubMed

    Tsai, Chin-Shaw Stella; Luo, Shue-Fen; Ning, Chung-Chu; Lin, Chien-Liang; Jiang, Ming-Chung; Liao, Ching-Fong

    2009-08-01

    Epidemiological studies indicate that acetylsalicylic acid may reduce the risk of mortality due to colon cancers. Metastasis is the major cause of cancer death. Matrix metalloproteinases (MMPs) play important roles in tumor invasion regulation, and prostaglandin F(2)alpha (PGF(2)alpha) is a key stimulator of MMP production. Thus, we investigated whether acetylsalicylic acid regulated MMP activity and the invasion of cancer cells and whether PGF(2)alpha attenuated acetylsalicylic acid-inhibited invasion of cancer cells. Gelatin-based zymography assays showed that acetylsalicylic acid inhibited the MMP-2 activity of B16F0 melanoma cells. Matrigel-based chemoinvasion assays showed that acetylsalicylic acid inhibited the invasion of B16F0 cells. Acetylsalicylic acid can inhibit PGF(2)alpha synthesis and PGF(2)alpha is a key stimulator of MMP-2 production. Our data showed that PGF(2)alpha treatment attenuated the acetylsalicylic acid-inhibited invasion of B16F0 cells. In animal experiments, acetylsalicylic acid reduced colorectal metastasis of B16F0 cells in C57BL/6J mice by 44%. Our results suggest that PGF(2)alpha is a therapeutic target for metastasis inhibition and acetylsalicylic acid may possess anti-metastasis ability.

  20. Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats

    PubMed Central

    LIN, RUHUI; YU, KUNQIANG; LI, XIAOJIE; TAO, JING; LIN, YUKUN; ZHAO, CONGKUAI; LI, CHUNYAN; CHEN, LI-DIAN

    2016-01-01

    The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)-2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP-2/MMP-9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury. PMID:27177163

  1. Form factors in quantum integrable models with GL(3)-invariant R-matrix

    NASA Astrophysics Data System (ADS)

    Pakuliak, S.; Ragoucy, E.; Slavnov, N. A.

    2014-04-01

    We study integrable models solvable by the nested algebraic Bethe ansatz and possessing GL(3)-invariant R-matrix. We obtain determinant representations for form factors of off-diagonal entries of the monodromy matrix. These representations can be used for the calculation of form factors and correlation functions of the XXX SU(3)-invariant Heisenberg chain.

  2. An electrochemical peptide cleavage-based biosensor for matrix metalloproteinase-2 detection with exonuclease III-assisted cycling signal amplification.

    PubMed

    Wang, Ding; Yuan, Yali; Zheng, Yingning; Chai, Yaqin; Yuan, Ruo

    2016-05-01

    In this work, an electrochemical peptide biosensor was developed for matrix metalloproteinase-2 (MMP-2) detection by conversion of a peptide cleavage event into DNA detection with exonuclease III (Exo III)-assisted cycling signal amplification.

  3. Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity.

    PubMed

    Halasz, Melinda; Polgar, Beata; Berta, Gergely; Czimbalek, Livia; Szekeres-Bartho, Julia

    2013-12-01

    Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while-based on our previous data-PIBF might control trophoblast invasion by suppressing proinvasive genes.

  4. O-6-methylguanine-DNA Methyltransferase Inhibits Gastric Carcinoma Cell Migration and Invasion by Downregulation of Matrix Metalloproteinase 2.

    PubMed

    Li, Chenglong; Deng, Li; Shen, Hugang; Meng, Qingyou; Qian, Aimin; Sang, Hongfei; Xia, Jiazeng; Li, Xiaoqiang

    2016-01-01

    MGMT plays a key role in many kinds of cancers. However, the molecular mechanisms of MGMT involvement in gastric cancer (GC) are poorly elucidated. Here, we investigated the role of MGMT in GC cell migration, invasion and metastatic potential. Our data showed that MGMT expression was negatively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by downregulation of matrix metalloproteinase 2 (MMP2). Loss of MGMT expression induced increases in GC cell metastasis and invasion potential in vitro and in vivo. These effects were reversed by inhibition of MGMT and MMP2. MGMT overexpression downregulated MMP2 protein levels, whereas this effect was counteracted by MGMT siRNA. In summary, MGMT is involved in gastric carcinogenesis via downregulation of MMP2. The MGMT/MMP2 pathway plays an essential role in GC metastasis and may be a potential therapeutic target for GC treatment. PMID:27291049

  5. Distribution and relative activity of matrix metalloproteinase-2 in human coronal dentin

    PubMed Central

    Boushell, Lee W; Kaku, Masaru; Mochida, Yoshiyuki; Yamauchi, Mitsuo

    2011-01-01

    The presence of matrix metalloproteinase-2 (MMP-2) in dentin has been reported, but its distribution and activity level in mature human coronal dentin are not well understood. The purpose of this study was to determine the MMP-2 distribution and relative activity in demineralized dentin. Crowns of twenty eight human molars were sectioned into inner (ID), middle (MD), and outer dentin (OD) regions and demineralized. MMP-2 was extracted with 0.33 mol·L−1 EDTA/2 mol·L−1 guanidine-HCl, pH 7.4, and MMP-2 concentration was estimated with enzyme-linked immunoabsorbant assay (ELISA). Further characterization was accomplished by Western blotting analysis and gelatin zymography. The mean concentrations of MMP-2 per mg dentin protein in the dentin regions were significantly different (P=0.043): 0.9 ng (ID), 0.4 ng (MD), and 2.2 ng (OD), respectively. The pattern of MMP-2 concentration was OD>ID>MD. Western blotting analysis detected ∼66 and ∼72 kDa immunopositive proteins corresponding to pro- and mature MMP-2, respectively, in the ID and MD, and a ∼66 kDa protein in the OD. Gelatinolytic activity consistent with MMP-2 was detected in all regions. Interestingly, the pattern of levels of Western blot immunodetection and gelatinolytic activity was MD>ID>OD. The concentration of MMP-2 in human coronal dentin was highest in the region of dentin that contains the dentinoenamel junction and least in the middle region of dentin. However, levels of Western blot immunodetection and gelatinolytic activity did not correlate with the estimated regional concentrations of MMP-2, potentially indicating region specific protein interactions. PMID:22010577

  6. Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression

    PubMed Central

    Chen, Jie-Wei; Bai, Hai-Yan; Li, Yan; Liao, Yi-Ji; Li, Chang-Peng; Tian, Xiao-Peng; Kung, Hsiang-Fu; Guan, Xin-Yuan; Xie, Dan

    2014-01-01

    Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. Conclusion: This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC. PMID:25071013

  7. Link prediction on evolving graphs using matrix and tensor factorizations.

    SciTech Connect

    Dunlavy, Daniel M.; Acar, Evrim; Kolda, Tamara Gibson

    2010-06-01

    The data in many disciplines such as social networks, web analysis, etc. is link-based, and the link structure can be exploited for many different data mining tasks. In this paper, we consider the problem of temporal link prediction: Given link data for time periods 1 through T, can we predict the links in time period T + 1? Specifically, we look at bipartite graphs changing over time and consider matrix- and tensor-based methods for predicting links. We present a weight-based method for collapsing multi-year data into a single matrix. We show how the well-known Katz method for link prediction can be extended to bipartite graphs and, moreover, approximated in a scalable way using a truncated singular value decomposition. Using a CANDECOMP/PARAFAC tensor decomposition of the data, we illustrate the usefulness of exploiting the natural three-dimensional structure of temporal link data. Through several numerical experiments, we demonstrate that both matrix- and tensor-based techniques are effective for temporal link prediction despite the inherent difficulty of the problem.

  8. EPA Positive Matrix Factorization (PMF) 5.0 Fundamentals and User Guide

    EPA Science Inventory

    PMF is a multivariate factor analysis tool that decomposes a matrix of speciated sample data into two matrices: factor contributions (G) and factor profiles (F). These factor profiles need to be interpreted by the user to identify the source types that may be contributing to the ...

  9. Cross talk between MMP2-Spm-Cer-S1P and ERK1/2 in proliferation of pulmonary artery smooth muscle cells under angiotensin II stimulation.

    PubMed

    Chowdhury, Animesh; Sarkar, Jaganmay; Pramanik, Pijush Kanti; Chakraborti, Tapati; Chakraborti, Sajal

    2016-08-01

    The aim of the present study is to establish the mechanism associated with the proliferation of PASMCs under ANG II stimulation. The results showed that treatment of PASMCs with ANG II induces an increase in cell proliferation and 100 nM was the optimum concentration for maximum increase in proliferation of the cells. Pretreatment of the cells with AT1, but not AT2, receptor antagonist inhibited ANG II induced cell proliferation. Pretreatment with pharmacological and genetic inhibitors of sphingomyelinase (SMase) and sphingosine kinase (SPHK) prevented ANG II-induced cell proliferation. ANG II has also been shown to induce SMase activity, SPHK phosphorylation and S1P production. In addition, ANG II caused an increase in proMMP-2 expression and activation, ERK1/2 phosphorylation and NADPH oxidase activation. Upon inhibition of MMP-2, SMase activity and S1P level were curbed leading to inhibition of cell proliferation. SPHK was phosphorylated by ERK1/2 during ET-1 stimulation of the cells. ANG II-induced ERK1/2 phosphorylation and proMMP-2 expression and activation in the cells were abrogated upon inhibition of NADPH oxidase activity. Overall, NADPH oxidase plays an important role in proMMP-2 expression and activation and that MMP-2 mediated SMC proliferation occurs through the involvement of Spm-Cer-S1P signaling axis under ANG II stimulation of PASMCs. PMID:27210740

  10. Original Research: The expression of MMP2 and MMP9 in the hippocampus and cerebral cortex of newborn mice under maternal lead exposure.

    PubMed

    Li, Ning; Li, Xing; Li, Li; Zhang, Pingan; Qiao, Mingwu; Zhao, Qiuyan; Song, Lianjun; Yu, Zengli

    2016-10-01

    The current study focused on the MMP2 and MMP9 expression in cerebral cortex and hippocampus of newborn mice under maternal lead exposure. Lead exposure was initiated from gestation to weaning. Lead acetate was dissolved in deionized water with concentration of 0.1, 0.2, and 0.5% and was absorbed through daily drinking. On day 21 after birth, lead in blood and tissue levels was examined by Graphite Furnace Atomic Absorption Spectrum (GFAAS). The protein expressions of MMP2 and MMP9 in hippocampus and cerebral cortex tissues were tested by western blotting and immunohistochemistry. Compared to the control group, blood, cerebral cortex, and hippocampus lead levels of newborn mice in 0.1, 0.2, and 0.5% lead exposure groups were markedly high (P < 0.05), and mice within the 0.2 and 0.5% lead exposure groups performed much worse than that of the control group in Water Maze test (P < 0.05). Compared with the control group, MMP2 and MMP9 expressions in hippocampus were up-regulated in the lead exposure groups (P < 0.05), and the MMP2 and MMP9 expressions in cerebral cortex were also higher (P < 0.05). The increased expression of MMP2 and MMP9 in the hippocampus and cerebral cortex may lead to the neurotoxicity in the context of maternal lead exposure. PMID:27190262

  11. Angiogenic Role of MMP-2/9 Expressed on the Cell Surface of Early Endothelial Progenitor Cells/Myeloid Angiogenic Cells.

    PubMed

    Kanayasu-Toyoda, Toshie; Tanaka, Takeshi; Ishii-Watabe, Akiko; Kitagawa, Hiroko; Matsuyama, Akifumi; Uchida, Eriko; Yamaguchi, Teruhide

    2015-11-01

    Since the introduction of angiogenic cell therapy using early endothelial progenitor cells (EPCs), myeloid angiogenic cells (MACs) have been expected to be useful in treating ischemic diseases. In order to elucidate the angiogenic properties of MACs/EPCs, we clarified the characteristics of MACs as compared to M2 macrophages (Mϕs). Comparison of the gene expression profiles of MACs and late EPCs revealed that MACs expressed greater amounts of metalloproteinase (MMP)-9. It should be noted that the profile of MMP-2/9 expression on the cell surface of MACs was similar to that of M2 Mϕs, and that cell surface MMP-2/9 might be an active form based on molecular size. In addition, the invasion of MACs was prohibited not only by MMP-2/9 inhibitor, but also by the hyaluronidase treatment that caused the down-regulation of MMP-9 on the cell surface of MACs and inhibited their invasion activity. These results indicate that cell surface MMP-2/9 plays an important role in the high invasion ability of MACs. The conditioned medium of both MACs and M2 Mϕs stimulated tube formation of endothelial cells in vitro. MACs caused an increase in vessel formation in in vivo models through the production of IL-8. We propose that the role of MACs with cell surfaces expressing MMP-2/9 is rapidly invading ischemic tissue. PMID:25820539

  12. Serum matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in esophageal cancer patients.

    PubMed

    Groblewska, Magdalena; Mroczko, Barbara; Kozlowski, Miroslaw; Niklinski, Jacek; Laudanski, Jerzy; Szmitkowski, Maciej

    2012-01-01

    The positive expression of MMP-2 and TIMP-2 were found in esophageal cancer (EC) tissue and correlated with cancer stage and clinico-pathological features of tumor and patients' survival. However, little is known about serum levels of those proteins in EC patients. The aim of the present study was to investigate the diagnostic significance of MMP-2 and TIMP-2 serum levels in EC patients in relation to clinico-pathological features of cancer. The study included 53 EC patients and 92 healthy controls. The serum levels of MMP-2, TIMP-2 and classical tumor markers CEA (carcinoembryonic antigen) and SCC (squamous cell carcinoma antigen) were assayed. The prognostic values and diagnostic criteria for the biomarkers tested were defined. Serum levels of MMP-2, TIMP-2 in EC patients were significantly lower, whereas CEA and SCC significantly higher than in control group. The diagnostic sensitivity of TIMP-2 (57%) was higher than those for other biomarkers tested and increased in combination with SCC (70%). Area under ROC curve for TIMP-2 (0.8698) was larger than for other proteins. In Cox's univariate analysis only SCC serum levels were significant prognostic factors for EC patients' survival. The results suggest the limited value of serum analyses of MMP-2 for tumor staging and prognosis in EC and the better usefulness of TIMP-2 than MMP-2 as a tumor marker in the diagnosis of EC, especially in combined use with SCC.

  13. Piceatannol suppresses the metastatic potential of MCF10A human breast epithelial cells harboring mutated H-ras by inhibiting MMP-2 expression

    PubMed Central

    SONG, NURY; HWANG, MUN KYUNG; HEO, YONG-SEOK; LEE, KI WON; LEE, HYONG JOO

    2013-01-01

    Metastasis is one of the most threatening features of the oncogenic process and the main cause of cancer-related mortality. Several studies have demonstrated that matrix metalloproteinases (MMPs) are critical for tumor invasion and metastasis. Resveratrol (3,5,4′-trihydroxystilbene), a phenolic compound of red wine, has been reported to be a natural chemopreventive agent. However, the cancer preventive effects of piceatannol (3,5,3′,4′-tetrahydroxystilbene), a metabolite of resveratrol and the underlying molecular mechanisms have not yet been fully elucidated. In this study, we report that piceatannol inhibits H-ras-induced MMP-2 activity and the invasive phenotype of MCF10A human breast epithelial cells harboring mutated H-ras (H-ras MCF10A cells) more effectively than resveratrol. Piceatannol attenuated the H-ras-induced phosphorylation of Akt in a time- and dose-dependent manner, whereas resveratrol, at the same concentrations, did not exert an inhibitory effect. In vitro kinase assays demonstrated that piceatannol significantly inhibited phosphatidylinositol 3-kinase (PI3K) activity and suppressed phosphatidylinositol (3,4,5)-trisphosphate (PIP3) expression in the H-ras MCF10A cells. Ex vivo pull-down assays revealed that piceatannol directly bound to PI3K, inhibiting PI3K activity. Data from molecular docking suggested that piceatannol is a more tight-binding inhibitor than resveratrol due to the additional hydrogen bond between the hydroxyl group and the backbone amide group of Val882 in the ATP-binding pocket of PI3K. PMID:23877152

  14. Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors.

    PubMed

    Lipari, L; Mauro, A; Gallina, S; Tortorici, S; Buscemi, M; Tete, S; Gerbino, A

    2012-01-01

    Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made.

  15. Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases ▿

    PubMed Central

    Scian, Romina; Barrionuevo, Paula; Giambartolomei, Guillermo H.; De Simone, Emilio A.; Vanzulli, Silvia I.; Fossati, Carlos A.; Baldi, Pablo C.; Delpino, M. Victoria

    2011-01-01

    Arthritis is one of the most common complications of human brucellosis, but its pathogenic mechanisms have not been elucidated. Fibroblast-like synoviocytes (FLS) are known to be central mediators of joint damage in inflammatory arthritides through the production of matrix metalloproteinases (MMPs) that degrade collagen and of cytokines and chemokines that mediate the recruitment and activation of leukocytes. In this study we show that Brucella abortus infects and replicates in human FLS (SW982 cell line) in vitro and that infection results in the production of MMP-2 and proinflammatory mediators (interleukin-6 [IL-6], IL-8, monocyte chemotactic protein 1 [MCP-1], and granulocyte-macrophage colony-stimulating factor [GM-CSF]). Culture supernatants from Brucella-infected FLS induced the migration of monocytes and neutrophils in vitro and also induced these cells to secrete MMP-9 in a GM-CSF- and IL-6-dependent fashion, respectively. Reciprocally, culture supernatants from Brucella-infected monocytes and neutrophils induced FLS to produce MMP-2 in a tumor necrosis factor alpha (TNF-α)-dependent fashion. The secretion of proinflammatory mediators and MMP-2 by FLS did not depend on bacterial viability, since it was also induced by heat-killed B. abortus (HKBA) and by a model Brucella lipoprotein (L-Omp19). These responses were mediated by the recognition of B. abortus antigens through Toll-like receptor 2. The intra-articular injection of HKBA or L-Omp19 into the knee joint of mice resulted in the local induction of the proinflammatory mediators MMP-2 and MMP-9 and in the generation of a mixed inflammatory infiltrate. These results suggest that FLS, and phagocytes recruited by them to the infection focus, may be involved in joint damage during brucellar arthritis through the production of MMPs and proinflammatory mediators. PMID:21730088

  16. RECEPTOR MODELING OF AMBIENT PARTICULATE MATTER DATA USING POSITIVE MATRIX FACTORIZATION REVIEW OF EXISTING METHODS

    EPA Science Inventory

    Methods for apportioning sources of ambient particulate matter (PM) using the positive matrix factorization (PMF) algorithm are reviewed. Numerous procedural decisions must be made and algorithmic parameters selected when analyzing PM data with PMF. However, few publications docu...

  17. The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3.

    PubMed

    Qin, Chao; He, Bing; Dai, Wenbing; Lin, Zhiqiang; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Wang, Guangji; Yin, Lifang; Zhang, Qiang

    2014-07-01

    Currently, it is unknown whether a receptor-associated protein will be affected when a ligand modified delivery system interacts with its receptor. Besides, chlorotoxin (ClTx)-modified liposomes can target to glioma cells, but the target molecule is not clear: MMP-2, ClC-3 or both? Here a comparative study of ClTx-conjugated liposomes was conducted on two types of tumor cells: U87, a human glioma cell line with high expression of both MMP-2 and ClC-3, and A549, a human lung cancer cell line with expression of only MMP-2. ClTx-modified liposomes behaved similarly in these two cancer cells in terms of in vitro cell uptake, endocytosis pathway, intracellular trafficking and in vivo targeting efficacy, though the two tested cell lines were very different in ClC-3 expression. These results revealed that the targeted delivery of ClTx modified liposomes to U87 tumor was MMP-2-mediated and not correlated with the chloride channel ClC-3. On the other hand, ClTx modified on the liposomes did activate the receptor-associated protein ClC-3 via the binding with MMP-2, leading to the inhibition on cell migration and chloride currents. This is significant because cell migration is a key step in tumor metastasis. Interestingly, higher in vitro cellular uptake and lower in vivo tumor accumulation of liposomal systems was found in U87 compared to the A549 model, possibly due to the biological differences between in vitro and in vivo models. In general, ClTx-modified delivery systems may potentially target to tumors other than glioma that express a high level of MMP-2, and its effect on ClC-3 may help prevent tumor metastasis.

  18. Strategic Endothelial Cell Tube Formation Assay: Comparing Extracellular Matrix and Growth Factor Reduced Extracellular Matrix.

    PubMed

    Xie, Daniel; Ju, Donghong; Speyer, Cecilia; Gorski, David; Kosir, Mary A

    2016-08-14

    Malignant tumors require a blood supply in order to survive and spread. These tumors obtain their needed blood from the patient's blood stream by hijacking the process of angiogenesis, in which new blood vessels are formed from existing blood vessels. The CXCR2 (chemokine (C-X-C motif) receptor 2) receptor is a transmembrane G-protein-linked molecule found in many cells that is closely associated with angiogenesis(1). Specific blockade of the CXCR2 receptor inhibits angiogenesis, as measured by several assays such as the endothelial tube formation assay. The tube formation assay is useful for studying angiogenesis because it is an excellent method of studying the effects that any given compound or environmental condition may have on angiogenesis. It is a simple and quick in vitro assay that generates quantifiable data and requires relatively few components. Unlike in vivo assays, it does not require animals and can be carried out in less than two days. This protocol describes a variation of the extracellular matrix supporting endothelial tube formation assay, which tests the CXCR2 receptor.

  19. Strategic Endothelial Cell Tube Formation Assay: Comparing Extracellular Matrix and Growth Factor Reduced Extracellular Matrix.

    PubMed

    Xie, Daniel; Ju, Donghong; Speyer, Cecilia; Gorski, David; Kosir, Mary A

    2016-01-01

    Malignant tumors require a blood supply in order to survive and spread. These tumors obtain their needed blood from the patient's blood stream by hijacking the process of angiogenesis, in which new blood vessels are formed from existing blood vessels. The CXCR2 (chemokine (C-X-C motif) receptor 2) receptor is a transmembrane G-protein-linked molecule found in many cells that is closely associated with angiogenesis(1). Specific blockade of the CXCR2 receptor inhibits angiogenesis, as measured by several assays such as the endothelial tube formation assay. The tube formation assay is useful for studying angiogenesis because it is an excellent method of studying the effects that any given compound or environmental condition may have on angiogenesis. It is a simple and quick in vitro assay that generates quantifiable data and requires relatively few components. Unlike in vivo assays, it does not require animals and can be carried out in less than two days. This protocol describes a variation of the extracellular matrix supporting endothelial tube formation assay, which tests the CXCR2 receptor. PMID:27585062

  20. The serum levels of MMP-9, MMP-2 and vWF in patients with low doses of urokinase peritoneal dialysis decreased uremia complicated with cerebral infarction

    PubMed Central

    Wang, Shu-Jin; Qu, Zhong-Sen; Zhang, Qing-De; Li, Liang; Wang, Feng; Zhang, Bin; Wu, Bang-Li; Zhao, Yu-Wu

    2015-01-01

    To investigate the effect of MMP-9, MMP-2 and vWF in patients with low doses of urokinase peritoneal dialysis decreased uremia complicated with cerebral infarction. 112 cases of uremia complicated with cerebral infarction were randomly divided into the peritoneal dialysate with urokinase treatment group (66 cases) and the conventional treatment group (46 cases). At the same time, 50 cases of healthy people who were more than 45 years old were enrolled in the control group. The basic treatment in both treatment groups was the same. In urokinase therapy group based on the conventional treatment, urokinase was added into peritoneal dialysis fluid, and changes of serum MMP-9, MMP-2 and vWF were observed by drawing blood at different time points within 8 weeks. The changes of serum MMP-2, MMP-9 and vWF were detected by enzyme-linked immunosorbent assay. At the time of the onset of uremia complicated with cerebral infarction patients the serum MMP-9, MMP-2, vWF were significantly higher (P<0.05, P<0.05, P<0.01). Conventional antiplatelet therapy in brain protection only reduce MMP-9 to the normal range (P>0.05) within 8 weeks. But the MMP-2 and vWF cannot be reduced to the normal range (P<0.01, P<0.01). Low doses of urokinase can reduce MMP-9 (7 d) and MMP-2 (14 d) to the normal range (P>0.05, P>0.05) at the early stage and decrease the vWF to a normal range within 8 weeks (P>0.05). At the time of the onset of uremia complicated with cerebral infarction patients the serum MMP-9, MMP-2 and vWF increased significantly. Low doses of urokinase dialysis can reduce serum MMP-9, MMP-2, and vWF in acute uremia complicated with cerebral infarction without recurrence of cerebral infarction and cerebral hemorrhagic transformation, indicating that low dose of urokinase peritoneal dialysis may have a certain effect on the early treatment of this disease. PMID:26550224

  1. Perfluorooctanoic acid enhances colorectal cancer DLD-1 cells invasiveness through activating NF-κB mediated matrix metalloproteinase-2/-9 expression

    PubMed Central

    Miao, Chen; Ma, Jun; Zhang, Yajie; Chu, Yimin; Li, Ji; Kuai, Rong; Wang, Saiyu; Peng, Haixia

    2015-01-01

    Objective: Perfluorooctanoic acid (PFOA) is widely used in consumer products and detected in human serum. Our study meant to elucidate the uncovered molecular mechanisms underlying the PFOA induced colorectal cancer cell DLD-1 invasion and matrix metalloproteinases (MMP) expression. Methods and results: Trans-well filter assay appeared that PFOA treatment stimulated DLD-1 cells invasion significantly. Meanwhile, the results of luciferase reporter, quantitative real-time PCR, western blotting, and gelatin zymography showed that PFOA induced MMP-2/-9 expression and enzyme activation levels consistently (P < 0.05 each). Subsequently, western blotting and immunofluorescence assay demonstrated that PFOA could enhance nuclear factor kappaB (NF-κB) activity by stimulating NF-κB translocation into nuclear in DLD-1 cells. Furthermore, JSH-23, a well-known NF-κB inhibitor, could reverse the PFOA induced colorectal cancer cell invasion and MMP-2/-9 expression. Conclusions: Our study confirmed that PFOA could induce colorectal cancer cell DLD-1 invasive ability and MMP-2/-9 expression through activating NF-κB, which deserves more concerns on environmental pollutant-resulted public health risk. PMID:26617761

  2. Endothelial Cell-Derived Basic Fibroblast Growth Factor: Synthesis and Deposition into Subendothelial Extracellular Matrix

    NASA Astrophysics Data System (ADS)

    Vlodavsky, Israel; Folkman, Judah; Sullivan, Robert; Fridman, Rafael; Ishai-Michaeli, Rivka; Sasse, Joachim; Klagsbrun, Michael

    1987-04-01

    Bovine aortic and corneal endothelial cells synthesize a growth factor that remains mostly cell-associated but can also be extracted from the subendothelial extracellular matrix (ECM) deposited by these cells. The endothelial cell-derived growth factors extracted from cell lysates and from the extracellular matrix appear to be structurally related to basic fibroblast growth factor by the criteria that they (i) bind to heparin-Sepharose and are eluted at 1.4-1.6 M NaCl, (ii) have a molecular weight of about 18,400, (iii) cross-react with anti-basic fibroblast growth factor antibodies when analyzed by electrophoretic blotting and immunoprecipitation, and (iv) are potent mitogens for bovine aortic and capillary endothelial cells. It is suggested that endothelium can store growth factors capable of autocrine growth promotion in two ways: by sequestering growth factor within the cell and by incorporating it into the underlying extracellular matrix.

  3. Timosaponin AIII inhibits migration and invasion of A549 human non-small-cell lung cancer cells via attenuations of MMP-2 and MMP-9 by inhibitions of ERK1/2, Src/FAK and β-catenin signaling pathways.

    PubMed

    Jung, Okkeun; Lee, Jongsung; Lee, Yu Jin; Yun, Jung-Mi; Son, Young-Jin; Cho, Jae Youl; Ryou, Chongsuk; Lee, Sang Yeol

    2016-08-15

    Timosaponin AIII (TAIII) is a type of steroidal saponins isolated from Anemarrhena asphodeloides. It was known to improve learning and memory deficits through anti-inflammatory effects. TAIII was also reported to induce autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells and inhibit the growth of human colorectal cancer cells, thus regarded as a potential candidate for anti-cancer agent. In this study, we verified apoptosis-inducing and cell-cycle-arresting effects of TAIII in A549 human non-small-cell lung cancer (NSCLC) cells. Then, we report that TAIII suppresses migration and invasion of A549 human NSCLC cells. We propose that two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, which are well known to be involved in cancer-metastasis, are attenuated by the treatment of TAIII. TAIII exerts its suppressive effects on MMP-2 and MMP-9 via inhibitions of ERK1/2, Src/FAK and β-catenin signalings which are closely related with the regulations of MMP-2 and MMP-9. PMID:27422337

  4. Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2.

    PubMed

    Ali, Mohammad A M; Kandasamy, Arulmozhi D; Fan, Xiaohu; Schulz, Richard

    2013-09-01

    Matrix metalloproteinase-2 (MMP-2) is well known to proteolyse both extracellular and intracellular proteins. Reactive oxygen species activate MMP-2 at both transcriptional and post-translational levels, thus MMP-2 activation is considered an early event in oxidative stress injury. Although hydrogen peroxide is widely used to trigger oxidative stress-induced cell death, the type of cell death (apoptosis vs. necrosis) in cardiomyocytes is still controversial depending on the concentration used and the exposure time. We carefully investigated the mode of cell death in neonatal rat cardiomyocytes induced by different concentrations (50-500 μM) of hydrogen peroxide at various time intervals after exposure and determined whether MMP-2 is implicated in hydrogen peroxide-induced cardiomyocyte death. Treating cardiomyocytes with hydrogen peroxide led to elevated MMP-2 level/activity with maximal effects seen at 200 μM. Hydrogen peroxide caused necrotic cell death by disrupting the plasmalemma as evidenced by the release of lactate dehydrogenase in a concentration- and time-dependent manner as well as the necrotic cleavage of PARP-1. The absence of both caspase-3 cleavage/activation and apoptotic cleavage of PARP-1 illustrated the weak contribution of apoptosis. Pre-treatment with selective MMP inhibitors did not protect against hydrogen peroxide-induced necrosis. In conclusion hydrogen peroxide increases MMP-2 level/activity in cardiomyocytes and induces necrotic cell death, however, the later effect is MMP-2 independent.

  5. Involvement of matrix metalloproteinases in the adipose conversion of 3T3-L1 preadipocytes.

    PubMed Central

    Croissandeau, Gilles; Chrétien, Michel; Mbikay, Majambu

    2002-01-01

    When mouse 3T3-L1 preadipocytes are induced to differentiate into adipocytes, they change from an extended fibroblast-like morphology to a rounded one. This change most likely occurs through extracellular matrix remodelling, a process known to be mediated in part by matrix metalloproteinases (MMPs). In this study, we have shown by semi-quantitative reverse transcriptase-PCR, zymographic and immunoblot analysis that MMP-2, MMP-9 and membrane type 1 (MT1)-MMP are regulated during adipose conversion. To assess the importance of MMPs for adipocytic differentiation we have used MMP-specific inhibitors as well as neutralizing antibodies. Treatment of 3T3-L1 preadipocytes with the broad MMP inhibitor Ilomastat or the more restricted MMP-2 Inhibitor I prevented their differentiation into adipocytes in a dose-dependent manner, as evidenced by absence of triglyceride accumulation. Inhibitor treatment prevented the fibronectin-network degradation, as well as the induction of the genes for peroxisome-proliferator-activated receptor gamma and adipsin, two adipocyte phenotype markers. Inhibitor treatment was effective when applied during the early stages of adipocytic conversion, whereas inhibitor treatment during later stages had little effect. Inhibitor treatment did not inhibit clonal mitotic expansion; nor did it affect the expression pattern of the adipogenic transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) or its nuclear translocation. It did, however, markedly reduce C/EBPbeta DNA-binding capacity. Taken together, these results suggest that MMPs, and notably MMP-2 and MMP-9, may be necessary mediators of adipocytic differentiation of 3T3-L1 cells. PMID:12049638

  6. Engineering a growth factor embedded nanofiber matrix niche to promote vascularization for functional cardiac regeneration.

    PubMed

    Lakshmanan, Rajesh; Kumaraswamy, Priyadharshini; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

    2016-08-01

    The major loss of tissue extracellular matrix (ECM) after myocardial ischemia is a serious burden that gradually leads to heart failure. Due to lack of available treatment methods to restore the cardiac function, various research strategies have come up to treat the ischemic myocardium. However these have met with limited success due to the complexity of the cardiac tissue, which exhibits a nanofibrous collagenous matrix with spatio-temporal localization of a combination of growth factors. To mimic the topographical and chemical cues of the natural cardiac tissue, we have fabricated a growth factor embedded nanofibrous scaffold through electrospinning. In our previous work, we have reported a nanofibrous matrix made of PLCL and PEOz with an average diameter of 500 nm. The scaffold properties were specifically characterized in vitro for cardio-compatibility. In the present study, we have loaded dual growth factors VEGF and bFGF in the nanofiber matrix and investigated its suitability for cardiac tissue engineering. The encapsulation and release of dual growth factors from the matrix were studied using XPS and ELISA. Bioactivity of the loaded growth factors towards proliferation and migration of endothelial cells (HUVECs) was evaluated through MTS and Boyden chamber assays respectively. The efficiency of growth factors on the nanofibrous matrix to activate signaling molecules was studied in HUVECs through gene expression analysis. Preclinical evaluation of the growth factor embedded nanofibrous patch in a rabbit acute myocardial infarction (AMI) model was studied and cardiac function assessment was made through ECG and echocardiography. The evidence for angiogenesis in the patch secured regions was analyzed through histopathology and immunohistochemistry. Our results confirm the effectiveness of growth factor embedded nanofiber matrix in restoration of cardiac function after ischemia when compared to conventional patch material thereby exhibiting promise as a

  7. Effect of Androgen Blockade on HER-2 and Matrix Metalloproteinase-2 Expression on Bone Marrow Micrometastasis and Stromal Cells in Men with Prostate Cancer

    PubMed Central

    Murray, N. P.; Reyes, E.; Badinez, L.; Orellana, N.; Fuentealba, C.; Olivares, R.; Porcell, J.; Dueñas, R.

    2013-01-01

    Introduction. HER-2 has been associated with castrate resistant prostate cancer and matrix metalloproteinase-2 (MMP-2) in the dissemination and invasion of tumor cells as well as activating angiogenesis. We present an immunocytochemical study of the effect of androgen blockade on the expression of HER-2 and MMP-2 in bone marrow micrometastasis and the surrounding stromal cells in men with prostate cancer. Methods and Patients. A cross-sectional study of men with prostate cancer. Touch preps were obtained from bone marrow biopsies of men with prostate cancer, before and after radical prostatectomy and during androgen blockade. Micrometastasis detected with anti-PSA immunocytochemistry underwent processing with anti-HER-2 and anti-MMP-2 immunocytochemistry. Patients were defined as HER-2 positive or negative, MMP-2 negative or an MMP-2 pattern described as border or central and stromal MMP-2 defined as positive or negative. The expression of the biomarkers was compared before and after primary treatment and during androgen blockade in relation to the serum PSA at the time of sampling and duration of androgen blockade. Results. 191 men participated, 35 men before surgery and 43 after surgery; there were no significant differences in HER-2 expression between groups, there was no MMP-2 expression centrally or stromal expression of MMP-2. In men with androgen blockade, HER-2 expression was significantly higher; there was a trend for increasing HER-2 expression up to 5 years; central MMP-2 expression significantly increased after 3 years, while stromal MMP-2 significantly increased after 6 years. MMP-2 expression both in micrometastasis and stroma was significantly associated with HER-2 expression. Expression of MMP-2 at the border of the micrometastasis was not associated with HER-2 expression and occurred in the absence of androgen blockade. Conclusions. Androgen blockade decreases serum PSA by eliminating HER-2 negative prostate cancer cells. However, there is early

  8. Significant relation of tissue inhibitor of matrix metalloproteinase-2 and its combination with matrix metalloproteinase-2 to survival of patients with cancer of uterine cervix.

    PubMed

    Wang, Po-Hui; Ko, Jiunn-Liang; Yang, Shun-Fa; Tsai, Hsiu-Ting; Tee, Yi-Torng; Han, Chih-Ping; Lin, Long-Yau; Chen, Shiuan-Chih; Shih, Yang-Tse

    2011-08-01

    Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) has high affinity for matrix metalloproteinase-2 (MMP-2). Few studies simultaneously investigate their implication in prognosis of patients with cervical cancer. We used reverse transcription-polymerase chain reaction and immunohistochemical method for cervical tissues and microarrays to investigate the association among TIMP-2, MMP-2, clinicopathological parameters, and prognosis of patients with cancer. Our results showed that cancer tissues exhibited less TIMP-2 expression and patients with pelvic lymph node metastasis had less TIMP-2 expression. Positive TIMP-2 constellated with negative MMP-2 indicated lower recurrence probability and better overall survival. The protective effect of TIMP-2 expression may overcome the adverse effect of MMP-2 expression in terms of disease-free interval and overall survival while neither TIMP-2 nor MMP-2 alone can be used to predict outcome. We suggest that following patients other than those with positive TIMP-2 and negative MMP-2 expression more closely and intensely may improve their prognosis.

  9. [Reference ranges of matrix metalloproteinase-1, -2, -9 and tissue inhibitor of matrix metalloproteinases-1 concentrations in amniotic fluid in physiological pregnancy].

    PubMed

    Korenovsky, Yu V; Remneva, O V

    2016-01-01

    The aim of this study was to determine reference values of matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in the amniotic fluid at the first stage of labor in physiological pregnancy. 89 women at the first stage of term labor have been examined. Samples of amniotic fluid were taken at the first period of labor by vaginal amniotomy. Concentrations ofMMP-1, MMP-2, MMP-9, and TIMP-1 were investigated in amniotic fluid by ELISA kits. We have determined normal concentration ranges for MMP-1, MMP-2, MMP-9, TIMP-1, and ratios of concentrations of MMPs and TIMP-1 (MMP-1/TIMP-1, MMP-2/TIMP-1, MMP-9/TIMP-1) in the amniotic fluid at the first period of labor in physiological pregnancy. These included: MMP-1--5.1-16.8 pg/mg of protein, MMP-2--238.3-374.1 pg/mg of protein, MMP-9--66.1-113.3 pg/mg of protein, TIMP-1--4.7-13.6 pg/mg of protein, ratio of MMP-1/TIMP-1--0.1-2.2, ratio of MMP-2/TIMP-1--19.9-55.7, ratio of MMP-9/TIMP-1--4.2-17.2.

  10. Spinal fusion with recombinant human growth and differentiation factor-5 combined with a mineralized collagen matrix.

    PubMed

    Spiro, R C; Thompson, A Y; Poser, J W

    2001-08-01

    The availability of recombinant osteoinductive growth factors and new osteoconductive matrices offers an alternative to the use of autogenous bone (autograft) for grafting indications. This study evaluates the bone-forming activity of a mineralized collagen matrix combined with recombinant human growth and differentiation factor-5 in a rabbit posterolateral spinal fusion model. The activity of three distinct matrix-growth factor formulations is assessed by radiographic, histologic, and mechanical strength methods. Results show that the radiographic density, histologic quality, and mechanical strength of fusion at 12 weeks post-treatment rank consistently within the treatment groups. Optimal formulations are shown to perform similar to autograft in both the rate and strength of fusion. Fusion rates as high as 80% are observed within specific matrix/growth factor formulations. The average biomechanical strength of treated motion segments in the most efficacious formulation is 82% higher than that obtained with autograft, although this difference is not statistically significant. The fusion mass formed in response to matrix/growth factor formulations is composed of normal trabecular bone with a thin outer cortical plate and modest hematopoietic bone marrow. These results demonstrate that the combination of a mineralized collagen matrix with recombinant human growth and differentiation factor-5 maximizes the inherent conductive and inductive properties of each component, respectively, to provide an effective alternative to autograft for bone grafting procedures.

  11. Low-dose radiation pretreatment improves survival of human ceiling culture-derived proliferative adipocytes (ccdPAs) under hypoxia via HIF-1 alpha and MMP-2 induction

    SciTech Connect

    Adachi, Naoki; Kubota, Yoshitaka; Kosaka, Kentarou; Akita, Shinsuke; Sasahara, Yoshitarou; Kira, Tomoe; Kuroda, Masayuki; Mitsukawa, Nobuyuki; Bujo, Hideaki; Satoh, Kaneshige

    2015-08-07

    Poor survival is a major problem of adipocyte transplantation. We previously reported that VEGF and MMPs secreted from transplanted adipocytes are essential for angiogenesis and adipogenesis. Pretreatment with low-dose (5 Gy) radiation (LDR) increased VEGF, MMP-2, and HIF-1 alpha mRNA expression in human ceiling culture-derived proliferative adipocytes (hccdPAs). Gene expression after LDR differed between adipose-derived stem cells (hASCs) and hccdPAs. Pretreatment with LDR improved the survival of hccdPAs under hypoxia, which is inevitable in the early stages after transplantation. Upregulation of VEGF and MMP-2 after LDR in hccdPAs is mediated by HIF-1 alpha expression. Our results suggest that pretreatment with LDR may improve adipocyte graft survival in a clinical setting through upregulation of VEGF and MMP-2 via HIF-1 alpha. - Highlights: • Ceiling culture-derived proliferative adipocytes (ccdPAs) react to radiation. • Low-dose radiation (LDR) pretreatment improves survival of ccdPAs under hypoxia. • Gene expression after LDR differs between ccdPAs and adipose-derived stem cells. • LDR-induced increase in MMP-2 and VEGF is dependent on HIF-1 alpha induction. • LDR pretreatment may improve the adipocyte graft survival rate in clinical settings.

  12. Analysis of Gene Expression in PTHrP−/− Mammary Buds Supports a Role for BMP Signaling and MMP2 in the Initiation of Ductal Morphogenesis

    PubMed Central

    Hens, Julie; Dann, Pamela; Hiremath, Minoti; Pan, Tien-Chi; Chodosh, Lewis; Wysolmerski, John

    2010-01-01

    Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP’s effects on mesenchymal cells, we profiled gene expression in WT and PTHrP−/− mammary buds, and in WT and K14-PTHrP ventral skin at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds. PMID:19795511

  13. The VEGFR2, COX-2 and MMP-2 polymorphisms are associated with clinical outcome of patients with inoperable non-small cell lung cancer.

    PubMed

    Butkiewicz, Dorota; Krześniak, Małgorzata; Drosik, Anna; Giglok, Monika; Gdowicz-Kłosok, Agnieszka; Kosarewicz, Agata; Rusin, Marek; Masłyk, Barbara; Gawkowska-Suwińska, Marzena; Suwiński, Rafał

    2015-11-15

    Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP-1, MMP-2, MMP-3, VEGF, VEGFR2, FGFR4 and COX-2 genes on overall (OS) and progression-free survival (PFS) of 350 Caucasian patients with inoperable non-small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 -906C and COX-2 -1195G alleles were strongly associated with poor OS and PFS (p = 0.002 and 0.015, respectively, for OS; p = 0.009 and 0.015, respectively, for PFS), while MMP-2 -1306 T allele carriers had significantly reduced PFS (p = 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX-2 (p = 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX-2/MMP-2 combinations (p = 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX-2 AG/GG and MMP-2 CT/TT genotypes as well as "at risk" allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX-2 and MMP-2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.

  14. Synovial fluid matrix metalloproteinase-2 and -9 activities in dogs suffering from joint disorders

    PubMed Central

    MURAKAMI, Kohei; MAEDA, Shingo; YONEZAWA, Tomohiro; MATSUKI, Naoaki

    2016-01-01

    The activity of matrix metalloproteinase (MMP)-2 and MMP-9 in synovial fluids (SF) sampled from dogs with joint disorders was investigated by gelatin zymography and densitometry. Pro-MMP-2 showed similar activity levels in dogs with idiopathic polyarthritis (IPA; n=17) or canine rheumatoid arthritis (cRA; n=4), and healthy controls (n=10). However, dogs with cranial cruciate ligament rupture (CCLR; n=5) presented significantly higher pro-MMP-2 activity than IPA and healthy dogs. Meanwhile, dogs with IPA exhibited significantly higher activity of pro- and active MMP-9 than other groups. Activity levels in pro- and active MMP-9 in cRA and CCLR dogs were not significantly different from those in healthy controls. Different patterns of MMP-2 and MMP-9 activity may reflect the differences in the underlying pathological processes. PMID:26902805

  15. Followee Recommendation in Microblog Using Matrix Factorization Model with Structural Regularization

    PubMed Central

    Yu, Yan; Qiu, Robin G.

    2014-01-01

    Microblog that provides us a new communication and information sharing platform has been growing exponentially since it emerged just a few years ago. To microblog users, recommending followees who can serve as high quality information sources is a competitive service. To address this problem, in this paper we propose a matrix factorization model with structural regularization to improve the accuracy of followee recommendation in microblog. More specifically, we adapt the matrix factorization model in traditional item recommender systems to followee recommendation in microblog and use structural regularization to exploit structure information of social network to constrain matrix factorization model. The experimental analysis on a real-world dataset shows that our proposed model is promising. PMID:25143979

  16. Reconstruct modular phenotype-specific gene networks by knowledge-driven matrix factorization

    PubMed Central

    Yang, Xuerui; Zhou, Yang; Jin, Rong; Chan, Christina

    2009-01-01

    Motivation: Reconstructing gene networks from microarray data has provided mechanistic information on cellular processes. A popular structure learning method, Bayesian network inference, has been used to determine network topology despite its shortcomings, i.e. the high-computational cost when analyzing a large number of genes and the inefficiency in exploiting prior knowledge, such as the co-regulation information of the genes. To address these limitations, we are introducing an alternative method, knowledge-driven matrix factorization (KMF) framework, to reconstruct phenotype-specific modular gene networks. Results: Considering the reconstruction of gene network as a matrix factorization problem, we first use the gene expression data to estimate a correlation matrix, and then factorize the correlation matrix to recover the gene modules and the interactions between them. Prior knowledge from Gene Ontology is integrated into the matrix factorization. We applied this KMF algorithm to hepatocellular carcinoma (HepG2) cells treated with free fatty acids (FFAs). By comparing the module networks for the different conditions, we identified the specific modules that are involved in conferring the cytotoxic phenotype induced by palmitate. Further analysis of the gene modules of the different conditions suggested individual genes that play important roles in palmitate-induced cytotoxicity. In summary, KMF can efficiently integrate gene expression data with prior knowledge, thereby providing a powerful method of reconstructing phenotype-specific gene networks and valuable insights into the mechanisms that govern the phenotype. Contact: krischan@msu.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19542155

  17. Matrix metalloproteinase expression and activity in trophoblast-decidual tissues at organogenesis in CF-1 mouse.

    PubMed

    Fontana, Vanina; Coll, Tamara A; Sobarzo, Cristian M A; Tito, Leticia Perez; Calvo, Juan Carlos; Cebral, Elisa

    2012-10-01

    During early placentation, matrix metalloproteinases (MMPs) play important roles in decidualization, trophoblast migration, invasion, angiogenesis, vascularization and extracellular matrix (ECM) remodeling of the endometrium. The aim of our study was to analyze the localization, distribution and differential expression of MMP-2 and -9 in the organogenic implantation site and to evaluate in vivo and in vitro decidual MMP-2 and -9 activities on day 10 of gestation in CF-1 mouse. Whole extracts for Western blotting of organogenic E10-decidua expressed MMP-2 and -9 isoforms. MMP-2 immunoreactivity was found in a granular and discrete pattern in ECM of mesometrial decidua (MD) near maternal blood vessels and slightly in non-decidualized endometrium (NDE). Immunoexpression of MMP-9 was also detected in NDE, in cytoplasm of decidual cells and ECM of vascular MD, in trophoblastic area and in growing antimesometrial deciduum. Gelatin zymography showed that MMP-9 activity was significantly lower in CM compared to the active form of direct (not cultured) and cultured decidua. The decidual active MMP-9 was significantly higher than the active MMP-2. These results show differential localization, protein expression and enzymatic activation of MMPs, suggesting specific roles for MMP-2 and MMP-9 in decidual and trophoblast tissues related to organogenic ECM remodeling and vascularization during early establishment of mouse placentation. PMID:22714107

  18. A distance difference matrix approach to identifying transcription factors that regulate differential gene expression

    PubMed Central

    De Bleser, Pieter; Hooghe, Bart; Vlieghe, Dominique; van Roy, Frans

    2007-01-01

    We introduce a method that considers target genes of a transcription factor, and searches for transcription factor binding sites (TFBSs) of secondary factors responsible for differential responses among these targets. Based on the distance difference matrix concept, the method simultaneously integrates statistical overrepresentation and co-occurrence of TFBSs. Our approach is validated on datasets of differentially regulated human genes and is shown to be highly effective in detecting TFBSs responsible for the observed differential gene expression. PMID:17504544

  19. Form factors of the monodromy matrix entries in gl (2 | 1)-invariant integrable models

    NASA Astrophysics Data System (ADS)

    Hutsalyuk, A.; Liashyk, A.; Pakuliak, S. Z.; Ragoucy, E.; Slavnov, N. A.

    2016-10-01

    We study integrable models solvable by the nested algebraic Bethe ansatz and described by gl (2 | 1) or gl (1 | 2) superalgebras. We obtain explicit determinant representations for form factors of the monodromy matrix entries. We show that all form factors are related to each other at special limits of the Bethe parameters. Our results allow one to obtain determinant formulas for form factors of local operators in the supersymmetric t- J model.

  20. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves matrix metalloproteinase-2 modulation by homocysteine.

    PubMed

    Liu, Tingjiao; Lin, Jinghan; Ju, Ting; Chu, Lei; Zhang, Liming

    2015-08-01

    Arterial calcification is common in vascular diseases and involves conversion of vascular smooth muscle cells (VSMCs) to an osteoblast phenotype. Clinical studies suggest that the development of atherosclerosis can be promoted by homocysteine (HCY), but the mechanisms remain unclear. Here, we determined whether increases in HCY levels lead to an increase in VSMC calcification and differentiation, and examined the role of an extracellular matrix remodeler, matrix metalloproteinase-2 (MMP-2). Rat VSMCs were exposed to calcification medium in the absence or presence of HCY (10, 100 or 200 μmol/L) or an MMP-2 inhibitor (10(-6) or 10(-5) mol/L). MTT assays were performed to determine the cytotoxicity of the MMP-2 inhibitor in calcification medium containing 200 μmol/L HCY. Calcification was assessed by measurements of calcium deposition and alkaline phosphatase (ALP) activity as well as von Kossa staining. Expression of osteocalcin, bone morphogenetic protein (BMP)-2, and osteopontin, and MMP-2 was determined by immunoblotting. Calcification medium induced osteogenic differentiation of VSMCs. HCY promoted calcification, increased osteocalcin and BMP-2 expression, and decreased expression of osteopontin. MMP-2 expression was increased by HCY in a dose-dependent manner in VSMCs exposed to both control and calcification medium. The MMP-2 inhibitor decreased the calcium content and ALP activity, and attenuated the osteoblastic phenotype of VSMCs. Vascular calcification and osteogenic differentiation of VSMCs were positively regulated by HCY through increased/restored MMP-2 expression, increased expression of calcification proteins, and decreased anti-calcification protein levels. In summary, MMP-2 inhibition may be a protective strategy against VSMC calcification. PMID:25987498

  1. Upconversion fluorescence resonance energy transfer based biosensor for ultrasensitive detection of matrix metalloproteinase-2 in blood.

    PubMed

    Wang, Yuhui; Shen, Pei; Li, Chunya; Wang, Yanying; Liu, Zhihong

    2012-02-01

    Matrix metalloproteinase-2 (MMP-2) is a very important biomarker in blood. Presently, sensitive and selective determination of MMP-2 directly in blood samples is still a challenging job because of the high complexity of the sample matrix. In this work, we reported a new homogeneous biosensor for MMP-2 based on fluorescence resonance energy transfer (FRET) from upconversion phosphors (UCPs) to carbon nanoparticles (CNPs). A polypeptide chain (NH(2)-GHHYYGPLGVRGC-COOH) comprising both the specific MMP-2 substrate domain (PLGVR) and a π-rich motif (HHYY) was designed and linked to the surface of UCPs at the C terminus. The FRET process was initiated by the π-π interaction between the peptide and CNPs, which thus quenched the fluorescence of the donor. Upon the cleavage of the substrate by the protease at the amide bond between Gly and Val, the donor was separated from the acceptor while the π-rich motif stayed on the acceptor. As a result, the fluorescence of the donor was restored. The fluorescence recovery was found to be proportional to the concentration of MMP-2 within the range from 10-500 pg/mL in an aqueous solution. The quantification limit of this sensor was at least 1 order of magnitude lower than that of other reported assays for MMP-2. The sensor was used to determine the MMP-2 level directly in human plasma and whole blood samples with satisfactory results obtained. Owing to the hypersensitivity of the method, clinical samples of only less than 1 μL were needed for accurate quantification, which can be meaningful in MMP-2-related clinical and bioanalytical applications.

  2. Sparse Non-negative Matrix Factorization (SNMF) based color unmixing for breast histopathological image analysis.

    PubMed

    Xu, Jun; Xiang, Lei; Wang, Guanhao; Ganesan, Shridar; Feldman, Michael; Shih, Natalie N C; Gilmore, Hannah; Madabhushi, Anant

    2015-12-01

    Color deconvolution has emerged as a popular method for color unmixing as a pre-processing step for image analysis of digital pathology images. One deficiency of this approach is that the stain matrix is pre-defined which requires specific knowledge of the data. This paper presents an unsupervised Sparse Non-negative Matrix Factorization (SNMF) based approach for color unmixing. We evaluate this approach for color unmixing of breast pathology images. Compared to Non-negative Matrix Factorization (NMF), the sparseness constraint imposed on coefficient matrix aims to use more meaningful representation of color components for separating stained colors. In this work SNMF is leveraged for decomposing pure stained color in both Immunohistochemistry (IHC) and Hematoxylin and Eosin (H&E) images. SNMF is compared with Principle Component Analysis (PCA), Independent Component Analysis (ICA), Color Deconvolution (CD), and Non-negative Matrix Factorization (NMF) based approaches. SNMF demonstrated improved performance in decomposing brown diaminobenzidine (DAB) component from 36 IHC images as well as accurately segmenting about 1400 nuclei and 500 lymphocytes from H & E images.

  3. Sparse Non-negative Matrix Factorization (SNMF) based color unmixing for breast histopathological image analysis.

    PubMed

    Xu, Jun; Xiang, Lei; Wang, Guanhao; Ganesan, Shridar; Feldman, Michael; Shih, Natalie N C; Gilmore, Hannah; Madabhushi, Anant

    2015-12-01

    Color deconvolution has emerged as a popular method for color unmixing as a pre-processing step for image analysis of digital pathology images. One deficiency of this approach is that the stain matrix is pre-defined which requires specific knowledge of the data. This paper presents an unsupervised Sparse Non-negative Matrix Factorization (SNMF) based approach for color unmixing. We evaluate this approach for color unmixing of breast pathology images. Compared to Non-negative Matrix Factorization (NMF), the sparseness constraint imposed on coefficient matrix aims to use more meaningful representation of color components for separating stained colors. In this work SNMF is leveraged for decomposing pure stained color in both Immunohistochemistry (IHC) and Hematoxylin and Eosin (H&E) images. SNMF is compared with Principle Component Analysis (PCA), Independent Component Analysis (ICA), Color Deconvolution (CD), and Non-negative Matrix Factorization (NMF) based approaches. SNMF demonstrated improved performance in decomposing brown diaminobenzidine (DAB) component from 36 IHC images as well as accurately segmenting about 1400 nuclei and 500 lymphocytes from H & E images. PMID:25958195

  4. Technique for information retrieval using enhanced latent semantic analysis generating rank approximation matrix by factorizing the weighted morpheme-by-document matrix

    DOEpatents

    Chew, Peter A; Bader, Brett W

    2012-10-16

    A technique for information retrieval includes parsing a corpus to identify a number of wordform instances within each document of the corpus. A weighted morpheme-by-document matrix is generated based at least in part on the number of wordform instances within each document of the corpus and based at least in part on a weighting function. The weighted morpheme-by-document matrix separately enumerates instances of stems and affixes. Additionally or alternatively, a term-by-term alignment matrix may be generated based at least in part on the number of wordform instances within each document of the corpus. At least one lower rank approximation matrix is generated by factorizing the weighted morpheme-by-document matrix and/or the term-by-term alignment matrix.

  5. Matrix Metalloproteinases in Primary Culture of Cardiomyocytes.

    PubMed

    Bildyug, N B; Voronkina, I V; Smagina, L V; Yudintseva, N M; Pinaev, G P

    2015-10-01

    The highly organized contractile apparatus of cardiomyocytes in heart tissue allows for their continuous contractility, whereas extracellular matrix components are synthesized and spatially organized by fibroblasts and endothelial cells. However, reorganization of the cardiomyocyte contractile apparatus occurs upon their 2D cultivation, which is accompanied by transient loss of their contractility and acquired capability of extracellular matrix synthesis (Bildyug, N. B., and Pinaev, G. P. (2013) Tsitologiya, 55, 713-724). In this study, matrix metalloproteinases were investigated at different times of cardiomyocyte 2D cultivation and 3D cultivation in collagen gels. It was found that cardiomyocytes in 2D culture synthesize matrix metalloproteinases MMP-2 and MMP-9, wherein their amount varies with the cultivation time. The peak MMP-9 amount is at early cultivation time, when the reorganization of cardiomyocyte contractile apparatus occurs, and the MMP-2 peak precedes the recovery of the initial organization of their contractile apparatus. Upon cardiomyocyte cultivation in 3D collagen gels, in which case their contractile apparatus does not rearrange, a steady small amount of MMP-2 and MMP-9 is observed. These data indicate that the cardiomyocyte contractile apparatus reorganization in culture is associated with synthesis and spatial organization of their own extracellular matrix.

  6. Effects of eplerenone on the activation of matrix metalloproteinase-2 stimulated by high glucose and interleukin-1β in human cardiac fibroblasts.

    PubMed

    Chi, J F; Uzui, H; Guo, H Y; Ueda, T; Lee, J D

    2014-01-01

    The aim of this study was to determine the influence of high glucose (HG) and interleukin (IL)-1β on human cardiac fibroblast (HCF) functions, and to evaluate the effects of eplerenone in these responses. HCFs were cultured in normal or HG media in the absence or presence of IL-1β and/or eplerenone. We assessed matrix metalloproteinase-2 (MMP-2) activity in the supernatant by in-gel zymography, and determined mRNA expression levels of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) by reverse transcription-polymerase chain reaction. Equimolar D-mannitol was used as an osmotic control. HG stimulated MMP-2 activity and promoted MMP-2 mRNA synthesis. Increased effects were also observed in equimolar D-mannitol treatments, but these effects were weaker compared to those of glucose. The combination of HG and IL-1β resulted in a 2-fold increase in MMP-2 activity and mRNA expression compared with HG or IL-1β alone. Increases in HG- or IL-1β-induced MMP-2 activity and mRNA expression were blocked by eplerenone. Neither HG nor IL-1β affected TIMP-2 mRNA expression. HG increased MMP-2 activity by regulation of MMP- 2 mRNA expression in HCFs through osmotic and non-osmotic pathways. Synergistic effects of IL-1β added to HG media on MMP-2 activity and mRNA expression were observed in HCFs. Eplerenone normalized the effect of MMP-2 activity and HG- or IL-1β-induced expression in HCFs.

  7. A Transfer Learning Approach for Applying Matrix Factorization to Small ITS Datasets

    ERIC Educational Resources Information Center

    Voß, Lydia; Schatten, Carlotta; Mazziotti, Claudia; Schmidt-Thieme, Lars

    2015-01-01

    Machine Learning methods for Performance Prediction in Intelligent Tutoring Systems (ITS) have proven their efficacy; specific methods, e.g. Matrix Factorization (MF), however suffer from the lack of available information about new tasks or new students. In this paper we show how this problem could be solved by applying Transfer Learning (TL),…

  8. Analysis of incomplete matrix factorizations as multigrid smoothers for vector and parallel computers

    SciTech Connect

    Axelsson, O.

    1986-07-01

    The cost of smoothing is usually a major expense in multigrid codes. Efficient vectorizable and parallelizable versions of incomplete block-matrix factorization methods used as smoothers for multigrid methods are discussed in this paper. The methods are particularly interesting for computers with parallel processors with pipelines, because both multitasking with little overhead and vectorization can be achieved. 21 references.

  9. A Flexible and Efficient Algorithmic Framework for Constrained Matrix and Tensor Factorization

    NASA Astrophysics Data System (ADS)

    Huang, Kejun; Sidiropoulos, Nicholas D.; Liavas, Athanasios P.

    2016-10-01

    We propose a general algorithmic framework for constrained matrix and tensor factorization, which is widely used in signal processing and machine learning. The new framework is a hybrid between alternating optimization (AO) and the alternating direction method of multipliers (ADMM): each matrix factor is updated in turn, using ADMM, hence the name AO-ADMM. This combination can naturally accommodate a great variety of constraints on the factor matrices, and almost all possible loss measures for the fitting. Computation caching and warm start strategies are used to ensure that each update is evaluated efficiently, while the outer AO framework exploits recent developments in block coordinate descent (BCD)-type methods which help ensure that every limit point is a stationary point, as well as faster and more robust convergence in practice. Three special cases are studied in detail: non-negative matrix/tensor factorization, constrained matrix/tensor completion, and dictionary learning. Extensive simulations and experiments with real data are used to showcase the effectiveness and broad applicability of the proposed framework.

  10. In Spite of Indeterminacy Many Common Factor Score Estimates Yield an Identical Reproduced Covariance Matrix

    ERIC Educational Resources Information Center

    Beauducel, Andre

    2007-01-01

    It was investigated whether commonly used factor score estimates lead to the same reproduced covariance matrix of observed variables. This was achieved by means of Schonemann and Steiger's (1976) regression component analysis, since it is possible to compute the reproduced covariance matrices of the regression components corresponding to different…

  11. A multivariate approach to filling gaps in large ecological data sets using probabilistic matrix factorization techniques

    NASA Astrophysics Data System (ADS)

    Schrodt, F. I.; Shan, H.; Kattge, J.; Reich, P.; Banerjee, A.; Reichstein, M.

    2012-12-01

    With the advent of remotely sensed data and coordinated efforts to create global databases, the ecological community has progressively become more data-intensive. However, in contrast to other disciplines, statistical ways of handling these large data sets, especially the gaps which are inherent to them, are lacking. Widely used theoretical approaches, for example model averaging based on Akaike's information criterion (AIC), are sensitive to missing values. Yet, the most common way of handling sparse matrices - the deletion of cases with missing data (complete case analysis) - is known to severely reduce statistical power as well as inducing biased parameter estimates. In order to address these issues, we present novel approaches to gap filling in large ecological data sets using matrix factorization techniques. Factorization based matrix completion was developed in a recommender system context and has since been widely used to impute missing data in fields outside the ecological community. Here, we evaluate the effectiveness of probabilistic matrix factorization techniques for imputing missing data in ecological matrices using two imputation techniques. Hierarchical Probabilistic Matrix Factorization (HPMF) effectively incorporates hierarchical phylogenetic information (phylogenetic group, family, genus, species and individual plant) into the trait imputation. Kernelized Probabilistic Matrix Factorization (KPMF) on the other hand includes environmental information (climate and soils) into the matrix factorization through kernel matrices over rows and columns. We test the accuracy and effectiveness of HPMF and KPMF in filling sparse matrices, using the TRY database of plant functional traits (http://www.try-db.org). TRY is one of the largest global compilations of plant trait databases (750 traits of 1 million plants), encompassing data on morphological, anatomical, biochemical, phenological and physiological features of plants. However, despite of unprecedented

  12. Factorization of a class of matrix-functions with stable partial indices

    NASA Astrophysics Data System (ADS)

    Mishuris, G.; Rogosin, S.

    2016-09-01

    A new effective method for factorization of a class of nonrational $n\\times n$ matrix-functions with \\emph{stable partial indices} is proposed. The method is a generalization of the one recently proposed by the authors which was valid for the canonical factorization only. The class of considered matrices is motivated by problems originated from applications. The properties and details of the asymptotic procedure are illustrated by examples. The efficiency of the procedure is highlighted by numerical results.

  13. Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome

    PubMed Central

    Aluri, Hema S.; Kublin, Claire L.; Thotakura, Suharika; Armaos, Helene; Samizadeh, Mahta; Hawley, Dillon; Thomas, William M.; Leavis, Paul; Makarenkova, Helen P.; Zoukhri, Driss

    2015-01-01

    Purpose Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair. Methods The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above. Results There was a 2.5- and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands. Conclusions We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands. PMID:26244298

  14. Extracellular matrix-inspired growth factor delivery systems for bone regeneration

    SciTech Connect

    Martino, Mikaël M.; Briquez, Priscilla S.; Maruyama, Kenta; Hubbell, Jeffrey A.

    2015-04-17

    Growth factors are very promising molecules to enhance bone regeneration. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems derive from the vastly supra-physiological doses of growth factor used without optimized delivery systems. Therefore, these issues have motivated the development of new delivery systems allowing better control of the spatio-temporal release and signaling of growth factors. Because the extracellular matrix (ECM) naturally plays a fundamental role in coordinating growth factor activity in vivo, a number of novel delivery systems have been inspired by the growth factor regulatory function of the ECM. After introducing the role of growth factors during the bone regeneration process, this review exposes different issues that growth factor-based therapies have encountered in the clinic and highlights recent delivery approaches based on the natural interaction between growth factor and the ECM.

  15. Extracellular matrix-inspired growth factor delivery systems for bone regeneration.

    PubMed

    Martino, Mikaël M; Briquez, Priscilla S; Maruyama, Kenta; Hubbell, Jeffrey A

    2015-11-01

    Growth factors are very promising molecules to enhance bone regeneration. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems derive from the vastly supra-physiological doses of growth factor used without optimized delivery systems. Therefore, these issues have motivated the development of new delivery systems allowing better control of the spatiotemporal release and signaling of growth factors. Because the extracellular matrix (ECM) naturally plays a fundamental role in coordinating growth factor activity in vivo, a number of novel delivery systems have been inspired by the growth factor regulatory function of the ECM. After introducing the role of growth factors during the bone regeneration process, this review exposes different issues that growth factor-based therapies have encountered in the clinic and highlights recent delivery approaches based on the natural interaction between growth factor and the ECM.

  16. Time-dependent Expression of MMP-2 and TIMP-2 after Rats Skeletal Muscle Contusion and Their Application to Determine Wound Age.

    PubMed

    Yu, Tian-shui; Li, Zhuang; Zhao, Rui; Zhang, Yan; Zhang, Zhen-hua; Guan, Da-wei

    2016-03-01

    The ability to determine vitality and estimate the survival period after a wound is critical in routine forensic practice. The mRNA levels of MMP-2 and TIMP-2 were examined using quantitative real-time RT-PCR to determine the age of a wound. Furthermore, the colocalization of them with Macrophage Marker, respectively, was detected by double immunofluorescence, and a standardized rat model of skeletal muscle contusion was established. In the antemortem contused groups, a large number of macrophages showed positive staining for MMP-2 and TIMP-2, and the expression of MMP-2 and TIMP-2 mRNA increased sharply at 3 days postinjury, with relative quantities of 5.75 and 2.98. No samples in the other groups showed relative quantities of >5.75 and 2.98; therefore, relative quantities exceeding 5.75 and 2.98 were strongly indicated 3 days after contusion. In addition, there was a significant decrease in the relative quantity in the postmortem contused groups, indicating that they were useful for diagnosing vitality. PMID:27404628

  17. Aligned Electrospun Scaffolds and Elastogenic Factors for Vascular Cell-Mediated Elastic Matrix Assembly

    PubMed Central

    Bashur, Chris A.; Ramamurthi, Anand

    2011-01-01

    Strategies to enhance the production of organized elastic matrix by smooth muscle cells (SMCs) are critical in engineering functional vascular conduits. Therefore, the goal of this study was to determine the effect of different surfaces (i.e. random and aligned electrospun poly(ε-caprolactone) meshes and two-dimensional controls) and exogenous elastogenic factors on cultured rat aortic SMC phenotype and production of extracellular matrix. This study demonstrated that aligned electrospun fibers guide cell alignment, induce a more elongated cell morphology, and promote a more synthetic phenotype. Importantly, these cells produced greater amounts of elastin-rich matrix per cell on the electrospun scaffolds. In addition, exogenous elastogenic factors severely limited RASMC proliferation and promoted a more synthetic SMC phenotype on electrospun meshes, but they had less effect on two-dimensional controls. Finally, the elastogenic factors induced the SMCs to generate more matrix collagen and elastin on a per cell basis. Together, these results demonstrate the elastogenic benefits of electrospun meshes. PMID:21953981

  18. A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation.

    PubMed

    Romanchikova, Nadezhda; Trapencieris, Pēteris; Zemītis, Jānis; Turks, Māris

    2014-12-01

    A novel matrix metalloproteinase-2 (MMP-2) inhibitor JaZ-30, which belongs to the class of C(2)-monosubstituted aziridine - aryl-1,2,3-triazole conjugates, was developed. MTT and crystal violet assays were used to determine cytotoxicity- IC(50) values of compound JaZ-30 on melanoma cell line B16 4A5. Our study proves the anti-cancer properties of JaZ-30 with a wide spectrum of activities. JaZ-30 was revealed as selective inhibitor of matrix metalloproteinase-2. JaZ-30-mediated decrease of Vascular Endothelial Growth Factor (VEGF) secretion results in inhibition of angiogenesis, performed with the human umbilical vein endothelial cell line (HUVEC-2) on Matrigel. A novel inhibitor decreases invasive properties of melanoma cells measured in Matrigel chambers assay. JaZ-30 downregulates phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in melanoma cells stimulated by phorbol-12-myristate-13-acetate (PMA). Our findings propose a novel MMP-2 inhibitor JaZ-30 as an attractive potential agent for melanoma treatment.

  19. Fast and efficient fully 3D PET image reconstruction using sparse system matrix factorization with GPU acceleration

    NASA Astrophysics Data System (ADS)

    Zhou, Jian; Qi, Jinyi

    2011-10-01

    Statistically based iterative image reconstruction has been widely used in positron emission tomography (PET) imaging. The quality of reconstructed images depends on the accuracy of the system matrix that defines the mapping from the image space to the data space. However, an accurate system matrix is often associated with high computation cost and huge storage requirement. In this paper, we present a method to address this problem using sparse matrix factorization and graphics processor unit (GPU) acceleration. We factor the accurate system matrix into three highly sparse matrices: a sinogram blurring matrix, a geometric projection matrix and an image blurring matrix. The geometrical projection matrix is precomputed based on a simple line integral model, while the sinogram and image blurring matrices are estimated from point-source measurements. The resulting factored system matrix has far less nonzero elements than the original system matrix, which substantially reduces the storage and computation cost. The smaller matrix size also allows an efficient implementation of the forward and backward projectors on a GPU, which often has a limited memory space. Our experimental studies show that the proposed method can dramatically reduce the computation cost of high-resolution iterative image reconstruction, while achieving better performance than existing factorization methods.

  20. One-factor model for the cross-correlation matrix in the Vietnamese stock market

    NASA Astrophysics Data System (ADS)

    Nguyen, Quang

    2013-07-01

    Random matrix theory (RMT) has been applied to the analysis of the cross-correlation matrix of a financial time series. The most important findings of previous studies using this method are that the eigenvalue spectrum largely follows that of random matrices but the largest eigenvalue is at least one order of magnitude higher than the maximum eigenvalue predicted by RMT. In this work, we investigate the cross-correlation matrix in the Vietnamese stock market using RMT and find similar results to those of studies realized in developed markets (US, Europe, Japan) [9-18] as well as in other emerging markets[20,21,19,22]. Importantly, we found that the largest eigenvalue could be approximated by the product of the average cross-correlation coefficient and the number of stocks studied. We demonstrate this dependence using a simple one-factor model. The model could be extended to describe other characteristics of the realistic data.

  1. Matrix metalloproteinase-2 is elevated in midtrimester amniotic fluid prior to the development of preeclampsia

    PubMed Central

    Lavee, Michal; Goldman, Shlomit; Daniel-Spiegel, Etty; Shalev, Eliezer

    2009-01-01

    Objective To evaluate levels of matrix metalloproteinases (MMP) and their inhibitors (TIMP) in second trimester amniotic fluid of women with hypertensive disorders compared to normotensive women. Study Design Amniotic fluid was obtained from 133 women undergoing genetic second trimester amniocentesis. Zymography was performed for MMP characterization and an MMP-2 ELISA kit was used to determine MMP-2 levels. TIMP-2 expression was evaluated using western blot. Results Mean amniotic fluid MMP-2 and TIMP-2 levels were significantly higher in women who developed a hypertensive disorder compared to normotensive women (P < 0.0004 and P < 0.01, respectively). When subdivided into subgroups, amniotic fluid from women who eventually developed preeclampsia or superimposed preeclampsia showed significantly higher MMP-2 levels than normotensive women (P < 0.05). However, no statistical difference in MMP-2 levels was found between patients with gestational hypertension and normotensive patients. Conclusion Higher amniotic fluid MMP-2 and TIMP-2 levels are found in women who eventually develop preeclampsia. PMID:19698156

  2. Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes.

    PubMed

    Fan, Xiaohu; Hughes, Bryan G; Ali, Mohammad A M; Chan, Brandon Y H; Launier, Katherine; Schulz, Richard

    2016-07-01

    Cardiomyocyte dedifferentiation may be an important source of proliferating cardiomyocytes facilitating cardiac repair. Cardiomyocyte dedifferentiation and proliferation induced by oncostatin-M (OSM) is characterized by sarcomere degeneration. However, the mechanism underlying sarcomere degeneration remains unclear. We hypothesized that this process may involve matrix metalloproteinase-2 (MMP-2), a key protease localized at the sarcomere in cardiomyocytes. We tested the hypothesis that MMP-2 is involved in the sarcomere degeneration that characterizes cardiomyocyte dedifferentiation. Confocal immunofluorescence and biochemical methods were used to explore the role of MMP-2 in OSM-induced dedifferentiation of neonatal rat ventricular myocytes (NRVM). OSM caused a concentration- and time-dependent loss of sarcomeric α-actinin and troponin-I in NRVM. Upon OSM-treatment, the mature sarcomere transformed to a phenotype resembling a less-developed sarcomere, i.e., loss of sarcomeric proteins and Z-disk transformed into disconnected Z bodies, characteristic of immature myofibrils. OSM dose dependently increased MMP-2 activity. Both the pan-MMP inhibitor GM6001 and the selective MMP-2 inhibitor ARP 100 prevented sarcomere degeneration induced by OSM treatment. OSM also induced NRVM cell cycling and increased methyl-thiazolyl-tetrazolium (MTT) staining, preventable by MMP inhibition. These results suggest that MMP-2 mediates sarcomere degeneration in OSM-induced cardiomyocyte dedifferentiation and thus potentially contributes to cardiomyocyte regeneration.

  3. Activation of toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic-cell-mediated inflammatory responses.

    PubMed

    Godefroy, Emmanuelle; Gallois, Anne; Idoyaga, Juliana; Merad, Miriam; Tung, Navpreet; Monu, Ngozi; Saenger, Yvonne; Fu, Yichun; Ravindran, Rajesh; Pulendran, Bali; Jotereau, Francine; Trombetta, Sergio; Bhardwaj, Nina

    2014-12-11

    Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity.

  4. Activation of Toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic cell-mediated inflammatory responses

    PubMed Central

    Godefroy, Emmanuelle; Gallois, Anne; Idoyaga, Juliana; Merad, Miriam; Tung, Navpreet; Monu, Ngozi; Saenger, Yvonne; Fu, Yichun; Nair, Rajesh; Pulendran, Bali; Jotereau, Francine; Trombetta, Sergio; Bhardwaj, Nina

    2015-01-01

    SUMMARY Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both up-regulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L up-regulation on DCs and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells towards type-2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type-2 polarization may represent a key immune regulatory mechanism to protect against a broad array of disorders, such as inflammatory, infectious and autoimmune diseases, which can be hijacked by tumors to evade immunity. PMID:25466255

  5. [Extracellular matrix as a microbial virulence factor in the development of human diseases].

    PubMed

    Moryl, Magdalena

    2015-01-01

    Extracellular polymers which build a biofilm matrix possess a complicated structure, where the polysaccharide fraction, composed of homo- or heteropolysaccharides, is the largest. Other important components are proteins, eDNA, glycoproteins and lipids. The matrix has a protective function against the surrounding environment, plays a role in biofilm formation and maturation processes, stabilizes the biofilm structure, and also is a source of nutrients and water for the cells. It is noteworthy that the biofilm matrix is a virulence factor and plays an important role in the pathogenesis of many human diseases. Pseudomonas aeruginosa growing in the lungs of patients with cystic fibrosis produces three major exopolysaccharides (Pel, Psl and alginate) and synthesizes numerous proteins such as lectins and enzymes, e.g. PasP, chitinase, aminopeptidase, and protease IV, which facilitate the tissue colonization. Extracellular polymers play a significant role in the course of caries, which is associated with the development of multi-species biofilm on the teeth surface. The structure of the matrix surrounding that biofilm is complicated--different for each patient. The components of the matrix are constantly changing depending on the environmental conditions, e.g. the presence of sucrose affects the synthesis of mutan and dextran. Infections associated with biofilm formation on implants pose significant medical and economic problems. The main components of the matrices are saccharides (e.g., PIA, EC-TA), as well as surface and extracellular proteins. Studies on the matrix structure and the factors regulating its synthesis are necessary to develop techniques for biofilm eradication and better control of biofilm-related infections.

  6. Matrix metallopeptidase 2 activity in tendon regions: effects of mechanical loading exercise associated to anabolic-androgenic steroids.

    PubMed

    Marqueti, Rita C; Prestes, Jonato; Paschoal, Milena; Ramos, Oscar H P; Perez, Sérgio E A; Carvalho, Hernandes F; Selistre-de-Araujo, Heloisa S

    2008-12-01

    Matrix metallopeptidases (MMPs) are responsible for degradation of the extracellular matrix components and tissue remodeling. To achieve a better understanding of AAS effects in rat tendon, MMP-2 activity in the proximal and distal regions of the calcanear tendon (CT) and proximal, intermediate and distal region of superficial (SFT) and deep flexor tendons (DFT) after mechanical load exercise associated with AAS was investigated. Animals were grouped into four groups: sedentary animals (S); sedentary animals with ASS supplementation (S + A); trained animals (T) and trained animals with AAS supplementation (T + A). Analysis of MMP activity in tendon extracts was done by gelatin zymography. Both proximal and distal regions of the calcanear tendon showed the lowest MMP-2 concentration and the highest proportion in MMP-2 active form. The intermediate region of the SFT differed (P < 0.01) from the proximal and distal regions with higher % of active MMP-2 in the sedentary group. The proportion of active MMP-2 decreased in the proximal region of the CT. AAS treatment strongly decreased both MMP-2 concentration and active form in the three regions of the SFT and on the proximal region of the CT, but not on the DFT. The differences in the response to exercise and AAS treatment are a result of distinct metabolism and recruitment of these tendon regions in the exercise program employed in this study.

  7. Source apportionment of stack emissions from research and development facilities using positive matrix factorization

    NASA Astrophysics Data System (ADS)

    Ballinger, Marcel Y.; Larson, Timothy V.

    2014-12-01

    Research and development (R&D) facility emissions are difficult to characterize due to their variable processes, changing nature of research, and large number of chemicals. Positive matrix factorization (PMF) was applied to volatile organic compound (VOC) concentrations measured in the main exhaust stacks of four different R&D buildings to identify the number and composition of major contributing sources. PMF identified between 9 and 11 source-related factors contributing to stack emissions, depending on the building. Similar factors between buildings were major contributors to trichloroethylene (TCE), acetone, and ethanol emissions; other factors had similar profiles for two or more buildings but not all four. At least one factor for each building was identified that contained a broad mix of many species and constraints were used in PMF to modify the factors to resemble more closely the off-shift concentration profiles. PMF accepted the constraints with little decrease in model fit.

  8. Non-negative matrix factorization and term structure of interest rates

    NASA Astrophysics Data System (ADS)

    Takada, Hellinton H.; Stern, Julio M.

    2015-01-01

    Non-Negative Matrix Factorization (NNMF) is a technique for dimensionality reduction with a wide variety of applications from text mining to identification of concentrations in chemistry. NNMF deals with non-negative data and results in non-negative factors and factor loadings. Consequently, it is a natural choice when studying the term structure of interest rates. In this paper, NNMF is applied to obtain factors from the term structure of interest rates and the procedure is compared with other very popular techniques: principal component analysis and Nelson-Siegel model. The NNMF approximation for the term structure of interest rates is better in terms of fitting. From a practitioner point of view, the NNMF factors and factor loadings obtained possess straightforward financial interpretations due to their non-negativeness.

  9. Recursive Factorization of the Inverse Overlap Matrix in Linear-Scaling Quantum Molecular Dynamics Simulations.

    PubMed

    Negre, Christian F A; Mniszewski, Susan M; Cawkwell, Marc J; Bock, Nicolas; Wall, Michael E; Niklasson, Anders M N

    2016-07-12

    We present a reduced complexity algorithm to compute the inverse overlap factors required to solve the generalized eigenvalue problem in a quantum-based molecular dynamics (MD) simulation. Our method is based on the recursive, iterative refinement of an initial guess of Z (inverse square root of the overlap matrix S). The initial guess of Z is obtained beforehand by using either an approximate divide-and-conquer technique or dynamical methods, propagated within an extended Lagrangian dynamics from previous MD time steps. With this formulation, we achieve long-term stability and energy conservation even under the incomplete, approximate, iterative refinement of Z. Linear-scaling performance is obtained using numerically thresholded sparse matrix algebra based on the ELLPACK-R sparse matrix data format, which also enables efficient shared-memory parallelization. As we show in this article using self-consistent density-functional-based tight-binding MD, our approach is faster than conventional methods based on the diagonalization of overlap matrix S for systems as small as a few hundred atoms, substantially accelerating quantum-based simulations even for molecular structures of intermediate size. For a 4158-atom water-solvated polyalanine system, we find an average speedup factor of 122 for the computation of Z in each MD step. PMID:27267207

  10. A regularized matrix factorization approach to induce structured sparse-low-rank solutions in the EEG inverse problem

    NASA Astrophysics Data System (ADS)

    Montoya-Martínez, Jair; Artés-Rodríguez, Antonio; Pontil, Massimiliano; Hansen, Lars Kai

    2014-12-01

    We consider the estimation of the Brain Electrical Sources (BES) matrix from noisy electroencephalographic (EEG) measurements, commonly named as the EEG inverse problem. We propose a new method to induce neurophysiological meaningful solutions, which takes into account the smoothness, structured sparsity, and low rank of the BES matrix. The method is based on the factorization of the BES matrix as a product of a sparse coding matrix and a dense latent source matrix. The structured sparse-low-rank structure is enforced by minimizing a regularized functional that includes the ℓ 21-norm of the coding matrix and the squared Frobenius norm of the latent source matrix. We develop an alternating optimization algorithm to solve the resulting nonsmooth-nonconvex minimization problem. We analyze the convergence of the optimization procedure, and we compare, under different synthetic scenarios, the performance of our method with respect to the Group Lasso and Trace Norm regularizers when they are applied directly to the target matrix.

  11. Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated Kinase-1

    PubMed Central

    Zhou, Ling; Yan, Chunli; Gieling, Roben G; Kida, Yujiro; Garner, Warren; Li, Wei; Han, Yuan-Ping

    2009-01-01

    Background Expressed in embryonic development, matrix metalloprotein-9 (MMP-9) is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM). While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1) and the down stream signaling. Results In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK) and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in part, by boost JNK

  12. Matrix metalloproteinases (MMPs) inhibitory effects of an octameric oligopeptide isolated from abalone Haliotis discus hannai.

    PubMed

    Nguyen, Van-Tinh; Qian, Zhong-Ji; Ryu, Bomi; Kim, Kil-Nam; Kim, Daekyung; Kim, Young-Mog; Jeon, You-Jin; Park, Won Sun; Choi, Il-Whan; Kim, Geun Hyung; Je, Jae-Young; Jung, Won-Kyo

    2013-11-01

    Abalone (Haliotis discus hannai) is a marine gastropod, and an important fishery and food industrial resource that is massively maricultured in Asia, Africa, Australia and America. However, its health benefits have rarely been studied for nutraceutical and pharmaceutical application. In this study, the purified abalone oligopeptide (AOP) with anti-matrix metalloproteinases (anti-MMPs) effects was isolated from the digests of abalone intestine using recycle HPLC with a JAI W253 column and an OHpak SB-803 HQ column. The AOP was identified as Ala-Glu-Leu-Pro-Ser-Leu-Pro-Gly (MW=782.4 Da) with a de novo peptide sequencing technique using a tandem mass spectrometer. The AOP exhibited a specific inhibitory effect against MMP-2/-9 activity and attenuated protein expression of p50 and p65 in the human fibrosarcoma (HT1080) cells, dose-dependently. The results presented illustrate that the AOP could inhibit MMP-2/-9 expression in HT1080 cells via the nuclear factor-kappaB (NF-κB)-mediated pathway. This data suggest that the AOP from H. discus hannai intestine may possess therapeutic and preventive potential for the treatment of MMPs-related disorders such as angiogenesis and cardiovascular diseases.

  13. Structural and functional discovery in dynamic networks with non-negative matrix factorization.

    PubMed

    Mankad, Shawn; Michailidis, George

    2013-10-01

    Time series of graphs are increasingly prevalent in modern data and pose unique challenges to visual exploration and pattern extraction. This paper describes the development and application of matrix factorizations for exploration and time-varying community detection in time-evolving graph sequences. The matrix factorization model allows the user to home in on and display interesting, underlying structure and its evolution over time. The methods are scalable to weighted networks with a large number of time points or nodes and can accommodate sudden changes to graph topology. Our techniques are demonstrated with several dynamic graph series from both synthetic and real-world data, including citation and trade networks. These examples illustrate how users can steer the techniques and combine them with existing methods to discover and display meaningful patterns in sizable graphs over many time points. PMID:24229230

  14. Structural and functional discovery in dynamic networks with non-negative matrix factorization

    NASA Astrophysics Data System (ADS)

    Mankad, Shawn; Michailidis, George

    2013-10-01

    Time series of graphs are increasingly prevalent in modern data and pose unique challenges to visual exploration and pattern extraction. This paper describes the development and application of matrix factorizations for exploration and time-varying community detection in time-evolving graph sequences. The matrix factorization model allows the user to home in on and display interesting, underlying structure and its evolution over time. The methods are scalable to weighted networks with a large number of time points or nodes and can accommodate sudden changes to graph topology. Our techniques are demonstrated with several dynamic graph series from both synthetic and real-world data, including citation and trade networks. These examples illustrate how users can steer the techniques and combine them with existing methods to discover and display meaningful patterns in sizable graphs over many time points.

  15. Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)‑2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway.

    PubMed

    Li, Xiaolei; Yang, Zhaoxu; Song, Wenjie; Zhou, Liang; Li, Qingjun; Tao, Kaishan; Zhou, Jingshi; Wang, Xing; Zheng, Zhigang; You, Nan; Dou, Kefeng; Li, Haimin

    2013-09-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and it carries a poor prognosis due to a high rate of recurrence or metastasis after surgery. Bmi-1 plays a significant role in the growth and metastasis of many solid tumours. However, the exact mechanisms underlying Bmi-1-mediated cell invasion and metastasis, especially in HCC, are not yet known. In the present study, we sought to evaluate the expression of Bmi-1 in HCC samples and its relationship with clinicopathological characteristics and prognostic value, we also investigated related mechanisms underlying Bmi-1-mediated cell invasion in HCC. Our results showed that Bmi-1 is upregulated in HCC tissues compared to matched non-cancer liver tissues; and its expression is positively associated with tumour size, metastasis, venous invasion and AJCC TNM stage, respectively; multivariate analysis showed that high expression of Bmi-1 was an independent prognostic factor for overall survival. In addition, the shRNA-mediated inhibition of Bmi-1 reduced the invasiveness of two HCC cell lines in vitro by upregulating phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) expression, inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and downregulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 and vascular endothelial growth factor (VEGF). These data demonstrate that Bmi-1 plays a vital role in HCC invasion and that Bmi-1 is a potential therapeutic target for HCC.

  16. Matrix Factorization-Based Prediction of Novel Drug Indications by Integrating Genomic Space.

    PubMed

    Dai, Wen; Liu, Xi; Gao, Yibo; Chen, Lin; Song, Jianglong; Chen, Di; Gao, Kuo; Jiang, Yongshi; Yang, Yiping; Chen, Jianxin; Lu, Peng

    2015-01-01

    There has been rising interest in the discovery of novel drug indications because of high costs in introducing new drugs. Many computational techniques have been proposed to detect potential drug-disease associations based on the creation of explicit profiles of drugs and diseases, while seldom research takes advantage of the immense accumulation of interaction data. In this work, we propose a matrix factorization model based on known drug-disease associations to predict novel drug indications. In addition, genomic space is also integrated into our framework. The introduction of genomic space, which includes drug-gene interactions, disease-gene interactions, and gene-gene interactions, is aimed at providing molecular biological information for prediction of drug-disease associations. The rationality lies in our belief that association between drug and disease has its evidence in the interactome network of genes. Experiments show that the integration of genomic space is indeed effective. Drugs, diseases, and genes are described with feature vectors of the same dimension, which are retrieved from the interaction data. Then a matrix factorization model is set up to quantify the association between drugs and diseases. Finally, we use the matrix factorization model to predict novel indications for drugs.

  17. Matrix factorization-based data fusion for gene function prediction in baker's yeast and slime mold.

    PubMed

    Zitnik, Marinka; Zupan, Blaž

    2014-01-01

    The development of effective methods for the characterization of gene functions that are able to combine diverse data sources in a sound and easily-extendible way is an important goal in computational biology. We have previously developed a general matrix factorization-based data fusion approach for gene function prediction. In this manuscript, we show that this data fusion approach can be applied to gene function prediction and that it can fuse various heterogeneous data sources, such as gene expression profiles, known protein annotations, interaction and literature data. The fusion is achieved by simultaneous matrix tri-factorization that shares matrix factors between sources. We demonstrate the effectiveness of the approach by evaluating its performance on predicting ontological annotations in slime mold D. discoideum and on recognizing proteins of baker's yeast S. cerevisiae that participate in the ribosome or are located in the cell membrane. Our approach achieves predictive performance comparable to that of the state-of-the-art kernel-based data fusion, but requires fewer data preprocessing steps.

  18. Matrix factorization-based data fusion for gene function prediction in baker's yeast and slime mold.

    PubMed

    Zitnik, Marinka; Zupan, Blaž

    2014-01-01

    The development of effective methods for the characterization of gene functions that are able to combine diverse data sources in a sound and easily-extendible way is an important goal in computational biology. We have previously developed a general matrix factorization-based data fusion approach for gene function prediction. In this manuscript, we show that this data fusion approach can be applied to gene function prediction and that it can fuse various heterogeneous data sources, such as gene expression profiles, known protein annotations, interaction and literature data. The fusion is achieved by simultaneous matrix tri-factorization that shares matrix factors between sources. We demonstrate the effectiveness of the approach by evaluating its performance on predicting ontological annotations in slime mold D. discoideum and on recognizing proteins of baker's yeast S. cerevisiae that participate in the ribosome or are located in the cell membrane. Our approach achieves predictive performance comparable to that of the state-of-the-art kernel-based data fusion, but requires fewer data preprocessing steps. PMID:24297565

  19. Augmenting matrix factorization technique with the combination of tags and genres

    NASA Astrophysics Data System (ADS)

    Ma, Tinghuai; Suo, Xiafei; Zhou, Jinjuan; Tang, Meili; Guan, Donghai; Tian, Yuan; Al-Dhelaan, Abdullah; Al-Rodhaan, Mznah

    2016-11-01

    Recommender systems play an important role in our daily life and are becoming popular tools for users to find what they are really interested in. Matrix factorization methods, which are popular recommendation methods, have gained high attention these years. With the rapid growth of the Internet, lots of information has been created, like social network information, tags and so on. Along with these, a few matrix factorization approaches have been proposed which incorporate the personalized information of users or items. However, except for ratings, most of the matrix factorization models have utilized only one kind of information to understand users' interests. Considering the sparsity of information, in this paper, we try to investigate the combination of different information, like tags and genres, to reveal users' interests accurately. With regard to the generalization of genres, a constraint is added when genres are utilized to find users' similar "soulmates". In addition, item regularizer is also considered based on latent semantic indexing (LSI) method with the item tags. Our experiments are conducted on two real datasets: Movielens dataset and Douban dataset. The experimental results demonstrate that the combination of tags and genres is really helpful to reveal users' interests.

  20. Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

    PubMed Central

    Tamborino, Carmine; Baldi, Eleonora; Kostic, Vladimir; Drulovic, Jelena; Dujmovic, Irena

    2016-01-01

    Matrix Metalloproteases (MMPs) and cytokines have been involved in the pathogenesis of multiple sclerosis (MS). However, no studies have still explored the possible associations between the two families of molecules. The present study aimed to evaluate the contribution of active MMP-9, active MMP-2, interleukin- (IL-) 17, IL-18, IL-23, and monocyte chemotactic proteins-3 to the pathogenesis of MS and the possible interconnections between MMPs and cytokines. The proteins were determined in the serum and cerebrospinal fluid (CSF) of 89 MS patients and 92 other neurological disorders (OND) controls. Serum active MMP-9 was increased in MS patients and OND controls compared to healthy subjects (p < 0.001 and p < 0.01, resp.), whereas active MMP-2 and ILs did not change. CSF MMP-9, but not MMP-2 or ILs, was selectively elevated in MS compared to OND (p < 0.01). Regarding the MMPs and cytokines intercorrelations, we found a significant association between CSF active MMP-2 and IL-18 (r = 0.3, p < 0.05), while MMP-9 did not show any associations with the cytokines examined. Collectively, our results suggest that active MMP-9, but not ILs, might be a surrogate marker for MS. In addition, interleukins and MMPs might synergistically cooperate in MS, indicating them as potential partners in the disease process. PMID:27555667

  1. Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients.

    PubMed

    Trentini, Alessandro; Castellazzi, Massimiliano; Cervellati, Carlo; Manfrinato, Maria Cristina; Tamborino, Carmine; Hanau, Stefania; Volta, Carlo Alberto; Baldi, Eleonora; Kostic, Vladimir; Drulovic, Jelena; Granieri, Enrico; Dallocchio, Franco; Bellini, Tiziana; Dujmovic, Irena; Fainardi, Enrico

    2016-01-01

    Matrix Metalloproteases (MMPs) and cytokines have been involved in the pathogenesis of multiple sclerosis (MS). However, no studies have still explored the possible associations between the two families of molecules. The present study aimed to evaluate the contribution of active MMP-9, active MMP-2, interleukin- (IL-) 17, IL-18, IL-23, and monocyte chemotactic proteins-3 to the pathogenesis of MS and the possible interconnections between MMPs and cytokines. The proteins were determined in the serum and cerebrospinal fluid (CSF) of 89 MS patients and 92 other neurological disorders (OND) controls. Serum active MMP-9 was increased in MS patients and OND controls compared to healthy subjects (p < 0.001 and p < 0.01, resp.), whereas active MMP-2 and ILs did not change. CSF MMP-9, but not MMP-2 or ILs, was selectively elevated in MS compared to OND (p < 0.01). Regarding the MMPs and cytokines intercorrelations, we found a significant association between CSF active MMP-2 and IL-18 (r = 0.3, p < 0.05), while MMP-9 did not show any associations with the cytokines examined. Collectively, our results suggest that active MMP-9, but not ILs, might be a surrogate marker for MS. In addition, interleukins and MMPs might synergistically cooperate in MS, indicating them as potential partners in the disease process. PMID:27555667

  2. The butanol fraction of guava (Psidium cattleianum Sabine) leaf extract suppresses MMP-2 and MMP-9 expression and activity through the suppression of the ERK1/2 MAPK signaling pathway.

    PubMed

    Im, Inhwan; Park, Kyung-Ran; Kim, Sung-Moo; Kim, Chulwon; Park, Jeong Ha; Nam, Dongwoo; Jang, Hyeung-Jin; Shim, Bum Sang; Ahn, Kyoo Seok; Mosaddik, Ashik; Sethi, Gautam; Cho, Somi K; Ahn, Kwang Seok

    2012-01-01

    The leaf extract of guava (Psidium cattleianum Sabine) has traditionally been used for the treatment of diarrhea and diabetes in East Asia and other countries. Recently, the leaf extract has been employed in the therapy of cancer, bacterial infections, and inflammation in experimental models. However, the exact mechanisms of how guava leaf extract inhibits tumor metastasis and invasion are still unknown. In the present study, we investigated in detail the molecular mechanism(s) responsible for the potential antimetastatic and antiinvasive effects of the butanol fraction of guava leaf extract (GBF). Interestingly, we observed for the first time that GBF suppressed both matrix metalloproteinases (MMP)-9 and MMP-2 expression and activity in part through the downregulation of the ERK1/2 activation in lung cancer cells. Also, importantly, the major components of the GBF were identified as d-glucuronic acid, quercetin 3-glucuronide, loganin, and xanthyletin by LC-ESI-MS/MS. Collectively, our data indicate that the guava leaf could reduce the metastasis of lung cancer cells and therefore suggest that it could be advantageously used to control the metastatic process.

  3. Serum levels of matrix metalloproteinases 2 and 9 and TGFBR2 gene screening in patients with ascending aortic dilatation.

    PubMed

    Símová, J; Skvor, J; Reissigová, J; Dudra, J; Lindner, J; Capek, P; Zvárová, J

    2013-01-01

    Development of ascending aortic dilatation (AAD) in about 10 % of patients operated for aortic valve disease (AVD) is probably based on intrinsic pathology of the aortic wall. This may involve an abnormality in the process of extracellular matrix remodelling. The present study evaluated the serum levels of specific metalloproteinases (MMP-2 and MMP-9) and investigated the gene for transforming growth factor receptor 2 (TGFBR2) in 28 patients with AVD associated with AAD (mean age 60.6 years), in 29 patients (68.9 years) with AVD without AAD, and in 30 healthy controls (45.3 years). The serum levels of MMPs were determined by ELISA. Further, we focused on genetic screening of the TGFBR2 gene. Plasma MMP-2 concentrations were significantly higher in the groups of patients compared to the controls: median 1315.0 (mean 1265.2 ± SD 391.3) in AVD with AAD, 1240.0 (1327.8 ± 352.5) in AVD without AAD versus 902.5 (872.3 ± 166.2) ng/ml in the healthy controls, in both cases P < 0.001. The serum levels of MMP-9 were significantly higher in AVD with AAD patients [107.0 (202.3 ± 313.0)] and in AVD without AAD patients [107.0 (185.8 ± 264.3)] compared to the healthy controls [14.5 (21.2 ± 24.8) ng/ml], in both cases P < 0.001. No significant correlation was observed between plasma MMP-2 and MMP-9 and ascending aorta diameter. Genetic screening did not reveal any variation in the TGFBR2 gene in the patients. Measurement of MMP levels is a simple and relatively rapid laboratory test that could be used as a biochemical indicator when evaluated in combination with imaging techniques.

  4. Magnobovatol inhibits smooth muscle cell migration by suppressing PDGF-Rβ phosphorylation and inhibiting matrix metalloproteinase-2 expression

    PubMed Central

    KANG, HYREEN; AHN, DONG HYEON; PAK, JHANG HO; SEO, KYEONG-HWA; BAEK, NAM-IN; JANG, SUNG-WUK

    2016-01-01

    The migration of vascular smooth muscle cells (VSMCs) may play a crucial role in the pathogenesis of vascular diseases, such as atherosclerosis and post-angioplasty restenosis. Platelet-derived growth factor (PDGF)-BB is a potent mitogen for VSMCs and plays an important role in the intimal accumulation of VSMCs. Magnobovatol, a new neolignan from the fruits of Magnolia obovata, has been shown to have anticancer properties. However, the effects of magnobovatol on VSMCs are unknown. In the present study, we examined the effects of magnobovatol on the PDGF-BB-induced migration of mouse and human VSMCs, as well as the underlying mechanisms. Magnobovatol significantly inhibited the PDGF-BB-induced migration of mouse and human VSMCs without inducing cell death (as shown by MTT assay and wound healing assay). Additionally, we demonstrated that magnobovatol significantly blocked the PDGF-BB-induced phosphorylation of the PDGF receptor (PDGF-R), Akt and extracellular signal-regulated kinase (ERK)1/2 by inhibiting the activation of the PDGF-BB signaling pathway. Moreover, in both mouse and human VSMCs, magnobovatol inhibited PDGF-induced matrix metalloproteinase (MMP)-2 expression at the mRNA and protein level, as well as the proteolytic activity of MMP-2 (as shown by western blot analysis, RT-PCR, gelatin zymography and ELISA). In addition, the sprout outgrowth formation of aortic rings induced by PDGF-BB was inhibited by magnobovatol (as shown by aortic ring assay). Taken together, our findings indicate that magnobovatol inhibits VSMC migration by decreasing MMP-2 expression through PDGF-R and the ERK1/2 and Akt pathways. Our data may improve the understanding of the anti-atherogenic effects of magnobovatol in VSMCs. PMID:27049716

  5. Non-negative matrix factorization by maximizing correntropy for cancer clustering

    PubMed Central

    2013-01-01

    Background Non-negative matrix factorization (NMF) has been shown to be a powerful tool for clustering gene expression data, which are widely used to classify cancers. NMF aims to find two non-negative matrices whose product closely approximates the original matrix. Traditional NMF methods minimize either the l2 norm or the Kullback-Leibler distance between the product of the two matrices and the original matrix. Correntropy was recently shown to be an effective similarity measurement due to its stability to outliers or noise. Results We propose a maximum correntropy criterion (MCC)-based NMF method (NMF-MCC) for gene expression data-based cancer clustering. Instead of minimizing the l2 norm or the Kullback-Leibler distance, NMF-MCC maximizes the correntropy between the product of the two matrices and the original matrix. The optimization problem can be solved by an expectation conditional maximization algorithm. Conclusions Extensive experiments on six cancer benchmark sets demonstrate that the proposed method is significantly more accurate than the state-of-the-art methods in cancer clustering. PMID:23522344

  6. Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer.

    PubMed

    Komorowski, Jan; Pasieka, Z; Jankiewicz-Wika, J; Stepień, H

    2002-08-01

    Stimulation of growth of endothelial cells from preexisting blood vessels, i.e., angiogenesis, is one of the essential elements necessary to create a permissive environment in which a tumor can grow. During angiogenesis, the matrix metalloproteinase (MMP) family of tissue enzymes contributes to normal (embriogenesis or wound repair) and pathologic tissue remodeling (chronic inflammation and tumor genesis). The proposed pathogenic roles of MMPs in cancer are tissue breakdown and remodeling during invasive tumor growth and tumor angiogenesis. Tissue inhibitors of metalloproteinases (TIMPs) form a complex with MMPs, which in turn inhibits active MMPs. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are unique among mediators of angiogenesis with synergistic effect, and both can also be secreted by thyroid cancer cells. The goal of the study was to evaluate the plasma blood concentration of VEGF, bFGF, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1, and TIMP-2 in patients with cancer and in normal subjects. Twenty-two patients with thyroid cancers (papillary cancer, 11; partly papillary and partly follicular cancer, 3; anaplastic cancer, 5; medullary cancer, 3) and 16 healthy subjects (controls) were included in the study. VEGF, bFGF MMPs, and TIMPs were evaluated by enzyme-linked immunosorbent assay (ELISA). In patients with thyroid cancer, normal VEGF concentrations (74.29 +/- 13.38 vs. 84.85 +/- 21.71 pg/mL; p > 0.05) and increased bFGF (29.52 +/- 4.99 vs. 6.05 +/- 1.43 pg/mL; p < 0.001), MMP-2 (605.95 +/- 81.83 vs. 148.75 +/- 43.53 ng/mL; p < 0.001), TIMP-2 (114.19 +/- 6.62 vs. 60.75 +/- 9.18 ng/mL; p < 0.001), as well as lower MMP-1 (0.70 +/- 0.42 vs. 3.87 +/- 0.53; p < 0.001) levels have been noted. Increased plasma levels of MMP-3 and MMP-9 were also found in patients with medullary carcinoma. In conclusion, predominance of MMP-2 over TIMP-2 and TIMP-1 over MMP-1 as well as increased concentration of bFGF in peripheral blood are

  7. Growth factors and extracellular matrix proteins in interactions of cumulus-oocyte complex, spermatozoa and oviduct.

    PubMed

    Einspanier, R; Gabler, C; Bieser, B; Einspanier, A; Berisha, B; Kosmann, M; Wollenhaupt, K; Schams, D

    1999-01-01

    The expression and localization of selected growth factor systems and extracellular matrix (ECM) components that may influence oocyte maturation and fertilization within the mammalian oviduct are reported. Fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) systems could be detected by use of RT-PCR, RNase protection assay (RPA) and immunohistochemistry in bovine follicles, bovine cumulus-oocyte complexes (COC) and bovine and marmoset oviducts. Two different subtypes of the FGF receptor (FGFR-1 and -2) were identified in distinct cell types, indicating a functional difference. A complete epidermal growth factor (EGF) system was found in the porcine, but not in the bovine, oviduct. There were additional differences between bovine and primate oviducts: FGF-1/2 and FGFR were increased in the marmoset around ovulation, in contrast to an increase in FGF-1 in the cow. Immunohistochemistry revealed accumulation and storage of FGF and VEGF on the surface of the epithelium, possibly due to their binding property on heparanglycoproteins. Other ECM components, matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1), were found to be modulated in the ovarian follicle, COC and oviduct during the cycle. An oviduct-mediated depletion of sperm surface proteins (BSP1-3) was discovered as well as a sperm-induced novel oviductal mRNA related to an anti-oxidant protein family. Associated systems of growth factors and ECM components can be suggested as paracrine or autocrine mediators during fertilization in a species-, cycle- and tissue-dependent manner.

  8. Simultaneous Non-Negative Matrix Factorization for Multiple Large Scale Gene Expression Datasets in Toxicology

    PubMed Central

    Lee, Clare M.; Mudaliar, Manikhandan A. V.; Haggart, D. R.; Wolf, C. Roland; Miele, Gino; Vass, J. Keith; Higham, Desmond J.; Crowther, Daniel

    2012-01-01

    Non-negative matrix factorization is a useful tool for reducing the dimension of large datasets. This work considers simultaneous non-negative matrix factorization of multiple sources of data. In particular, we perform the first study that involves more than two datasets. We discuss the algorithmic issues required to convert the approach into a practical computational tool and apply the technique to new gene expression data quantifying the molecular changes in four tissue types due to different dosages of an experimental panPPAR agonist in mouse. This study is of interest in toxicology because, whilst PPARs form potential therapeutic targets for diabetes, it is known that they can induce serious side-effects. Our results show that the practical simultaneous non-negative matrix factorization developed here can add value to the data analysis. In particular, we find that factorizing the data as a single object allows us to distinguish between the four tissue types, but does not correctly reproduce the known dosage level groups. Applying our new approach, which treats the four tissue types as providing distinct, but related, datasets, we find that the dosage level groups are respected. The new algorithm then provides separate gene list orderings that can be studied for each tissue type, and compared with the ordering arising from the single factorization. We find that many of our conclusions can be corroborated with known biological behaviour, and others offer new insights into the toxicological effects. Overall, the algorithm shows promise for early detection of toxicity in the drug discovery process. PMID:23272042

  9. A novel edge-preserving nonnegative matrix factorization method for spectral unmixing

    NASA Astrophysics Data System (ADS)

    Bao, Wenxing; Ma, Ruishi

    2015-12-01

    Spectral unmixing technique is one of the key techniques to identify and classify the material in the hyperspectral image processing. A novel robust spectral unmixing method based on nonnegative matrix factorization(NMF) is presented in this paper. This paper used an edge-preserving function as hypersurface cost function to minimize the nonnegative matrix factorization. To minimize the hypersurface cost function, we constructed the updating functions for signature matrix of end-members and abundance fraction respectively. The two functions are updated alternatively. For evaluation purpose, synthetic data and real data have been used in this paper. Synthetic data is used based on end-members from USGS digital spectral library. AVIRIS Cuprite dataset have been used as real data. The spectral angle distance (SAD) and abundance angle distance(AAD) have been used in this research for assessment the performance of proposed method. The experimental results show that this method can obtain more ideal results and good accuracy for spectral unmixing than present methods.

  10. Source characterization of highly oxidized multifunctional compounds in a boreal forest environment using positive matrix factorization

    NASA Astrophysics Data System (ADS)

    Yan, Chao; Nie, Wei; Äijälä, Mikko; Rissanen, Matti P.; Canagaratna, Manjula R.; Massoli, Paola; Junninen, Heikki; Jokinen, Tuija; Sarnela, Nina; Häme, Silja A. K.; Schobesberger, Siegfried; Canonaco, Francesco; Yao, Lei; Prévôt, André S. H.; Petäjä, Tuukka; Kulmala, Markku; Sipilä, Mikko; Worsnop, Douglas R.; Ehn, Mikael

    2016-10-01

    Highly oxidized multifunctional compounds (HOMs) have been demonstrated to be important for atmospheric secondary organic aerosols (SOA) and new-particle formation (NPF), yet it remains unclear which the main atmospheric HOM formation pathways are. In this study, a nitrate-ion-based chemical ionization atmospheric-pressure-interface time-of-flight mass spectrometer (CI-APi-TOF) was deployed to measure HOMs in the boreal forest in Hyytiälä, southern Finland. Positive matrix factorization (PMF) was applied to separate the detected HOM species into several factors, relating these "factors" to plausible formation pathways. PMF was performed with a revised error estimation derived from laboratory data, which agrees well with an estimate based on ambient data. Three factors explained the majority (> 95 %) of the data variation, but the optimal solution found six factors, including two nighttime factors, three daytime factors, and a transport factor. One nighttime factor is almost identical to laboratory spectra generated from monoterpene ozonolysis, while the second likely represents monoterpene oxidation initiated by NO3. The exact chemical processes forming the different daytime factors remain unclear, but they all have clearly distinct diurnal profiles, very likely related to monoterpene oxidation with a strong influence from NO, presumably through its effect on peroxy radical (RO2) chemistry. Apart from these five "local" factors, the sixth factor is interpreted as a transport related factor. These findings improve our understanding of HOM production by confirming current knowledge and inspiring future research directions and provide new perspectives on using factorization methods to understand short-lived atmospheric species.

  11. Suppression of PKC-α attenuates TNF-α-evoked cerebral barrier breakdown via regulations of MMP-2 and plasminogen-plasmin system.

    PubMed

    Abdullah, Zuraidah; Bayraktutan, Ulvi

    2016-07-01

    Ischaemic stroke, accompanied by neuroinflammation, impairs blood-brain barrier integrity through a complex mechanism involving both protein kinase C (PKC) and urokinase. Using an in vitro model of human blood-brain barrier (BBB) composed of brain microvascular endothelial cells (HBMEC) and astrocytes, this study assessed the putative roles of these elements in BBB damage evoked by enhanced availability of pro-inflammatory cytokine, TNF-α. Treatment of HBMEC with TNF-α significantly increased the mRNA and protein expressions of all plasminogen-plasmin system (PPS) components, namely tissue plasminogen activator, urokinase, urokinase plasminogen activator receptor and plasminogen activator inhibitor-1 and also the activities of urokinase, total PKC and extracellular MMP-2. Inhibition of urokinase by amiloride abated the effects of TNF-α on BBB integrity and MMP-2 activity without affecting that of total PKC. Conversely, pharmacological inhibition of conventional PKC isoforms dramatically suppressed TNF-α-induced overactivation of urokinase. Knockdown of PKC-α gene via specific siRNA in HBMEC suppressed the stimulatory effects of TNF-α on protein expression of all PPS components, MMP-2 activity, DNA fragmentation rates and pro-apoptotic caspase-3/7 activities. Establishment of co-cultures with BMEC transfected with PKC-α siRNA attenuated the disruptive effects of TNF-α on BBB integrity and function. This was partly due to elevations observed in expression of a tight junction protein, claudin-5 and partly to prevention of stress fibre formation. In conclusion, specific inhibition of PKC-α in cerebral conditions associated with exaggerated release of pro-inflammatory cytokines, notably TNF-α may be of considerable therapeutic value and help maintain endothelial cell viability, appropriate cytoskeletal structure and basement membrane.

  12. Generic Uniqueness of a Structured Matrix Factorization and Applications in Blind Source Separation

    NASA Astrophysics Data System (ADS)

    Domanov, Ignat; Lathauwer, Lieven De

    2016-06-01

    Algebraic geometry, although little explored in signal processing, provides tools that are very convenient for investigating generic properties in a wide range of applications. Generic properties are properties that hold "almost everywhere". We present a set of conditions that are sufficient for demonstrating the generic uniqueness of a certain structured matrix factorization. This set of conditions may be used as a checklist for generic uniqueness in different settings. We discuss two particular applications in detail. We provide a relaxed generic uniqueness condition for joint matrix diagonalization that is relevant for independent component analysis in the underdetermined case. We present generic uniqueness conditions for a recently proposed class of deterministic blind source separation methods that rely on mild source models. For the interested reader we provide some intuition on how the results are connected to their algebraic geometric roots.

  13. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma.

    PubMed

    Davidson, B; Goldberg, I; Gotlieb, W H; Kopolovic, J; Ben-Baruch, G; Nesland, J M; Berner, A; Bryne, M; Reich, R

    1999-01-01

    The object of this study was to analyze the potential association between the expression of MMP-2, MMP-9, MT1-MMP and TIMP-2, and disease outcome in advanced-stage ovarian carcinomas. Sections from 70 paraffin-embedded blocks (36 primary ovarian carcinomas and 34 metastatic lesions) from 45 patients diagnosed with advanced stage ovarian carcinomas (FIGO stages III-IV) were studied using mRNA in situ hybridization (ISH) technique. Patients were divided retrospectively in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period for patients that were diagnosed with advanced-stage carcinoma was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Intense mRNA signals were detected more frequently in tumor cells of short-term survivors with use of all four probes. Comparable findings were observed in peritumoral stromal cells with ISH for MMP-2, MMP-9 and TIMP-2 mRNA. Notably, primary tumors with intense mRNA signal for TIMP-2 (No = 14) were uniformly associated with a fatal outcome. In univariate analysis of primary tumors, mRNA levels of TIMP-2 in stromal cells (P = 0.0002), as well as for MMP-9 (P = 0.012) and TIMP-2 (P = 0.02) in tumor cells, correlated with poor outcome. In univariate analysis of metastatic lesions, mRNA levels of TIMP-2 in stromal cells (P = 0.031), as well as for MMP-2 (P = 0.027) and MT1-MMP (P = 0.008) in tumor cells, correlated with poor outcome. Interestingly, the presence of MT1-MMP in stromal cells correlated with longer survival (P = 0.025). In a multivariate analysis of ISH results for primary tumors, TIMP-2 levels in stromal cells (P = 0.006) and MMP-9 levels in tumor cells (P = 0.011) retained their predictive value. We conclude that

  14. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.

    SciTech Connect

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; Burger, Maximilian; Schaefer, Dirk J.; Wolff, Thomas; Gurke, Lorenz; Briquez, Priscilla S.; Larsson, Hans M.; Gianni-Barrera, Roberto; Hubbell, Jeffrey A.; Banfi, Andrea

    2015-04-01

    Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.

  15. Chimeric Aptamer-Gelatin Hydrogels as an Extracellular Matrix Mimic for Loading Cells and Growth Factors

    PubMed Central

    Zhang, Xiaolong; Battig, Mark R.; Chen, Niancao; Gaddes, Erin R.; Duncan, Katelyn L.; Wang, Yong

    2016-01-01

    It is important to synthesize materials to recapitulate critical functions of biological systems for a variety of applications such as tissue engineering and regenerative medicine. The purpose of this study was to synthesize a chimeric hydrogel as a promising extracellular matrix (ECM) mimic using gelatin, a nucleic acid aptamer and polyethylene glycol (PEG). This hydrogel had a macroporous structure that was highly permeable for fast molecular transport. Despite its high permeability, it could strongly sequester and sustainably release growth factors with high bioactivity. Notably, growth factors retained in the hydrogel could maintain ~50% bioactivity during a 14-day release test. It also provided cells with effective binding sites, which led to high efficiency of cell loading into the macroporous hydrogel matrix. When cells and growth factors were co-loaded into the chimeric hydrogel, living cells could still be observed by day 14 in a static serum-reduced culture condition. Thus, this chimeric aptamer-gelatin hydrogel constitutes a promising biomolecular ECM mimic for loading cells and growth factors. PMID:26791559

  16. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

    DOE PAGESBeta

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; Burger, Maximilian; Schaefer, Dirk J.; Wolff, Thomas; Gurke, Lorenz; Briquez, Priscilla S.; Larsson, Hans M.; Gianni-Barrera, Roberto; et al

    2015-04-01

    In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular,more » the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less

  17. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

    SciTech Connect

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; Burger, Maximilian; Schaefer, Dirk J.; Wolff, Thomas; Gurke, Lorenz; Briquez, Priscilla S.; Larsson, Hans M.; Gianni-Barrera, Roberto; Hubbell, Jeffrey A.; Banfi, Andrea

    2015-04-01

    In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.

  18. Regulation of proliferation of embryonic heart mesenchyme: Role of transforming growth factor-beta 1 and the interstitial matrix

    SciTech Connect

    Choy, M.; Armstrong, M.T.; Armstrong, P.B. )

    1990-10-01

    Proliferation of atrioventricular cushion mesenchyme of the embryonic avian heart maintained in three-dimensional aggregate culture is stimulated by interaction with the interstitial matrix. Chicken serum or transforming growth factor-beta 1, which stimulates proliferation, induces matrix deposition in regions of the aggregate showing high labeling indices with tritiated thymidine. Dispersed heart mesenchyme interstitial matrix introduced into serum-free culture is incorporated into the aggregate and stimulates cellular proliferation similar to serum or transforming growth factor-beta 1. Proliferation is reversibly inhibited by the peptide Gly-Arg-Gly-Asp-Ser-Pro. It is suggested that transforming growth factor-beta 1 stimulates the production of interstitial matrix and that a sufficient stimulus for proliferation in this system is the presence of the matrix, which acts as the adhesive support for cellular anchorage.

  19. The application of Positive Matrix Factorization (PMF) to eco-efficiency analysis.

    PubMed

    Wu, Jiaying; Wu, Zhijun; Holländer, Robert

    2012-05-15

    A new method for weighting and aggregating eco-efficiency indicators is of the utmost importance, if researchers in the field are to provide simplified and physically meaningful information to policy makers. To date, there is still considerable debate over which weighting and aggregating methods to use in this context. We apply a new variant of factor analysis, Positive Matrix Factorization (PMF), to a simple eco-efficiency analysis case study. PMF constrains its solutions to be non-negative, providing two important advantages over traditional factor analysis (FA) or principal component analysis (PCA): the rotational ambiguity of the solution space is reduced, and all the results are guaranteed to be physically meaningful. We suggest that PMF is better choice than either FA or PCA for eco-efficiency indicators, especially when dealing with complex social-economic and environmental data.

  20. Source Apportionment of Stack Emissions from Research and Development Facilities Using Positive Matrix Factorization

    SciTech Connect

    Ballinger, Marcel Y.; Larson, Timothy V.

    2014-08-19

    Emissions from research and development (R&D) facilities are difficult to characterize due to the wide variety of processes used, changing nature of research, and large number of chemicals. Positive matrix factorization (PMF) was applied to volatile organic compounds (VOCs) concentrations measured in the main exhaust stacks of four different R&D buildings to identify the number and composition of major contributing sources. PMF identified from 9-11 source-related factors contributing to the stack emissions depending on the building. The factors that were similar between buildings were major contributors to trichloroethylene (TCE), acetone, and ethanol emissions. Several other factors had similar profiles for two or more buildings but not for all four. One factor for each building was a combination of p/m-xylene, o-xylene and ethylbenzene. At least one factor for each building was identified that contained a broad mix of many species and constraints were used in PMF to modify the factors to resemble more closely the off-shift concentration profiles. PMF accepted the constraints with little decrease in model fit. Although the PMF model predicted the profiles of the off-shift samples, the percent of total emissions was under-predicted by the model versus the measured data.

  1. Serum Concentrations of Endothelin-1 and Matrix Metalloproteinases-2, -9 in Pre-Hypertensive and Hypertensive Patients with Type 2 Diabetes

    PubMed Central

    Kostov, Krasimir; Blazhev, Alexander; Atanasova, Milena; Dimitrova, Anelia

    2016-01-01

    Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known to date. While its plasma or serum concentrations are elevated in some forms of experimental and human hypertension, this is not a consistent finding in all forms of hypertension. Matrix metalloproteinases -2 and -9 (MMP-2 and MMP-9), which degrade collagen type IV of the vascular basement membrane, are responsible for vascular remodeling, inflammation, and atherosclerotic complications, including in type 2 diabetes (T2D). In our study, we compared concentrations of ET-1, MMP-2, and MMP-9 in pre-hypertensive (PHTN) and hypertensive (HTN) T2D patients with those of healthy normotensive controls (N). ET-1, MMP-2, and MMP-9 were measured by ELISA. Concentrations of ET-1 in PHTN and N were very similar, while those in HTN were significantly higher. Concentrations of MMP-2 and MMP-9 in PHTN and HTN were also significantly higher compared to N. An interesting result in our study is that concentrations of MMP-2 and MMP-9 in HTN were lower compared to PHTN. In conclusion, we showed that increased production of ET-1 in patients with T2D can lead to long-lasting increases in blood pressure (BP) and clinical manifestation of hypertension. We also demonstrated that increased levels of MMP-2 and MMP-9 in pre-hypertensive and hypertensive patients with T2D mainly reflect the early vascular changes in extracellular matrix (ECM) turnover. PMID:27490532

  2. On the Equivalence of Nonnegative Matrix Factorization and K-means- Spectral Clustering

    SciTech Connect

    Ding, Chris; He, Xiaofeng; Simon, Horst D.; Jin, Rong

    2005-12-04

    We provide a systematic analysis of nonnegative matrix factorization (NMF) relating to data clustering. We generalize the usual X = FG{sup T} decomposition to the symmetric W = HH{sup T} and W = HSH{sup T} decompositions. We show that (1) W = HH{sup T} is equivalent to Kernel K-means clustering and the Laplacian-based spectral clustering. (2) X = FG{sup T} is equivalent to simultaneous clustering of rows and columns of a bipartite graph. We emphasizes the importance of orthogonality in NMF and soft clustering nature of NMF. These results are verified with experiments on face images and newsgroups.

  3. Matrix metalloproteinase 9 polymorphisms and systemic lupus erythematosus: correlation with systemic inflammatory markers and oxidative stress.

    PubMed

    Bahrehmand, F; Vaisi-Raygani, A; Kiani, A; Rahimi, Z; Tavilani, H; Ardalan, M; Vaisi-Raygani, H; Shakiba, E; Pourmotabbed, T

    2015-05-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs and is characterized by persistent systemic inflammation. Among the effects of inflammatory mediators, the induction of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and oxidative stress has been demonstrated to be important in the development of SLE. In this study, the possible association between MMP-9 and MMP-2 functional promoter polymorphism, stress, and inflammatory markers with development of severe cardiovascular disease (CVD), high blood pressure (HBP), and lupus nephropathy (LN) in SLE patients was investigated. The present case-control study consisted of 109 SLE patients with and without CVD, HBP and LN and 101 gender- and age-matched unrelated healthy controls from a population in western Iran. MMP-2 -G1575A and MMP-9 -C1562T polymorphisms were detected by PCR-RFLP, serum MMP-2 and MMP-9, neopterin, malondialdehyde (MDA) and lipid levels were determined by ELISA, HPLC and enzyme assay, respectively. We found that MMP-9 -C1562 T and MMP-2 -G1575A alleles act synergistically to increase the risk of SLE by 2.98 times (p = 0.015). Findings of this study also demonstrated that there is a significant increase in the serum levels of MMP-2, neopterin and MDA and a significant decrease in serum level of MMP-9 in the presence of MMP-9-C1562 T and MMP-2 -G1575A alleles in SLE patients compared to controls. Further, SLE patients with MMP-9 (C/T + T/T) genotype had significantly higher serum concentrations of MMP-2, neopterin, MDA and LDL-C, but lower serum MMP-9 and HDL-C levels than corresponding members of the control group. MMP-9 (C/T + T/T) genotype increased risk of hypertension in SLE patients 2.71-fold. This study for the first time not only suggests that MMP-9 -C1562 T and MMP-2 -G1575A alleles synergistically increase the risk of SLE but also high serum levels of MDA, neopterin, and circulatory levels of MMP-2 and lower MMP-9 in SLE patients. This

  4. Low-dose decitabine induces MAGE-A expression and inhibits invasion via suppression of NF-κB2 and MMP2 in Eca109 cells.

    PubMed

    Liu, Wei-hua; Sang, Mei-xiang; Hou, Shu-yun; Zhang, Chao; Shan, Bao-en

    2014-07-01

    Decitabine, a demethylating drug, is the first-line treatment for myelodysplastic syndromes and gains better overall survival, which is based on epigenetic mechanism. Activated by promoter demethylation, melanoma-associated antigens-A (MAGE-A), cancer-testis antigens are attractive targets for immunotherapy. Our purpose was to investigate whether decitabine could show anti-tumor effects for esophageal cancer and explore its mechanism. In addition, we aimed to examine its modulation for most MAGE-A members. The results showed the baseline expression were MAGE-A2, -3,-9, and -10 in Eca109 cells and decitabine (0.5 μM) could induce MAGE-A8 and -A4 whereas reduce MAGE-A9 and -A10. Moreover, decitabine (0.5 μM) inhibited cell proliferation, migration and invasive ability by 15%, 34% and 47.2%, respectively and decreased expressions of NF-κB2 and MMP2. Our results demonstrated that low-dose decitabine induced the expression of MAGE-A8 and -A4, and inhibited cell invasion through decreasing expression of MMP2 and NF-κB2, which provides possibilities for combing decitabine with immunotherapy targeting MAGE-A to treat advanced esophageal squamous cell carcinoma.

  5. Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells.

    PubMed

    Ishii, Takamichi; Fukumitsu, Ken; Yasuchika, Kentaro; Adachi, Keiko; Kawase, Eihachiro; Suemori, Hirofumi; Nakatsuji, Norio; Ikai, Iwao; Uemoto, Shinji

    2008-08-01

    Hepatocytes derived from human embryonic stem cells (hESCs) are a potential cell source for regenerative medicine. However, the definitive factors that are responsible for hepatic differentiation of hESCs remain unclear. We aimed to evaluate the effects of various extracellular matrixes and growth factors on endodermal differentiation and to optimize the culture conditions to induce hepatic differentiation of hESCs. The transgene vector that contained enhanced green fluorescent protein (EGFP) under the control of human alpha-fetoprotein (AFP) enhancer/promoter was transfected into hESC lines. The transgenic hESCs were cultured on extracellular matrixes (collagen type I, laminin, and Matrigel) in the presence or absence of growth factors including hepatocyte growth factor (HGF), bone morphogenetic protein 4, fibroblast growth factor 4, all-trans-retinoic acid, and activin A. The expression of AFP-EGFP was measured by flow cytometry. The culture on Matrigel-coated dishes with 100 ng/ml activin A showed 19.5% of EGFP-positive proportions. Moreover, the sequential addition of 100 ng/ml activin A and 20 ng/ml HGF resulted in 21.7% and produced a higher yield of EGFP-positive cells than the group stimulated by activin A alone. RT-PCR and immunocytochemical staining revealed these EGFP-positive cells to differentiate into mesendoderm-like cells by use of activin A and then into hepatic endoderm cells by use of HGF. Two other hESC lines also differentiated into endoderm on the hepatic lineage by our method. In conclusion, we therefore found this protocol to effectively differentiate multiple hESC lines to early hepatocytes using activin A and HGF on Matrigel.

  6. Orthogonal matrix factorization enables integrative analysis of multiple RNA binding proteins

    PubMed Central

    Stražar, Martin; Žitnik, Marinka; Zupan, Blaž; Ule, Jernej; Curk, Tomaž

    2016-01-01

    Motivation: RNA binding proteins (RBPs) play important roles in post-transcriptional control of gene expression, including splicing, transport, polyadenylation and RNA stability. To model protein–RNA interactions by considering all available sources of information, it is necessary to integrate the rapidly growing RBP experimental data with the latest genome annotation, gene function, RNA sequence and structure. Such integration is possible by matrix factorization, where current approaches have an undesired tendency to identify only a small number of the strongest patterns with overlapping features. Because protein–RNA interactions are orchestrated by multiple factors, methods that identify discriminative patterns of varying strengths are needed. Results: We have developed an integrative orthogonality-regularized nonnegative matrix factorization (iONMF) to integrate multiple data sources and discover non-overlapping, class-specific RNA binding patterns of varying strengths. The orthogonality constraint halves the effective size of the factor model and outperforms other NMF models in predicting RBP interaction sites on RNA. We have integrated the largest data compendium to date, which includes 31 CLIP experiments on 19 RBPs involved in splicing (such as hnRNPs, U2AF2, ELAVL1, TDP-43 and FUS) and processing of 3’UTR (Ago, IGF2BP). We show that the integration of multiple data sources improves the predictive accuracy of retrieval of RNA binding sites. In our study the key predictive factors of protein–RNA interactions were the position of RNA structure and sequence motifs, RBP co-binding and gene region type. We report on a number of protein-specific patterns, many of which are consistent with experimentally determined properties of RBPs. Availability and implementation: The iONMF implementation and example datasets are available at https://github.com/mstrazar/ionmf. Contact: tomaz.curk@fri.uni-lj.si Supplementary information: Supplementary data are available

  7. Source apportionment of ambient fine particle size distribution using positive matrix factorization in Erfurt, Germany

    PubMed Central

    Yue, Wei; Stölzel, Matthias; Cyrys, Josef; Pitz, Mike; Heinrich, Joachim; Kreyling, Wolfgang G.; Wichmann, H.-Erich; Peters, Annette; Wang, Sheng; Hopke, Philip K.

    2008-01-01

    Particle size distribution data collected between September 1997 and August 2001 in Erfurt, Germany were used to investigate the sources of ambient particulate matter by positive matrix factorization (PMF). A total of 29,313 hourly averaged particle size distribution measurements covering the size range of 0.01 to 3.0 μm were included in the analysis. The particle number concentrations (cm−3) for the 9 channels in the ultrafine range, and mass concentrations (ng m−3) for the 41 size bins in the accumulation mode and particle up to 3 μm in aerodynamic diameter were used in the PMF. The analysis was performed separately for each season. Additional analyses were performed including calculations of the correlations of factor contributions with gaseous pollutants (O3, NO, NO2, CO and SO2) and particle composition data (sulfate, organic carbon and elemental carbon), estimating the contributions of each factor to the total number and mass concentration, identifying the directional locations of the sources using the conditional probability function, and examining the diurnal patterns of factor scores. These results were used to assist in the interpretation of the factors. Five factors representing particles from airborne soil, ultrafine particles from local traffic, secondary aerosols from local fuel combustion, particles from remote traffic sources, and secondary aerosols from multiple sources were identified in all seasons. PMID:18433834

  8. Source apportionment of VOCs in the Los Angeles area using positive matrix factorization

    NASA Astrophysics Data System (ADS)

    Brown, Steven G.; Frankel, Anna; Hafner, Hilary R.

    Eight 3-h speciated hydrocarbon measurements were collected daily by the South Coast Air Quality Management District (SCAQMD) as part of the Photochemical Assessment Monitoring Stations (PAMS) program during the summers of 2001-03 at two sites in the Los Angeles air basin, Azusa and Hawthorne. Over 30 hydrocarbons from over 500 samples at Azusa and 600 samples at Hawthorne were subsequently analyzed using the multivariate receptor model positive matrix factorization (PMF). At Azusa and Hawthorne, five and six factors were identified, respectively, with a good comparison between predicted and measured mass. At Azusa, evaporative emissions (a median of 31% of the total mass), motor vehicle exhaust (22%), liquid/unburned gasoline (27%), coatings (17%), and biogenic emissions (3%) factors were identified. Factors identified at Hawthorne were evaporative emissions (a median of 34% of the total mass), motor vehicle exhaust (24%), industrial process losses (15%), natural gas (13%), liquid/unburned gasoline (13%), and biogenic emissions (1%). Together, the median contribution from mobile source-related factors (exhaust, evaporative emissions, and liquid/unburned gasoline) was 80% and 71% at Azusa and Hawthorne, respectively, similar to previous source apportionment results using the chemical mass balance (CMB) model. There is a difference in the distribution among mobile source factors compared to the CMB work, with an increase in the contribution from evaporative emissions, though the cause (changes in emissions or differences between models) is unknown.

  9. α-Solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities.

    PubMed

    Lu, Ming-Kun; Shih, Yuan-Wei; Chang Chien, Tzu-Tsung; Fang, Li-Heng; Huang, Hsiang-Ching; Chen, Pin-Shern

    2010-01-01

    α-Solanine, a naturally occurring steroidal glycoalkaloid in potato sprouts, was found to possess anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis of tumor cells. However, the effect of α-solanine on cancer metastasis remains unclear. In the present study, we examined the effect of α-solanine on metastasis in vitro. Data demonstrated that α-solanine inhibited proliferation of human melanoma cell line A2058 in a dose-dependent manner. When treated with non-toxic doses of α-solanine, cell migration and invasion were markedly suppressed. Furthermore, α-solanine reduced the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, which are involved in the migration and invasion of cancer cells. Our biochemical assays indicated that α-solanine potently suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), phosphatidylinositide-3 kinase (PI3K) and Akt, while it did not affect phosphorylation of extracellular signal regulating kinase (ERK). In addition, α-solanine significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that α-solanine inhibited NF-κB activity. Taken together, the results suggested that α-solanine inhibited migration and invasion of A2058 cells by reducing MMP-2/9 activities. It also inhibited JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for α-solanine in anti-metastatic therapy.

  10. Tumor Necrosis Factor-α-induced Proteolytic Activation of Pro-matrix Metalloproteinase-9 by Human Skin Is Controlled by Down-regulating Tissue Inhibitor of Metalloproteinase-1 and Mediated by Tissue-associated Chymotrypsin-like Proteinase*

    PubMed Central

    Han, Yuan-Ping; Nien, Yih-Dar; Garner, Warren L.

    2008-01-01

    The proteolytic activation of pro-matrix metalloproteinase (MMP)-9 by conversion of the 92-kDa precursor into an 82-kDa active form has been observed in chronic wounds, tumor metastasis, and many inflammation-associated diseases, yet the mechanistic pathway to control this process has not been identified. In this report, we show that the massive expression and activation of MMP-9 in skin tissue from patients with chronically unhealed wounds could be reconstituted in vitro with cultured normal human skin by stimulation with transforming growth factor-β and tumor necrosis factor (TNF)-α. We dissected the mechanistic pathway for TNF-α induced activation of pro-MMP-9 in human skin. We found that proteolytic activation of pro-MMP-9 was mediated by a tissue-associated chymotrypsin-like proteinase, designated here as pro-MMP-9 activator (pM9A). This unidentified activator specifically converted pro-MMP-9 but not pro-MMP-2, another member of the gelatinase family. The tissue-bound pM9A was steadily expressed and not regulated by TNF-α, which indicated that the cytokine-mediated activation of pro-MMP-9 might be regulated at the inhibitor level. Indeed, the skin constantly secreted tissue inhibitor of metalloproteinase-1 at the basal state. TNF-α, but not transforming growth factor-β, down-regulated this inhibitor. The TNF-α-mediated activation of pro-MMP-9 was tightly associated with down-regulation of tissue inhibitor of metalloproteinase-1 in a dose-dependent manner. To establish this linkage, we demonstrate that the recombinant tissue inhibitor of metalloproteinase-1 could block the activation of pro-MMP-9 by either the intact skin or skin fractions. Thus, these studies suggest a novel regulation for the proteolytic activation of MMP-9 in human tissue, which is mediated by tissue-bound activator and controlled by down-regulation of a specific inhibitor. PMID:12004062

  11. Impact of the Choice of Normalization Method on Molecular Cancer Class Discovery Using Nonnegative Matrix Factorization

    PubMed Central

    Yang, Haixuan; Seoighe, Cathal

    2016-01-01

    Nonnegative Matrix Factorization (NMF) has proved to be an effective method for unsupervised clustering analysis of gene expression data. By the nonnegativity constraint, NMF provides a decomposition of the data matrix into two matrices that have been used for clustering analysis. However, the decomposition is not unique. This allows different clustering results to be obtained, resulting in different interpretations of the decomposition. To alleviate this problem, some existing methods directly enforce uniqueness to some extent by adding regularization terms in the NMF objective function. Alternatively, various normalization methods have been applied to the factor matrices; however, the effects of the choice of normalization have not been carefully investigated. Here we investigate the performance of NMF for the task of cancer class discovery, under a wide range of normalization choices. After extensive evaluations, we observe that the maximum norm showed the best performance, although the maximum norm has not previously been used for NMF. Matlab codes are freely available from: http://maths.nuigalway.ie/~haixuanyang/pNMF/pNMF.htm. PMID:27741311

  12. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction

    PubMed Central

    Liu, Yong; Wu, Min; Miao, Chunyan; Zhao, Peilin; Li, Xiao-Li

    2016-01-01

    In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF). Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs) than negative observations (i.e., the unknown pairs). Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches. PMID:26872142

  13. A network and visual quality aware N-screen content recommender system using joint matrix factorization.

    PubMed

    Ullah, Farman; Sarwar, Ghulam; Lee, Sungchang

    2014-01-01

    We propose a network and visual quality aware N-Screen content recommender system. N-Screen provides more ways than ever before to access multimedia content through multiple devices and heterogeneous access networks. The heterogeneity of devices and access networks present new questions of QoS (quality of service) in the realm of user experience with content. We propose, a recommender system that ensures a better visual quality on user's N-screen devices and the efficient utilization of available access network bandwidth with user preferences. The proposed system estimates the available bandwidth and visual quality on users N-Screen devices and integrates it with users preferences and contents genre information to personalize his N-Screen content. The objective is to recommend content that the user's N-Screen device and access network are capable of displaying and streaming with the user preferences that have not been supported in existing systems. Furthermore, we suggest a joint matrix factorization approach to jointly factorize the users rating matrix with the users N-Screen device similarity and program genres similarity. Finally, the experimental results show that we also enhance the prediction and recommendation accuracy, sparsity, and cold start issues.

  14. A Network and Visual Quality Aware N-Screen Content Recommender System Using Joint Matrix Factorization

    PubMed Central

    Ullah, Farman; Sarwar, Ghulam; Lee, Sungchang

    2014-01-01

    We propose a network and visual quality aware N-Screen content recommender system. N-Screen provides more ways than ever before to access multimedia content through multiple devices and heterogeneous access networks. The heterogeneity of devices and access networks present new questions of QoS (quality of service) in the realm of user experience with content. We propose, a recommender system that ensures a better visual quality on user's N-screen devices and the efficient utilization of available access network bandwidth with user preferences. The proposed system estimates the available bandwidth and visual quality on users N-Screen devices and integrates it with users preferences and contents genre information to personalize his N-Screen content. The objective is to recommend content that the user's N-Screen device and access network are capable of displaying and streaming with the user preferences that have not been supported in existing systems. Furthermore, we suggest a joint matrix factorization approach to jointly factorize the users rating matrix with the users N-Screen device similarity and program genres similarity. Finally, the experimental results show that we also enhance the prediction and recommendation accuracy, sparsity, and cold start issues. PMID:24982999

  15. Rotation to a partially specified target matrix in exploratory factor analysis in practice.

    PubMed

    Myers, Nicholas D; Jin, Ying; Ahn, Soyeon; Celimli, Seniz; Zopluoglu, Cengiz

    2015-06-01

    The purpose of the present study was to explore the influence of the number of targets specified on the quality of exploratory factor analysis solutions with a complex underlying structure and incomplete substantive measurement theory. We extended previous research in this area by (a) exploring this phenomenon in situations in which both the common factor model and the targeted pattern matrix contained specification errors and (b) comparing the performance of target rotation to an easier-to-use default rotation criterion (i.e., geomin) under conditions commonly observed in practice. A Monte Carlo study manipulated target error, number of targets, model error, overdetermination, communality, and sample size. Outcomes included bias (i.e., accuracy) and variability (i.e., stability) with regard to the rotated pattern matrix. The effects of target error were negligible for both accuracy and stability, whereas small effects were observed for the number of targets for both outcomes. Further, target rotation outperformed geomin rotation with regard to accuracy but generally performed worse than geomin rotation with regard to stability. These findings underscore the potential importance (or caution, in the case of stability) of using extant, even if incomplete and somewhat inaccurate, substantive measurement theory to inform the rotation criterion in a nonmechanical way. PMID:24903693

  16. Robust and Non-Negative Collective Matrix Factorization for Text-to-Image Transfer Learning.

    PubMed

    Yang, Liu; Jing, Liping; Ng, Michael K

    2015-12-01

    Heterogeneous transfer learning has recently gained much attention as a new machine learning paradigm in which the knowledge can be transferred from source domains to target domains in different feature spaces. Existing works usually assume that source domains can provide accurate and useful knowledge to be transferred to target domains for learning. In practice, there may be noise appearing in given source (text) and target (image) domains data, and thus, the performance of transfer learning can be seriously degraded. In this paper, we propose a robust and non-negative collective matrix factorization model to handle noise in text-to-image transfer learning, and make a reliable bridge to transfer accurate and useful knowledge from the text domain to the image domain. The proposed matrix factorization model can be solved by an efficient iterative method, and the convergence of the iterative method can be shown. Extensive experiments on real data sets suggest that the proposed model is able to effectively perform transfer learning in noisy text and image domains, and it is superior to the popular existing methods for text-to-image transfer learning.

  17. In vivo fluorescence spectra unmixing and autofluorescence removal by sparse nonnegative matrix factorization.

    PubMed

    Montcuquet, Anne-Sophie; Hervé, Lionel; Navarro, Fabrice; Dinten, Jean-Marc; Mars, Jérôme I

    2011-09-01

    Fluorescence imaging locates fluorescent markers that specifically bind to targets; like tumors, markers are injected to a patient, optimally excited with near-infrared light, and located thanks to backward-emitted fluorescence analysis. To investigate thick and diffusive media, as the fluorescence signal decreases exponentially with the light travel distance, the autofluorescence of biological tissues comes to be a limiting factor. To remove autofluorescence and isolate specific fluorescence, a spectroscopic approach, based on nonnegative matrix factorization (NMF), is explored. To improve results on spatially sparse markers detection, we suggest a new constrained NMF algorithm that takes sparsity constraints into account. A comparative study between both algorithms is proposed on simulated and in vivo data.

  18. Nonnegative matrix factorization: a blind spectra separation method for in vivo fluorescent optical imaging.

    PubMed

    Montcuquet, Anne-Sophie; Hervé, Lionel; Navarro, Fabrice; Dinten, Jean-Marc; Mars, Jérôme I

    2010-01-01

    Fluorescence imaging in diffusive media is an emerging imaging modality for medical applications that uses injected fluorescent markers that bind to specific targets, e.g., carcinoma. The region of interest is illuminated with near-IR light and the emitted back fluorescence is analyzed to localize the fluorescence sources. To investigate a thick medium, as the fluorescence signal decreases with the light travel distance, any disturbing signal, such as biological tissues intrinsic fluorescence (called autofluorescence) is a limiting factor. Several specific markers may also be simultaneously injected to bind to different molecules, and one may want to isolate each specific fluorescent signal from the others. To remove the unwanted fluorescence contributions or separate different specific markers, a spectroscopic approach is explored. The nonnegative matrix factorization (NMF) is the blind positive source separation method we chose. We run an original regularized NMF algorithm we developed on experimental data, and successfully obtain separated in vivo fluorescence spectra.

  19. Activation and localization of matrix metalloproteinase-2 and -9 in the skeletal muscle of the muscular dystrophy dog (CXMDJ)

    PubMed Central

    Fukushima, Kazuhiro; Nakamura, Akinori; Ueda, Hideho; Yuasa, Katsutoshi; Yoshida, Kunihiro; Takeda, Shin'ichi; Ikeda, Shu-ichi

    2007-01-01

    Background Matrix metalloproteinases (MMPs) are key regulatory molecules in the formation, remodeling and degradation of all extracellular matrix (ECM) components in both physiological and pathological processes in various tissues. The aim of this study was to examine the involvement of gelatinase MMP family members, MMP-2 and MMP-9, in dystrophin-deficient skeletal muscle. Towards this aim, we made use of the canine X-linked muscular dystrophy in Japan (CXMDJ) model, a suitable animal model for Duchenne muscular dystrophy. Methods We used surgically biopsied tibialis cranialis muscles of normal male dogs (n = 3) and CXMDJ dogs (n = 3) at 4, 5 and 6 months of age. Muscle sections were analyzed by conventional morphological methods and in situ zymography to identify the localization of MMP-2 and MMP-9. MMP-2 and MMP-9 activity was examined by gelatin zymography and the levels of the respective mRNAs in addition to those of regulatory molecules, including MT1-MMP, TIMP-1, TIMP-2, and RECK, were analyzed by semi-quantitative RT-PCR. Results In CXMDJ skeletal muscle, multiple foci of both degenerating and regenerating muscle fibers were associated with gelatinolytic MMP activity derived from MMP-2 and/or MMP-9. In CXMDJ muscle, MMP-9 immunoreactivity localized to degenerated fibers with inflammatory cells. Weak and disconnected immunoreactivity of basal lamina components was seen in MMP-9-immunoreactive necrotic fibers of CXMDJ muscle. Gelatinolytic MMP activity observed in the endomysium of groups of regenerating fibers in CXMDJ did not co-localize with MMP-9 immunoreactivity, suggesting that it was due to the presence of MMP-2. We observed increased activities of pro MMP-2, MMP-2 and pro MMP-9, and levels of the mRNAs encoding MMP-2, MMP-9 and the regulatory molecules, MT1-MMP, TIMP-1, TIMP-2, and RECK in the skeletal muscle of CXMDJ dogs compared to the levels observed in normal controls. Conclusion MMP-2 and MMP-9 are likely involved in the pathology of dystrophin

  20. Stromal remodelling is required for progressive involution of the rat ventral prostate after castration: identification of a matrix metalloproteinase-dependent apoptotic wave.

    PubMed

    Bruni-Cardoso, A; Augusto, T M; Pravatta, H; Damas-Souza, D M; Carvalho, H F

    2010-10-01

    Prostate epithelial-cell apoptosis occurs in response to androgen deprivation. We have hypothesized that continued regression would require stromal changes. Studying apoptosis kinetics up to the 14th day after castration, we identified successive waves of apoptosis, with a prominent peak on day 11. This peak was associated with caspase-3 activity, nuclear translocation of apoptosis-inducing factor and clusterin expression. The apoptosis peak on day 11 was preceded by increased MMP-2 and MMP-7 activation, and MMP-9 expression on days 9 and 10. Treatment with the matrix metalloproteinases inhibitors doxycyclin, hydrocortisone, or GM6001 caused significant reduction in the apoptosis rate on day 11. The present data demonstrate that prostatic epithelial-cell deletion at the 11th day after castration was induced by focal degradation of the extracellular matrix associated with stromal remodelling. PMID:19906188

  1. Prodomains of transforming growth factor beta (TGFbeta) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability.

    PubMed

    Sengle, Gerhard; Ono, Robert N; Sasaki, Takako; Sakai, Lynn Y

    2011-02-18

    The specific functions of the prodomains of TGFβ superfamily members are largely unknown. Interactions are known between prodomains of TGFβ-1-3 and latent TGFβ-binding proteins and between prodomains of BMP-2, -4, -7, and -10 and GDF-5 and fibrillins, raising the possibility that latent TGFβ-binding proteins and fibrillins may mediate interactions with all other prodomains of this superfamily. This possibility is tested in this study. Results show that the prodomain of BMP-5 interacts with the N-terminal regions of fibrillin-1 and -2 in a site similar to the binding sites for other bone morphogenetic proteins. However, in contrast, the prodomain of GDF-8 (myostatin) interacts with the glycosaminoglycan side chains of perlecan. The binding site for the GDF-8 prodomain is likely the heparan sulfate chain present on perlecan domain V. These results support and extend the emerging concept that TGFβ superfamily prodomains target their growth factor dimers to extracellular matrix macromolecules. In addition, biochemical studies of prodomain·growth factor complexes were performed to identify inactive complexes. For some members of the superfamily, the prodomain is noncovalently associated with its growth factor dimer in an inactive complex; for others, the prodomain·growth factor complex is active, even though the prodomain is noncovalently associated with its growth factor dimer. Results show that the BMP-10 prodomain, in contrast to BMP-4, -5, and -7 prodomains, can inhibit the bioactivity of the BMP-10 growth factor and suggest that the BMP-10 complex is like TGFβ and GDF-8 complexes, which can be activated by cleavage of the associated prodomain.

  2. Source apportionment of ambient particle number concentrations in central Los Angeles using positive matrix factorization (PMF)

    NASA Astrophysics Data System (ADS)

    Sowlat, Mohammad Hossein; Hasheminassab, Sina; Sioutas, Constantinos

    2016-04-01

    In this study, the positive matrix factorization (PMF) receptor model (version 5.0) was used to identify and quantify major sources contributing to particulate matter (PM) number concentrations, using PM number size distributions in the range of 13 nm to 10 µm combined with several auxiliary variables, including black carbon (BC), elemental and organic carbon (EC/OC), PM mass concentrations, gaseous pollutants, meteorological, and traffic counts data, collected for about 9 months between August 2014 and 2015 in central Los Angeles, CA. Several parameters, including particle number and volume size distribution profiles, profiles of auxiliary variables, contributions of different factors in different seasons to the total number concentrations, diurnal variations of each of the resolved factors in the cold and warm phases, weekday/weekend analysis for each of the resolved factors, and correlation between auxiliary variables and the relative contribution of each of the resolved factors, were used to identify PM sources. A six-factor solution was identified as the optimum for the aforementioned input data. The resolved factors comprised nucleation, traffic 1, traffic 2 (with a larger mode diameter than traffic 1 factor), urban background aerosol, secondary aerosol, and soil/road dust. Traffic sources (1 and 2) were the major contributor to PM number concentrations, collectively making up to above 60 % (60.8-68.4 %) of the total number concentrations during the study period. Their contribution was also significantly higher in the cold phase compared to the warm phase. Nucleation was another major factor significantly contributing to the total number concentrations (an overall contribution of 17 %, ranging from 11.7 to 24 %), with a larger contribution during the warm phase than in the cold phase. The other identified factors were urban background aerosol, secondary aerosol, and soil/road dust, with relative contributions of approximately 12 % (7.4-17.1), 2.1 % (1

  3. Chitinases and Imaginal disc growth factors organize the extracellular matrix formation at barrier tissues in insects

    PubMed Central

    Pesch, Yanina-Yasmin; Riedel, Dietmar; Patil, Kapil R; Loch, Gerrit; Behr, Matthias

    2016-01-01

    The cuticle forms an apical extracellular-matrix (ECM) that covers exposed organs, such as epidermis, trachea and gut, for organizing morphogenesis and protection of insects. Recently, we reported that cuticle proteins and chitin are involved in ECM formation. However, molecular mechanisms that control assembly, maturation and replacement of the ECM and its components are not well known. Here we investigated the poorly described glyco-18-domain hydrolase family in Drosophila and identified the Chitinases (Chts) and imaginal-disc-growth-factors (Idgfs) that are essential for larval and adult molting. We demonstrate that Cht and idgf depletion results in deformed cuticles, larval and adult molting defects, and insufficient protection against wounding and bacterial infection, which altogether leads to early lethality. We show that Cht2/Cht5/Cht7/Cht9/Cht12 and idgf1/idgf3/idgf4/idgf5/idgf6 are needed for organizing proteins and chitin-matrix at the apical cell surface. Our data indicate that normal ECM formation requires Chts, which potentially hydrolyze chitin-polymers. We further suggest that the non-enzymatic idgfs act as structural proteins to maintain the ECM scaffold against chitinolytic degradation. Conservation of Chts and Idgfs proposes analogous roles in ECM dynamics across the insect taxa, indicating that Chts/Idgfs are new targets for species specific pest control. PMID:26838602

  4. Matrix metalloproteinase-9 and vascular endothelial growth factor expression change in experimental retinal neovascularization

    PubMed Central

    Di, Yu; Nie, Qing-Zhu; Chen, Xiao-Long

    2016-01-01

    AIM To investigate the signal transduction mechanism of matrix metalloproteinase-9 (MMP-9) mediated- vascular endothelial growth factor (VEGF) expression and retinal neovascularization (RNV) in oxygen-induced retinopathy (OIR) model. METHODS C57BL/6J mice were divided into four groups: control group, OIR group, OIR control group (phosphate-buffered saline by intravitreal injection) and treated group [tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) by intravitreal injection]. OIR model was established in C57BL/6J mice exposed to 75%±2% oxygen for 5d. mRNA level and protein expression of MMP-9, TIMP-1 and VEGF were measured by real-time polymerase chain reaction and Western blotting, and located by immunohistochemistry. RESULTS Levels of MMP-9 and VEGF in retina were significantly increased in animals with OIR and OIR control group. Levels of TIMP-1 in retina was significantly reduced in animals with OIR and OIR control group. Furthermore, a significant correlation was found between MMP-9 and VEGF. Intravitreal injection of TIMP-1 significantly reduced MMP-9 and VEGF expression of the OIR mouse model (all P<0.05). CONCLUSION These results demonstrate that MMP-9-mediated up-regulation of VEGF promotes RNV in retinopathy of prematurity (ROP). TIMP-1 may be a potential target for the prevention and treatment of ROP. PMID:27366678

  5. [Lake algae chemotaxonomy technology based on fluorescence excitation emission matrix and parallel factor analysis].

    PubMed

    Chen, Xiao-Na; Han, Xiu-Rong; Su, Rong-Guo; Shi, Xiao-Yong

    2014-03-01

    An in vivo three-dimensional fluorescence method for the determination of algae community structure was developed by parallel factor (PARAFAC) analysis and CHEMTAX. The PARAFAC model was applied to fluorescence excitation-emission matrix (EEM) of 23 algae species and 12 fluorescent components were identified according to the residual sum of squares and specificity of the composition profiles of fluorescent. Based on the 12 fluorescent components, the algae species at different growth stages were correctly classified at the division level using Bayesian discriminant analysis (BDA). Then the reference fluorescent component ratio matrix was constructed for CHEMTAX, and the EEM-PARAFAC-CHEMTAX method was developed to differentiate taxonomic groups of algae. When the fluorometric method was used for 531 single-species samples, the average correct discrimination ratio (CDR) was 99.1% and the correct discrimination ratios (CDRs) were 100% at the division level except Chlorophyta, the CDR of which was 97.5%. The CDRs for 95 mixtures were above 98.5% for the dominant algae species and above 90.5% for the subdominant algae species, with average relative contents of 69.7% and 26.4%, respectively. This technique would be of great aid when low-cost and rapid analysis is needed for samples in a large batch.

  6. Matrix Metalloproteinase-2 Mediates Intestinal Immunopathogenesis in Campylobacter Jejuni-Infected Infant Mice

    PubMed Central

    Alutis, Marie E.; Grundmann, Ursula; Hagen, Ulrike; Fischer, André; Kühl, Anja A.; Göbel, Ulf B.; Bereswill, Stefan; Heimesaat, Markus M.

    2015-01-01

    Increased levels of the matrix metalloproteinases (MMPs)-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in the inflamed gut. We have recently shown that synthetic gelatinase blockage reduces colonic apoptosis and pro-inflammatory immune responses following murine Campylobacter (C.) jejuni infection. In order to dissect whether MMP-2 and/or MMP-9 is involved in mediating C. jejuni-induced immune responses, infant MMP-2–/–, MMP-9–/–, and wildtype (WT) mice were perorally infected with the C. jejuni strain B2 immediately after weaning. Whereas, at day 2 postinfection (p.i.), fecal C. jejuni B2 loads were comparable in mice of either genotype, mice expelled the pathogen from the intestinal tract until day 4 p.i. Six days p.i., colonic MMP-2 but not MMP-9 mRNA was upregulated in WT mice. Remarkably, infected MMP-2–/– mice exhibited less frequent abundance of blood in feces, less distinct colonic histopathology and apoptosis, lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa, and higher colonic IL-22 mRNA levels as compared to infected WT mice. In conclusion, these results point towards an important role of MMP-2 in mediating C. jejuni-induced intestinal immunopathogenesis. PMID:26495129

  7. Resveratrol reduces matrix metalloproteinases and alleviates intrahepatic cholestasis of pregnancy in rats.

    PubMed

    Chen, Zhong; Hu, Lingqing; Lu, Mudan; Shen, Zongji

    2016-04-01

    Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disorder occurring specifically in pregnancy, and matrix metalloproteinase (MMP)-2 and MMP-9 were found to be elevated in ICP patients. Using ethinylestradiol-induced ICP rats as the model, we examined the effect of resveratrol on ICP symptoms such as bile flow rate, serum enzymatic activities, and TBA concentration, as well as MMP levels, and compared with the known ICP drug ursodeoxycholic acid. Both MMP-2 and MMP-9 were upregulated in ICP rats, and resveratrol treatment could inhibit the elevation of both MMPs, whereas ursodeoxycholic acid did not exhibit any effect. Although ursodeoxycholic acid alleviated ICP symptoms, resveratrol treatment in general exhibited better outcome in restoring bile flow rate, serum enzymatic activities, and TBA concentration. Our results for the first instance strongly supported the potential of RE as a new therapeutic agent in treating ICP, possibly through inhibiting MMP-2 and MMP-9. PMID:26913826

  8. Clustering Algorithm for Unsupervised Monaural Musical Sound Separation Based on Non-negative Matrix Factorization

    NASA Astrophysics Data System (ADS)

    Park, Sang Ha; Lee, Seokjin; Sung, Koeng-Mo

    Non-negative matrix factorization (NMF) is widely used for monaural musical sound source separation because of its efficiency and good performance. However, an additional clustering process is required because the musical sound mixture is separated into more signals than the number of musical tracks during NMF separation. In the conventional method, manual clustering or training-based clustering is performed with an additional learning process. Recently, a clustering algorithm based on the mel-frequency cepstrum coefficient (MFCC) was proposed for unsupervised clustering. However, MFCC clustering supplies limited information for clustering. In this paper, we propose various timbre features for unsupervised clustering and a clustering algorithm with these features. Simulation experiments are carried out using various musical sound mixtures. The results indicate that the proposed method improves clustering performance, as compared to conventional MFCC-based clustering.

  9. Extraction of food consumption systems by nonnegative matrix factorization (NMF) for the assessment of food choices.

    PubMed

    Zetlaoui, Mélanie; Feinberg, Max; Verger, Philippe; Clémençon, Stephan

    2011-12-01

    In Western countries where food supply is satisfactory, consumers organize their diets around a large combination of foods. It is the purpose of this article to examine how recent nonnegative matrix factorization (NMF) techniques can be applied to food consumption data to understand these combinations. Such data are nonnegative by nature and of high dimension. The NMF model provides a representation of consumption data through latent vectors with nonnegative coefficients, that we call consumption systems (CS), in a small number. As the NMF approach may encourage sparsity of the data representation produced, the resulting CS are easily interpretable. Beyond the illustration of its properties we provide through a simple simulation result, the NMF method is applied to data issued from a French consumption survey. The numerical results thus obtained are displayed and thoroughly discussed. A clustering based on the k-means method is also achieved in the resulting latent consumption space, to recover food consumption patterns easily usable for nutritionists. PMID:21418050

  10. Nonnegative matrix factorization: a blind sources separation method to extract content of fluorophores mixture media

    NASA Astrophysics Data System (ADS)

    Zhou, Kenneth J.; Chen, Jun

    2014-03-01

    The fluorophores of malignant human breast cells change their compositions that may be exposed in the fluorescence spectroscopy and blind source separation method. The content of the fluorophores mixture media such as tryptophan, collagen, elastin, NADH, and flavin were varied according to the cancer development. The native fluorescence spectra of these key fluorophores mixture media excited by the selective excitation wavelengths of 300 nm and 340 nm were analyzed using a blind source separation method: Nonnegative Matrix Factorization (NMF). The results show that the contribution from tryptophan, NADH and flavin to the fluorescence spectra of the mixture media is proportional to the content of each fluorophore. These data present a possibility that native fluorescence spectra decomposed by NMF can be used as potential native biomarkers for cancer detection evaluation of the cancer.

  11. Identifying overlapping communities as well as hubs and outliers via nonnegative matrix factorization

    PubMed Central

    Cao, Xiaochun; Wang, Xiao; Jin, Di; Cao, Yixin; He, Dongxiao

    2013-01-01

    Community detection is important for understanding networks. Previous studies observed that communities are not necessarily disjoint and might overlap. It is also agreed that some outlier vertices participate in no community, and some hubs in a community might take more important roles than others. Each of these facts has been independently addressed in previous work. But there is no algorithm, to our knowledge, that can identify these three structures altogether. To overcome this limitation, we propose a novel model where vertices are measured by their centrality in communities, and define the identification of overlapping communities, hubs, and outliers as an optimization problem, calculated by nonnegative matrix factorization. We test this method on various real networks, and compare it with several competing algorithms. The experimental results not only demonstrate its ability of identifying overlapping communities, hubs, and outliers, but also validate its superior performance in terms of clustering quality. PMID:24129402

  12. Adhesion properties of Lactobacillus rhamnosus mucus-binding factor to mucin and extracellular matrix proteins.

    PubMed

    Nishiyama, Keita; Nakamata, Koichi; Ueno, Shintaro; Terao, Akari; Aryantini, Ni Putu Desy; Sujaya, I Nengah; Fukuda, Kenji; Urashima, Tadasu; Yamamoto, Yuji; Mukai, Takao

    2015-01-01

    We previously described potential probiotic Lactobacillus rhamnosus strains, isolated from fermented mare milk produced in Sumbawa Island, Indonesia, which showed high adhesion to porcine colonic mucin (PCM) and extracellular matrix (ECM) proteins. Recently, mucus-binding factor (MBF) was found in the GG strain of L. rhamnosus as a mucin-binding protein. In this study, we assessed the ability of recombinant MBF protein from the FSMM22 strain, one of the isolates of L. rhamnosus from fermented Sumbawa mare milk, to adhere to PCM and ECM proteins by overlay dot blot and Biacore assays. MBF bound to PCM, laminin, collagen IV, and fibronectin with submicromolar dissociation constants. Adhesion of the FSMM22 mbf mutant strain to PCM and ECM proteins was significantly less than that of the wild-type strain. Collectively, these results suggested that MBF contribute to L. rhamnosus host colonization via mucin and ECM protein binding.

  13. Categorical Dimensions of Human Odor Descriptor Space Revealed by Non-Negative Matrix Factorization

    PubMed Central

    Castro, Jason B.; Ramanathan, Arvind; Chennubhotla, Chakra S.

    2013-01-01

    In contrast to most other sensory modalities, the basic perceptual dimensions of olfaction remain unclear. Here, we use non-negative matrix factorization (NMF) – a dimensionality reduction technique – to uncover structure in a panel of odor profiles, with each odor defined as a point in multi-dimensional descriptor space. The properties of NMF are favorable for the analysis of such lexical and perceptual data, and lead to a high-dimensional account of odor space. We further provide evidence that odor dimensions apply categorically. That is, odor space is not occupied homogenously, but rather in a discrete and intrinsically clustered manner. We discuss the potential implications of these results for the neural coding of odors, as well as for developing classifiers on larger datasets that may be useful for predicting perceptual qualities from chemical structures. PMID:24058466

  14. Accelerated multiplicative updates and hierarchical ALS algorithms for nonnegative matrix factorization.

    PubMed

    Gillis, Nicolas; Glineur, François

    2012-04-01

    Nonnegative matrix factorization (NMF) is a data analysis technique used in a great variety of applications such as text mining, image processing, hyperspectral data analysis, computational biology, and clustering. In this letter, we consider two well-known algorithms designed to solve NMF problems: the multiplicative updates of Lee and Seung and the hierarchical alternating least squares of Cichocki et al. We propose a simple way to significantly accelerate these schemes, based on a careful analysis of the computational cost needed at each iteration, while preserving their convergence properties. This acceleration technique can also be applied to other algorithms, which we illustrate on the projected gradient method of Lin. The efficiency of the accelerated algorithms is empirically demonstrated on image and text data sets and compares favorably with a state-of-the-art alternating nonnegative least squares algorithm. PMID:22168561

  15. Categorical dimensions of human odor descriptor space revealed by non-negative matrix factorization

    SciTech Connect

    Chennubhotla, Chakra; Castro, Jason

    2013-01-01

    In contrast to most other sensory modalities, the basic perceptual dimensions of olfaction remain un- clear. Here, we use non-negative matrix factorization (NMF) - a dimensionality reduction technique - to uncover structure in a panel of odor profiles, with each odor defined as a point in multi-dimensional descriptor space. The properties of NMF are favorable for the analysis of such lexical and perceptual data, and lead to a high-dimensional account of odor space. We further provide evidence that odor di- mensions apply categorically. That is, odor space is not occupied homogenously, but rather in a discrete and intrinsically clustered manner. We discuss the potential implications of these results for the neural coding of odors, as well as for developing classifiers on larger datasets that may be useful for predicting perceptual qualities from chemical structures.

  16. Identifying overlapping communities as well as hubs and outliers via nonnegative matrix factorization.

    PubMed

    Cao, Xiaochun; Wang, Xiao; Jin, Di; Cao, Yixin; He, Dongxiao

    2013-10-21

    Community detection is important for understanding networks. Previous studies observed that communities are not necessarily disjoint and might overlap. It is also agreed that some outlier vertices participate in no community, and some hubs in a community might take more important roles than others. Each of these facts has been independently addressed in previous work. But there is no algorithm, to our knowledge, that can identify these three structures altogether. To overcome this limitation, we propose a novel model where vertices are measured by their centrality in communities, and define the identification of overlapping communities, hubs, and outliers as an optimization problem, calculated by nonnegative matrix factorization. We test this method on various real networks, and compare it with several competing algorithms. The experimental results not only demonstrate its ability of identifying overlapping communities, hubs, and outliers, but also validate its superior performance in terms of clustering quality.

  17. Relationship between expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 and invasion ability of cervical cancer cells.

    PubMed

    Kato, Yasuhito; Yamashita, Tsuyoshi; Ishikawa, Mutsuo

    2002-01-01

    Constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumors. MMPs are a family of zinc endopeptidases consisting of at least 20 different members. In particular, MMP-2 and MMP-9 are reported to be closely associated with invasion and metastasis in several cancers. We investigated whether expression of MMP-2 and MMP-9 is associated with invasion ability of seven cervical cancer cells by administration of o-phenanthroline as MMP inhibitor. In two cell lines, Siha and Caski, MMP-2 mRNA and protein were expressed at high levels. After treatment with o-phenanthroline, the rate of invasion in these two cell lines was significantly decreased. In contrast, in the other two cell lines, HT-3 and Caski, high levels of MMP-9 mRNA and protein were expressed but there was no decrease in the rate of invasion in these cells after treatment with o-phenanthroline. The data suggest that expression level of MMP-2 mRNA may regulate with invasion ability of cervical cancer.

  18. Dual-Functions of miR-373 and miR-520c by Differently Regulating the Activities of MMP2 and MMP9.

    PubMed

    Lu, Shan; Zhu, Qingyi; Zhang, Yi; Song, Wei; Wilson, Michael J; Liu, Ping

    2015-08-01

    MicroRNA-520c (miR-520c) and microRNA-373 (miR-373) are originally characterized as both oncogenes and tumor suppressors in different types of human cancers. In this study, we found that translation of mRNA of MT1-MMP, an oncogene related to tumor metastasis, was well inhibited by miR-520c and miR-373 in several types of human cancer cells. Our experimental data demonstrated that these two microRNAs inhibited the translation of mRNA of MT1-MMP and down-regulated its proteolytic enzyme activities via targeting 3'UTR of mRNA of MT1-MMP, further decreased activating proMMP2 into active MMP2 in fibrosarcoma HT1080, benign prostatic hyperplasia epithelial cell BPH-1 and glioblastoma U87GM. More interestingly, from the effects of microRNAs on cell functions, we found that cell growth were all blocked on fibronectin and type IV collagen coated plates and also in three-dimension type I collagen lattice but enhanced only in HT1080 cells on type IV collagen coated plates and in three-dimension type I collagen lattice; cell migration results showed the same effect as that of cell growth. The difference was due to up-regulating the expression of MMP9 gene by miR-520c and miR-373 in HT1080 cells but not in BPH-1 and U87GM cells. Our findings suggest that miR-520c and miR-373, which have different roles in different type of cancer via regulating the translation of mRNA of MT1-MMP and the expression of MMP9 gene, might have an important clue on clinic when selecting the therapeutic regimen and finding new drugs for intervention in different kinds of cancer.

  19. Finding Imaging Patterns of Structural Covariance via Non-Negative Matrix Factorization

    PubMed Central

    Sotiras, Aristeidis; Resnick, Susan M.; Davatzikos, Christos

    2015-01-01

    In this paper, we investigate the use of Non-Negative Matrix Factorization (NNMF) for the analysis of structural neuroimaging data. The goal is to identify the brain regions that co-vary across individuals in a consistent way, hence potentially being part of underlying brain networks or otherwise influenced by underlying common mechanisms such as genetics and pathologies. NNMF offers a directly data-driven way of extracting relatively localized co-varying structural regions, thereby transcending limitations of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and other related methods that tend to produce dispersed components of positive and negative loadings. In particular, leveraging upon the well known ability of NNMF to produce parts-based representations of image data, we derive decompositions that partition the brain into regions that vary in consistent ways across individuals. Importantly, these decompositions achieve dimensionality reduction via highly interpretable ways and generalize well to new data as shown via split-sample experiments. We empirically validate NNMF in two data sets: i) a Diffusion Tensor (DT) mouse brain development study, and ii) a structural Magnetic Resonance (sMR) study of human brain aging. We demonstrate the ability of NNMF to produce sparse parts-based representations of the data at various resolutions. These representations seem to follow what we know about the underlying functional organization of the brain and also capture some pathological processes. Moreover, we show that these low dimensional representations favorably compare to descriptions obtained with more commonly used matrix factorization methods like PCA and ICA. PMID:25497684

  20. Finding imaging patterns of structural covariance via Non-Negative Matrix Factorization.

    PubMed

    Sotiras, Aristeidis; Resnick, Susan M; Davatzikos, Christos

    2015-03-01

    In this paper, we investigate the use of Non-Negative Matrix Factorization (NNMF) for the analysis of structural neuroimaging data. The goal is to identify the brain regions that co-vary across individuals in a consistent way, hence potentially being part of underlying brain networks or otherwise influenced by underlying common mechanisms such as genetics and pathologies. NNMF offers a directly data-driven way of extracting relatively localized co-varying structural regions, thereby transcending limitations of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and other related methods that tend to produce dispersed components of positive and negative loadings. In particular, leveraging upon the well known ability of NNMF to produce parts-based representations of image data, we derive decompositions that partition the brain into regions that vary in consistent ways across individuals. Importantly, these decompositions achieve dimensionality reduction via highly interpretable ways and generalize well to new data as shown via split-sample experiments. We empirically validate NNMF in two data sets: i) a Diffusion Tensor (DT) mouse brain development study, and ii) a structural Magnetic Resonance (sMR) study of human brain aging. We demonstrate the ability of NNMF to produce sparse parts-based representations of the data at various resolutions. These representations seem to follow what we know about the underlying functional organization of the brain and also capture some pathological processes. Moreover, we show that these low dimensional representations favorably compare to descriptions obtained with more commonly used matrix factorization methods like PCA and ICA.

  1. The analysis of time-resolved optical waveguide absorption spectroscopy based on positive matrix factorization.

    PubMed

    Liu, Ping; Li, Zhu; Li, Bo; Shi, Guolong; Li, Minqiang; Yu, Daoyang; Liu, Jinhuai

    2013-08-01

    Time-resolved optical waveguide absorption spectroscopy (OWAS) makes use of an evanescent field to detect the polarized absorption spectra of sub-monomolecular adlayers. This technique is suitable for the investigation of kinetics at the solid/liquid interface of dyes, pigments, fluorescent molecules, quantum dots, metallic nanoparticles, and proteins with chromophores. In this work, we demonstrate the application of positive matrix factorization (PMF) to analyze time-resolved OWAS for the first time. Meanwhile, PCA is researched to compare with PMF. The absorption/desorption kinetics of Rhodamine 6G (R6G) onto a hydrophilic glass surface and the dynamic process of Meisenheimer complex between Cysteine and TNT are selected as samples to verify experimental system and analytical methods. The results are shown that time-resolved OWAS can well record the absorption/desorption of R6G onto a hydrophilic glass surface and the dynamic formation process of Meisenheimer complexes. The feature of OWAS extracted by PMF is dynamic and consistent with the results analyzed by the traditional function of time/wavelength-absorbance. Moreover, PMF prevents the negative factors from occurring, avoids contradicting physical reality, and makes factors more easily interpretable. Therefore, we believe that PMF will provide a valuable analysis route to allow processing of increasingly large and complex data sets.

  2. Source apportionment and location by selective wind sampling and Positive Matrix Factorization.

    PubMed

    Venturini, Elisa; Vassura, Ivano; Raffo, Simona; Ferroni, Laura; Bernardi, Elena; Passarini, Fabrizio

    2014-10-01

    In order to determine the pollution sources in a suburban area and identify the main direction of their origin, PM2.5 was collected with samplers coupled with a wind select sensor and then subjected to Positive Matrix Factorization (PMF) analysis. In each sample, soluble ions, organic carbon, elemental carbon, levoglucosan, metals, and Polycyclic Aromatic Hydrocarbons (PAHs) were determined. PMF results identified six main sources affecting the area: natural gas home appliances, motor vehicles, regional transport, biomass combustion, manufacturing activities, and secondary aerosol. The connection of factor temporal trends with other parameters (i.e., temperature, PM2.5 concentration, and photochemical processes) confirms factor attributions. PMF analysis indicated that the main source of PM2.5 in the area is secondary aerosol. This should be mainly due to regional contributions, owing to both the secondary nature of the source itself and the higher concentration registered in inland air masses. The motor vehicle emission source contribution is also important. This source likely has a prevalent local origin. The most toxic determined components, i.e., PAHs, Cd, Pb, and Ni, are mainly due to vehicular traffic. Even if this is not the main source in the study area, it is the one of greatest concern. The application of PMF analysis to PM2.5 collected with this new sampling technique made it possible to obtain more detailed results on the sources affecting the area compared to a classical PMF analysis. PMID:24488520

  3. Extracellular Matrix-Regulated Gene Expression RequiresCooperation of SWI/SNF and Transcription Factors

    SciTech Connect

    Xu, Ren; Spencer, Virginia A.; Bissell, Mina J.

    2006-05-25

    Extracellular cues play crucial roles in the transcriptional regulation of tissue-specific genes, but whether and how these signals lead to chromatin remodeling is not understood and subject to debate. Using chromatin immunoprecipitation (ChIP) assays and mammary-specific genes as models, we show here that extracellular matrix (ECM) molecules and prolactin cooperate to induce histone acetylation and binding of transcription factors and the SWI/SNF complex to the {beta}- and ?-casein promoters. Introduction of a dominant negative Brg1, an ATPase subunit of SWI/SNF complex, significantly reduced both {beta}- and ?-casein expression, suggesting that SWI/SNF-dependent chromatin remodeling is required for transcription of mammary-specific genes. ChIP analyses demonstrated that the ATPase activity of SWI/SNF is necessary for recruitment of RNA transcriptional machinery, but not for binding of transcription factors or for histone acetylation. Coimmunoprecipitation analyses showed that the SWI/SNF complex is associated with STAT5, C/EBP{beta}, and glucocorticoid receptor (GR). Thus, ECM- and prolactin-regulated transcription of the mammary-specific casein genes requires the concerted action of chromatin remodeling enzymes and transcription factors.

  4. Collagen and matrix metalloproteinase-2 and -9 in the ewe cervix during the estrous cycle.

    PubMed

    Rodríguez-Piñón, M; Tasende, C; Casuriaga, D; Bielli, A; Genovese, P; Garófalo, E G

    2015-09-15

    The cervical collagen remodeling during the estrous cycle of the ewe was examined. The collagen concentration determined by a hydroxyproline assay and the area occupied by collagen fibers (%C), determined by van Gieson staining, were assessed in the cranial and caudal cervix of Corriedale ewes on Days 1 (n = 6), 6 (n = 5), or 13 (n = 6) after estrous detection (defined as Day 0). In addition, the gelatinase activity by in situ and SDS-PAGE gelatin zymographies and matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9, respectively) expression by immunohistochemistry were determined. The collagen concentration and %C were lowest on Day 1 of the estrous cycle (P < 0.04), when MMP-2 activity was highest (P < 0.006) and the ratio of activated to latent MMP-2 trend to be highest (P = 0.0819). The MMP-2 activity was detected in 73% of the homogenized cervical samples, and its expression was mainly detected in active fibroblasts. By contrast, the MMP-9 activity was detected in 9% of the samples, and its scarce expression was associated with plasmocytes, macrophages, and lymphocytes. Matrix metalloproteinase-2 expression was maximal on Day 1 in the cranial cervix and on Day 13 in the caudal cervix and was lower in the cranial than in the caudal cervix (P < 0.0001). This time-dependent increase in MMP-2 expression that differed between the cranial and caudal cervix may reflect their different physiological roles. The decrease in the collagen content and increase in fibroblast MMP-2 activity in sheep cervix on Day 1 of the estrous cycle suggests that cervical dilation at estrus is due to the occurrence of collagen fiber degradation modulated by changes in periovulatory hormone levels.

  5. Using Dynamic Multi-Task Non-Negative Matrix Factorization to Detect the Evolution of User Preferences in Collaborative Filtering.

    PubMed

    Ju, Bin; Qian, Yuntao; Ye, Minchao; Ni, Rong; Zhu, Chenxi

    2015-01-01

    Predicting what items will be selected by a target user in the future is an important function for recommendation systems. Matrix factorization techniques have been shown to achieve good performance on temporal rating-type data, but little is known about temporal item selection data. In this paper, we developed a unified model that combines Multi-task Non-negative Matrix Factorization and Linear Dynamical Systems to capture the evolution of user preferences. Specifically, user and item features are projected into latent factor space by factoring co-occurrence matrices into a common basis item-factor matrix and multiple factor-user matrices. Moreover, we represented both within and between relationships of multiple factor-user matrices using a state transition matrix to capture the changes in user preferences over time. The experiments show that our proposed algorithm outperforms the other algorithms on two real datasets, which were extracted from Netflix movies and Last.fm music. Furthermore, our model provides a novel dynamic topic model for tracking the evolution of the behavior of a user over time.

  6. Using Dynamic Multi-Task Non-Negative Matrix Factorization to Detect the Evolution of User Preferences in Collaborative Filtering

    PubMed Central

    Ju, Bin; Qian, Yuntao; Ye, Minchao; Ni, Rong; Zhu, Chenxi

    2015-01-01

    Predicting what items will be selected by a target user in the future is an important function for recommendation systems. Matrix factorization techniques have been shown to achieve good performance on temporal rating-type data, but little is known about temporal item selection data. In this paper, we developed a unified model that combines Multi-task Non-negative Matrix Factorization and Linear Dynamical Systems to capture the evolution of user preferences. Specifically, user and item features are projected into latent factor space by factoring co-occurrence matrices into a common basis item-factor matrix and multiple factor-user matrices. Moreover, we represented both within and between relationships of multiple factor-user matrices using a state transition matrix to capture the changes in user preferences over time. The experiments show that our proposed algorithm outperforms the other algorithms on two real datasets, which were extracted from Netflix movies and Last.fm music. Furthermore, our model provides a novel dynamic topic model for tracking the evolution of the behavior of a user over time. PMID:26270539

  7. Using Dynamic Multi-Task Non-Negative Matrix Factorization to Detect the Evolution of User Preferences in Collaborative Filtering.

    PubMed

    Ju, Bin; Qian, Yuntao; Ye, Minchao; Ni, Rong; Zhu, Chenxi

    2015-01-01

    Predicting what items will be selected by a target user in the future is an important function for recommendation systems. Matrix factorization techniques have been shown to achieve good performance on temporal rating-type data, but little is known about temporal item selection data. In this paper, we developed a unified model that combines Multi-task Non-negative Matrix Factorization and Linear Dynamical Systems to capture the evolution of user preferences. Specifically, user and item features are projected into latent factor space by factoring co-occurrence matrices into a common basis item-factor matrix and multiple factor-user matrices. Moreover, we represented both within and between relationships of multiple factor-user matrices using a state transition matrix to capture the changes in user preferences over time. The experiments show that our proposed algorithm outperforms the other algorithms on two real datasets, which were extracted from Netflix movies and Last.fm music. Furthermore, our model provides a novel dynamic topic model for tracking the evolution of the behavior of a user over time. PMID:26270539

  8. The matrix-binding domain of microfibril-associated glycoprotein-1 targets active connective tissue growth factor to a fibroblast-produced extracellular matrix.

    PubMed

    Weinbaum, Justin S; Tranquillo, Robert T; Mecham, Robert P

    2010-11-10

    It is advantageous to use biomaterials in tissue engineering that stimulate extracellular matrix (ECM) production by the cellular component. Connective tissue growth factor (CTGF) stimulates type I collagen (COL1A1) transcription, but is functionally limited as a free molecule. Using a matrix-binding domain (MBD) from microfibril-associated glycoprotein-1, the fusion protein MBD-CTGF was targeted to the ECM and tested for COL1A1 transcriptional activation. MBD-CTGF produced by the ECM-synthesizing fibroblasts, or provided exogenously, localized to the elastic fiber ECM. MBD-CTGF, but not CTGF alone, led to a two-fold enhancement of COL1A1 expression. This study introduces a targeting technology that can be used to elevate collagen transcription in engineered tissues and thereby improve tissue mechanics.

  9. Correlation between matrix metalloproteinase expression and activation of the focal adhesion kinase signaling pathway in herpes stromal keratitis

    PubMed Central

    CAO, TING; XING, YIQIAO; YANG, YANNING; MEI, HAIFENG

    2014-01-01

    The present study aimed to investigate the correlation between matrix metalloproteinase-2 (MMP-2) expression and activation of the focal adhesion kinase (FAK) signaling pathway in herpes stromal keratitis (HSK). The cornea of 24 BALB/c mice was infected with herpes simplex virus type 1 (HSV-1) to construct a model of HSK. Six additional mice served as negative controls. Immunohistochemical staining was used to detect FAK expression levels. Human corneal epithelial (HCE) cells cultured in vitro were infected with HSV-1 and the expression levels of MMP-2, FAK and phosphorylated-FAK (p-FAK) in HCE cells were detected using reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry at 2, 20 and 40 h following infection. In the HSK rat model, the corneal epithelial cells appeared deranged and the number of neutrophils and FAK-positive cells was significantly increased compared with that of the negative control group (P<0.05). Repeated measures analysis of variance of RT-PCR showed no significant differences in MMP-2 and FAK mRNA expression levels in the infected cells at various time points, and no significant differences between infected cells and the negative control group were observed. There was no interaction between groups and time points. Pairwise comparisons showed that MMP-2 and FAK mRNA expression levels were significantly increased in virus-infected cells compared with those of the control group. Over time, MMP-2 and FAK mRNA expression levels did not differ significantly in virus-infected cells or in control cells. Western blot analysis indicated no significant differences in p-FAK, FAK and MMP-2 expression levels between the infected and control cells at 2 h (P>0.05). Infected cells showed a significant increase in MMP-2 and p-FAK expression levels than that of the control cells at 20 and 40 h (P<0.05). p-FAK, FAK and MMP-2 expression levels in virus-infected cells at 2 h differed significantly from those at 20

  10. NF kappa B and Matrix Metalloproteinase induced Receptor Cleavage in the Spontaneously Hypertensive Rat

    PubMed Central

    Wu, Kwan-I Sharon; Schmid-Schönbein, Geert W.

    2011-01-01

    Recent evidence suggests that inflammation in the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor nuclear factor kappa B (NF–κB) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the beta-2 adrenergic receptor (β2AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NF-κB expression level and translocation were compared between Wistar Kyoto rat (WKY) and SHR kidney, heart and brain. The animals were treated with a NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), for ten weeks and correlations between NF-κB and MMP activity were determined. Immunohistochemistry showed that NF-κB expression is increased in untreated SHR kidney (~ 14%) and brain hypothalamus (~ 22%) compared to that in WKY (p <0.05), but not in myocardium and cerebral cortex. After PDTC treatment, the SHR systolic blood pressure was reduced close to WKY levels. NF-κB expression level in treated-SHR was also decreased in kidney and hypothalamus compared to non-treated animals (p <0.05). Furthermore, MMP-2 and -9 activities in SHR plasma were significantly reduced (~41%) by PDTC treatment. Additionally, zymographic analyses and in situ zymography showed decreased MMP-2 activity in kidney homogenates and decreased MMP-1,-9 activities in brain. The level of the β2AR extracellular, but not intracellular, domain density was found reduced in kidney showing a receptor cleavage process that can be blocked by PDTC treatment. These results suggest NF-κB is an important transcription factor in the SHR and may be involved in the enhanced MMP activity and consequently receptor cleavage. PMID:21220710

  11. Uterine cervical carcinoma: role of matrix metalloproteinases (review).

    PubMed

    Libra, Massimo; Scalisi, Aurora; Vella, Nadia; Clementi, Silvia; Sorio, Roberto; Stivala, Franca; Spandidos, Demetrios A; Mazzarino, Clorinda

    2009-04-01

    Epidemiological and experimental studies have provided evidence that human papillomavirus (HPV) infection is a main player in the development of uterine cervical neoplasms. Migration of cancer cells from the origin tissue to surrounding or distant organs is essential for tumor progression. Many studies of tumor invasion and metastases have focused on the degradation of the extracellular matrix where matrix metalloproteinases (MMPs) play a central role. Two of these enzymes, MMP-2 and MMP-9, have been correlated with the processes of tumor cell invasion and metastasis in human cancers, including uterine neoplasms. It has been shown that the up-regulation of MMPs is associated with progression of cervical uterine neoplasms. This review describes the current understanding of MMP-2 and MMP-9 expression and activity in pre-cancer and cancer lesions of cervical uterine, which may open new strategies for diagnostic and therapeutic interventions.

  12. Mesenchymal cell chondrogenesis is stimulated by basement membrane matrix and inhibited by age-associated factors.

    PubMed

    Bradham, D M; Passaniti, A; Horton, W E

    1995-07-01

    During development of the embryonic limb, differentiation of mesenchymal progenitor cells into chondrocytes is regulated by cell shape, extracellular matrix, and growth and differentiation factors. In this study, reconstituted basement membrane (Matrigel) prepared from mouse Englebreth-Holm-Swarm tumor tissue was found to stimulate mesenchymal cell chondrogenesis in vitro and the production of cartilage at ectopic sites in athymic mice. The rate of chondrogenesis of mesenchymal cells from chick limb bud was increased four-fold by the addition of 400 micrograms/ml Matrigel to the media of micromass cultures, and this activity was not blocked by neutralizing antibodies to transforming growth factor-beta (TGF-beta) or fibroblast growth factor (FGF). Mesenchymal cells cultured on Matrigel, but not laminin or collagen type I or IV, formed spheres of condensed cells which stained with Alcian blue. Chick limb-bud mesenchymal cells suspended in Matrigel prepared from tumors grown in C57 mice aged 3, 12, or 26 months formed disks of hyaline cartilage within 2 weeks with wet weights of 59.1 mg, 35.7 mg, and 21.4 mg, indicating that the Matrigel from the old animals was less biologically active. In agreement with the in vivo data, Alcian blue staining of proteoglycan was over two-fold higher in micromass cultures supplemented with the Matrigel from young animals than in cultures treated with the Matrigel from old mice. A high-salt wash preparation of Matrigel from tumors grown in old mice increased the rate of chondrogenesis and cartilage production, suggesting that an inhibitor of chondrogenesis is produced by the old host. Thus, Matrigel contains chondrogenic activity distinct from TGF-beta or FGF. The aged host may produce factors that are inhibitory to mesenchymal cell differentiation and adversely affect cartilage formation and repair.

  13. Nonlinear hyperspectral unmixing based on sparse non-negative matrix factorization

    NASA Astrophysics Data System (ADS)

    Li, Jing; Li, Xiaorun; Zhao, Liaoying

    2016-01-01

    Hyperspectral unmixing aims at extracting pure material spectra, accompanied by their corresponding proportions, from a mixed pixel. Owing to modeling more accurate distribution of real material, nonlinear mixing models (non-LMM) are usually considered to hold better performance than LMMs in complicated scenarios. In the past years, numerous nonlinear models have been successfully applied to hyperspectral unmixing. However, most non-LMMs only think of sum-to-one constraint or positivity constraint while the widespread sparsity among real materials mixing is the very factor that cannot be ignored. That is, for non-LMMs, a pixel is usually composed of a few spectral signatures of different materials from all the pure pixel set. Thus, in this paper, a smooth sparsity constraint is incorporated into the state-of-the-art Fan nonlinear model to exploit the sparsity feature in nonlinear model and use it to enhance the unmixing performance. This sparsity-constrained Fan model is solved with the non-negative matrix factorization. The algorithm was implemented on synthetic and real hyperspectral data and presented its advantage over those competing algorithms in the experiments.

  14. Stability-driven nonnegative matrix factorization to interpret spatial gene expression and build local gene networks

    PubMed Central

    Wu, Siqi; Joseph, Antony; Hammonds, Ann S.; Celniker, Susan E.; Yu, Bin; Frise, Erwin

    2016-01-01

    Spatial gene expression patterns enable the detection of local covariability and are extremely useful for identifying local gene interactions during normal development. The abundance of spatial expression data in recent years has led to the modeling and analysis of regulatory networks. The inherent complexity of such data makes it a challenge to extract biological information. We developed staNMF, a method that combines a scalable implementation of nonnegative matrix factorization (NMF) with a new stability-driven model selection criterion. When applied to a set of Drosophila early embryonic spatial gene expression images, one of the largest datasets of its kind, staNMF identified 21 principal patterns (PP). Providing a compact yet biologically interpretable representation of Drosophila expression patterns, PP are comparable to a fate map generated experimentally by laser ablation and show exceptional promise as a data-driven alternative to manual annotations. Our analysis mapped genes to cell-fate programs and assigned putative biological roles to uncharacterized genes. Finally, we used the PP to generate local transcription factor regulatory networks. Spatially local correlation networks were constructed for six PP that span along the embryonic anterior–posterior axis. Using a two-tail 5% cutoff on correlation, we reproduced 10 of the 11 links in the well-studied gap gene network. The performance of PP with the Drosophila data suggests that staNMF provides informative decompositions and constitutes a useful computational lens through which to extract biological insight from complex and often noisy gene expression data. PMID:27071099

  15. Stability-driven nonnegative matrix factorization to interpret spatial gene expression and build local gene networks.

    PubMed

    Wu, Siqi; Joseph, Antony; Hammonds, Ann S; Celniker, Susan E; Yu, Bin; Frise, Erwin

    2016-04-19

    Spatial gene expression patterns enable the detection of local covariability and are extremely useful for identifying local gene interactions during normal development. The abundance of spatial expression data in recent years has led to the modeling and analysis of regulatory networks. The inherent complexity of such data makes it a challenge to extract biological information. We developed staNMF, a method that combines a scalable implementation of nonnegative matrix factorization (NMF) with a new stability-driven model selection criterion. When applied to a set ofDrosophilaearly embryonic spatial gene expression images, one of the largest datasets of its kind, staNMF identified 21 principal patterns (PP). Providing a compact yet biologically interpretable representation ofDrosophilaexpression patterns, PP are comparable to a fate map generated experimentally by laser ablation and show exceptional promise as a data-driven alternative to manual annotations. Our analysis mapped genes to cell-fate programs and assigned putative biological roles to uncharacterized genes. Finally, we used the PP to generate local transcription factor regulatory networks. Spatially local correlation networks were constructed for six PP that span along the embryonic anterior-posterior axis. Using a two-tail 5% cutoff on correlation, we reproduced 10 of the 11 links in the well-studied gap gene network. The performance of PP with theDrosophiladata suggests that staNMF provides informative decompositions and constitutes a useful computational lens through which to extract biological insight from complex and often noisy gene expression data.

  16. Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion

    PubMed Central

    Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M

    2010-01-01

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using α6β1 and α3β1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. PMID:19382180

  17. Non-negative Matrix Factorization as a Method for Studying Coronal Heating

    NASA Astrophysics Data System (ADS)

    Barnes, Will; Bradshaw, Stephen

    2015-04-01

    Many theoretical efforts have been made to model the response of coronal loops to nanoflare heating, but the theory has long suffered from a lack of direct observations. Nanoflares, originally proposed by Parker (1988), heat the corona through short, impulsive bursts of energy. Because of their short duration and comparatively low amplitude, emission signatures from nanoflare heating events are often difficult to detect. Past algorithms (e.g. Ugarte-Urra and Warren, 2014) for measuring the frequency of transient brightenings in active region cores have provided only a lower bound for such measurements. We present the use of non-negative matrix factorization (NMF) to analyze spectral data in active region cores in order to provide more accurate determinations of nanoflare heating properties. NMF, a matrix deconvolution technique, has a variety of applications , ranging from Raman spectroscopy to face recognition, but, to our knowledge, has not been applied in the field of solar physics. The strength of NMF lies in its ability to estimate sources (heating events) from measurements (observed spectral emission) without any knowledge of the mixing process (Cichocki et al., 2009). We apply our NMF algorithm to forward-modeled emission representative of that produced by nanoflare heating events in an active region core. The heating events are modeled using a state-of-the-art hydrodynamics code (Bradshaw and Cargill, 2013) and the emission and active regions are synthesized using advanced forward modeling and visualization software (Bradshaw and Klimchuk, 2011; Reep et al., 2013). From these active region visualizations, our NMF algorithm is then able to predict the heating event frequency and amplitudes. Improved methods of nanoflare detection will help to answer fundamental questions regarding the frequency of energy release in the solar corona and how the corona responds to such impulsive heating. Additionally, development of reliable, automated nanoflare detection

  18. Plasma Membrane Factor XIIIA Transglutaminase Activity Regulates Osteoblast Matrix Secretion and Deposition by Affecting Microtubule Dynamics

    PubMed Central

    Al-Jallad, Hadil F.; Myneni, Vamsee D.; Piercy-Kotb, Sarah A.; Chabot, Nicolas; Mulani, Amina; Keillor, Jeffrey W.; Kaartinen, Mari T.

    2011-01-01

    Transglutaminase activity, arising potentially from transglutaminase 2 (TG2) and Factor XIIIA (FXIIIA), has been linked to osteoblast differentiation where it is required for type I collagen and fibronectin matrix deposition. In this study we have used an irreversible TG-inhibitor to ‘block –and-track’ enzyme(s) targeted during osteoblast differentiation. We show that the irreversible TG-inhibitor is highly potent in inhibiting osteoblast differentiation and mineralization and reduces secretion of both fibronectin and type I collagen and their release from the cell surface. Tracking of the dansyl probe by Western blotting and immunofluorescence microscopy demonstrated that the inhibitor targets plasma membrane-associated FXIIIA. TG2 appears not to contribute to crosslinking activity on the osteoblast surface. Inhibition of FXIIIA with NC9 resulted in defective secretory vesicle delivery to the plasma membrane which was attributable to a disorganized microtubule network and decreased microtubule association with the plasma membrane. NC9 inhibition of FXIIIA resulted in destabilization of microtubules as assessed by cellular Glu-tubulin levels. Furthermore, NC9 blocked modification of Glu-tubulin into 150 kDa high-molecular weight Glu-tubulin form which was specifically localized to the plasma membrane. FXIIIA enzyme and its crosslinking activity were colocalized with plasma membrane-associated tubulin, and thus, it appears that FXIIIA crosslinking activity is directed towards stabilizing the interaction of microtubules with the plasma membrane. Our work provides the first mechanistic cues as to how transglutaminase activity could affect protein secretion and matrix deposition in osteoblasts and suggests a novel function for plasma membrane FXIIIA in microtubule dynamics. PMID:21283799

  19. Liver functions in silica-exposed workers in Egypt: possible role of matrix remodeling and immunological factors

    PubMed Central

    Zawilla, Nermin; Taha, Fatma; Ibrahim, Yasser

    2014-01-01

    Background: Brick manufacturing constitutes an important industrial sector in Egypt with considerable exposure to silica. Objectives: We aimed for evaluating hepatic functions in silica-exposed workers in the clay brick industry, and the possible role of matrix remodeling and immunological factors. Methods: A case–control study, 87 workers as exposed and 45 as control subjects. Questionnaire, clinical examination, and laboratory investigations: liver functions, matrix metalloproteinase-9, immunoglobulins G and E, and anti-liver kidney microsomal antibody. Results: In the exposed workers, mean levels of liver functions, matrix metalloproteinase-9 (MMP-9), and IgG and IgE were significantly higher. In the silicotic subgroup the mean level of GGT was almost twice the level in the non-silicotic subjects. Logistic regression showed that abnormal GGT and ALT were associated with production workers. Conclusion: Workers in the clay brick industry showed evidence of liver disease that could be related to matrix remodeling. PMID:24999850

  20. Apportioning visibility degradation to sources of PM2.5 using positive matrix factorization.

    PubMed

    Eatough, Delbert J; Farber, Robert

    2009-09-01

    Intensive monitoring studies of aerosol have been conducted in two regions of California with poor air quality. Winter monitoring in the Fresno area was conducted in December 2003. Two summer samplings were collected from the eastern Los Angeles Basin, from Rubidoux in 2003 and Riverside in 2005. All three of these studies featured a suite of semicontinuous aerosol monitors. The speciated aerosol data with continuous gaseous measurements from these studies were combined with continuous Automated Surface Observing System (ASOS) measurements of visibility and extinction from nearby airports and modeled aerosol water content to conduct source apportionment analyses. The data were analyzed using three different techniques. A conventional positive matrix factorization (PMF) method was used. Then a novel approach was used that coupled PMF with added extinction and modeled water data. Another technique involved integrating conventional PMF with linear regression to obtain the extinction associated with each source. The novel PMF with added extinction and modeled water data provided the most robust results. The Fresno winter study was meteorologically characterized by stagnant conditions, a shallow mixing height, and intermittent periods of fog and low clouds. Six factors were identified using PMF. The secondary nitrate and gasoline mobile combustion emission associated sources exhibited the highest extinction coefficients. PMF also identified six factors in the summer 2003 study at Rubidoux. The secondary nitrate and the ozone-related secondary semi-volatile organic material (SVOM) sources exhibited the highest extinction levels. Water associated with the aerosols plays an important role because of the marine influence and stratus clouds typically occurring in the basin during the summer months. The summer of 2005 study in Riverside lead to the identification of 11 sources. The highest contributors to extinction are associated with material transported across the basin

  1. Increasing matrix stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin β1.

    PubMed

    Dong, Yinying; Xie, Xiaoying; Wang, Zhiming; Hu, Chao; Zheng, Qiongdan; Wang, Yaohui; Chen, Rongxin; Xue, Tongchun; Chen, Jie; Gao, Dongmei; Wu, Weizhong; Ren, Zhenggang; Cui, Jiefeng

    2014-02-14

    Matrix stiffness as a novel regulation factor involves in modulating the pathogenesis of hepatocellular carcinoma (HCC) invasion or metastasis. However, the mechanism by which matrix stiffness modulates HCC angiogenesis remains unknown. Here, using buffalo rat HCC models with different liver matrix stiffness backgrounds and an in vitro cell culture system of mechanically tunable Collagen1 (COL1)-coated polyacrylamide gel, we investigated the effects of different matrix stiffness levels on vascular endothelial growth factor (VEGF) expression in HCC cells and explored its regulatory mechanism for controlling HCC angiogenesis. Tissue microarray analysis showed that the expression levels of VEGF and CD31 were gradually upregulated in tumor tissues with increasing COL1 and lysyl oxidase (LOX) expression, indicating a positive correlation between tumor angiogenesis and matrix rigidity. The expression of VEGF and the phosphorylation levels of PI3K and Akt were all upregulated in HCC cells on high-stiffness gel than on low-stiffness gel. Meanwhile, alteration of intergrin β1 expression was found to be the most distinctive, implying that it might mediate the response of HCC cells to matrix stiffness simulation. After integrin β1 was blocked in HCC cells using specific monoclonal antibody, the expression of VEGF and the phosphorylation levels of PI3K and Akt at different culture times were accordingly suppressed and downregulated in the treatment group as compared with those in the control group. All data suggested that the extracellular matrix stiffness stimulation signal was transduced into HCC cells via integrin β1, and this signal activated the PI3K/Akt pathway and upregulated VEGF expression. This study unveils a new paradigm in which matrix stiffness as initiators to modulate HCC angiogenesis.

  2. Identification of the sources of PM10 in a subway tunnel using positive matrix factorization.

    PubMed

    Park, Duckshin; Lee, Taejeong; Hwang, Doyeon; Jung, Wonseok; Lee, Yongil; Cho, KiChul; Kim, Dongsool; Lees, Kiyoung

    2014-12-01

    The level of particulate matter of less than 10 μm diameter (PM10) at subway platforms can be significantly reduced by installing a platform screen-door system. However, both workers and passengers might be exposed to higher PM10 levels while the cars are within the tunnel because it is a more confined environment. This study determined the PM10 levels in a subway tunnel, and identified the sources of PM10 using elemental analysis and receptor modeling. Forty-four PM10 samples were collected in the tunnel between the Gireum and Mia stations on Line 4 in metropolitan Seoul and analyzed using inductively coupled plasma-atomic emission spectrometry and ion chromatography. The major PM10 sources were identified using positive matrix factorization (PMF). The average PM10 concentration in the tunnels was 200.8 ± 22.0 μg/m3. Elemental analysis indicated that the PM10 consisted of 40.4% inorganic species, 9.1% anions, 4.9% cations, and 45.6% other materials. Iron was the most abundant element, with an average concentration of 72.5 ± 10.4 μg/m3. The PM10 sources characterized by PMF included rail, wheel, and brake wear (59.6%), soil combustion (17.0%), secondary aerosols (10.0%), electric cable wear (8.1%), and soil and road dust (5.4%). Internal sources comprising rail, wheel, brake, and electric cable wear made the greatest contribution to the PM10 (67.7%) in tunnel air. Implications: With installation of a platform screen door, PM10 levels in subway tunnels were higher than those on platforms. Tunnel PM10 levels exceeded 150 µg/m3 of the Korean standard for subway platform. Elemental analysis of PM10 in a tunnel showed that Fe was the most abundant element. Five PM10 sources in tunnel were identified by positive matrix factorization. Railroad-related sources contributed 68% of PM10 in the subway tunnel. PMID:25562932

  3. Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

    PubMed Central

    Hu, Ping; Thinschmidt, Jeffrey S.; Caballero, Sergio; Adamson, Samuel; Cole, Louise; Chan-Ling, Tailoi

    2015-01-01

    Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12- and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P < 0.05) and reduced neuronal expression of IGFBP-3 (−32%, P < 0.05) and IGF-I (−15%, P < 0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P < 0.01), and IDO+ cell density rose by (62%, P < 0.05). CD39 expression dropped by 30% (P < 0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P < 0.05). Our results suggest that increased IDO and early loss of CD39+ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D. PMID:25714673

  4. Dexamethasone Ameliorates H2S-Induced Acute Lung Injury by Alleviating Matrix Metalloproteinase-2 and -9 Expression

    PubMed Central

    Su, Chenglei; Chen, Junjie; Zhu, Baoli; Zhang, Hengdong; Xiao, Hang; Zhang, Jinsong

    2014-01-01

    Acute lung injury (ALI) is one of the fatal outcomes after exposure to high levels of hydrogen sulfide (H2S), and the matrix metalloproteinases (MMPs) especially MMP-2 and MMP-9 are believed to be involved in the development of ALI by degrading the extracellular matrix (ECM) of blood-air barrier. However, the roles of MMP-2 and MMP-9 in H2S-induced ALI and the mechanisms of dexamethasone (DXM) in treating ALI in clinical practice are still largely unknown. The present work was aimed to investigate the roles of MMP-2 and MMP-9 in H2S-induced ALI and the protective effects of DXM. In our study, SD rats were exposed to H2S to establish the ALI model and in parallel, A549 cells were incubated with NaHS (a H2S donor) to establish cell model. The lung HE staining, immunohistochemisty, electron microscope assay and wet/dry ratio were used to identify the ALI induced by H2S, then the MMP-2 and MMP-9 expression in both rats and A549 cells were detected. Our results revealed that MMP-2 and MMP-9 were obviously increased in both mRNA and protein level after H2S exposure, and they could be inhibited by MMP inhibitor doxycycline (DOX) in rat model. Moreover, DXM significantly ameliorated the symptoms of H2S-induced ALI including alveolar edema, infiltration of inflammatory cells and the protein leakage in BAFL via up-regulating glucocorticoid receptor(GR) to mediate the suppression of MMP-2 and MMP-9. Furthermore, the protective effects of DXM in vivo and vitro study could be partially blocked by co-treated with GR antagonist mifepristone (MIF). Our results, taken together, demonstrated that MMP-2 and MMP-9 were involved in the development of H2S-induced ALI and DXM exerted protective effects by alleviating the expression of MMP-2 and MMP-9. Therefore, MMP-2 and MMP-9 might represent novel pharmacological targets for the treatment of H2S and other hazard gases induced ALI. PMID:24722316

  5. Factors affecting miniature Izod impact strength of tungsten-fiber-metal-matrix

    NASA Technical Reports Server (NTRS)

    Winsa, E. A.; Petrasek, D. W.

    1973-01-01

    The miniature Izod and Charpy impact strengths of copper, copper-nickel, and nickel-base superalloy uniaxially reinforced with continuous tungsten fibers were studied. In most cases, impact strength was increased by increasing fiber or matrix toughness, decreasing fibermatrix reaction, increasing test temperature, hot working, or heat treating. Notch sensitivity was reduced by increasing fiber content or matrix toughness. An equation relating impact strength to fiber and matrix properties and fiber content was developed. Program results imply that tungsten alloy-fiber/superalloy matrix composites can be made with adequate impact resistance for turbine blade or vane applications.

  6. HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases

    PubMed Central

    Kaewprag, Jittranan; Umnajvijit, Wareerat; Ngamkham, Jarunya; Ponglikitmongkol, Mathurose

    2013-01-01

    Production of matrix metalloproteinases (MMPs) for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7), either individually or combined, on the transcription of 7 MMPs implicated in cervical cancer invasiveness. The levels of 7 MMPs reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using in vitro invasion and wound healing assays. Overexpression of MMP-2 and MT1-MMP was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced in vivo expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the MMP-2 and MT1-MMP promoters were investigated and PEA3 (at −552/−540 for MMP-2, −303 for MT1-MMP) and Sp1 (at −91 for MMP-2, −102 for MT1-MMP) binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating MMP-2 and MT1-MMP transcription in a similar manner. PMID:23967226

  7. HPV16 oncoproteins promote cervical cancer invasiveness by upregulating specific matrix metalloproteinases.

    PubMed

    Kaewprag, Jittranan; Umnajvijit, Wareerat; Ngamkham, Jarunya; Ponglikitmongkol, Mathurose

    2013-01-01

    Production of matrix metalloproteinases (MMPs) for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7), either individually or combined, on the transcription of 7 MMPs implicated in cervical cancer invasiveness. The levels of 7 MMPs reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using in vitro invasion and wound healing assays. Overexpression of MMP-2 and MT1-MMP was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced in vivo expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the MMP-2 and MT1-MMP promoters were investigated and PEA3 (at -552/-540 for MMP-2, -303 for MT1-MMP) and Sp1 (at -91 for MMP-2, -102 for MT1-MMP) binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating MMP-2 and MT1-MMP transcription in a similar manner.

  8. Substrate stiffness-regulated matrix metalloproteinase output in myocardial cells and cardiac fibroblasts: implications for myocardial fibrosis.

    PubMed

    Xie, Jing; Zhang, Quanyou; Zhu, Ting; Zhang, Yanyan; Liu, Bailin; Xu, Jianwen; Zhao, Hucheng

    2014-06-01

    Cardiac fibrosis, an important pathological feature of structural remodeling, contributes to ventricular stiffness, diastolic dysfunction, arrhythmia and may even lead to sudden death. Matrix stiffness, one of the many mechanical factors acting on cells, is increasingly appreciated as an important mediator of myocardial cell behavior. Polydimethylsiloxane (PDMS) substrates were fabricated with different stiffnesses to mimic physiological and pathological heart tissues, and the way in which the elastic modulus of the substrate regulated matrix-degrading gelatinases in myocardial cells and cardiac fibroblasts was explored. Initially, an increase in cell spreading area was observed, concomitant with the increase in PDMS stiffness in both cells. Later, it was demonstrated that the MMP-2 gene expression and protein activity in myocardial cells and cardiac fibroblasts can be enhanced with an increase in PDMS substrate stiffness and, moreover, such gene- and protein-related increases had a significant linear correlation with the elastic modulus. In comparison, the MMP-9 gene and protein expressions were up-regulated in cardiac fibroblasts only, not in myocardial cells. These results implied that myocardial cells and cardiac fibroblasts in the myocardium could sense the stiffness in pathological fibrosis and showed a differential but positive response in the expression of matrix-degrading gelatinases when exposed to an increased stiffening of the matrix in the microenvironment. The phenomenon of cells sensing pathological matrix stiffness can help to increase understanding of the mechanism underlying myocardial fibrosis and may ultimately lead to planning cure strategies.

  9. Fluorescence tomography of targets in a turbid medium using non-negative matrix factorization

    NASA Astrophysics Data System (ADS)

    Wu, Binlin; Gayen, S. K.

    2014-04-01

    A near-infrared optical tomography approach for detection, three-dimensional localization, and cross-section imaging of fluorescent targets in a turbid medium is introduced. The approach uses multisource probing of targets, multidetector acquisition of diffusely transmitted fluorescence signal, and a non-negative matrix factorization based blind source separation scheme to obtain three-dimensional location of the targets. A Fourier transform back-projection algorithm provides an estimate of target cross section. The efficacy of the approach is demonstrated in an experiment involving two laterally separated small fluorescent targets embedded in a human breast tissue-simulating sample of thickness 60 times the transport mean free path. The approach could locate the targets within ˜1 mm of their known positions, and provide estimates of their cross sections. The high spatial resolution, fast reconstruction speed, noise tolerance, and ability to detect small targets are indicative of the potential of the approach for detecting and locating fluorescence contrast-enhanced breast tumors in early growth stages, when they are more amenable to treatment.

  10. [Assessing PM10 and SO2 networks using positive matrix factorization in Beijing city].

    PubMed

    Gao, Tao; Xie, Shao-dong; Bo, Yu; Zhao, Yue

    2010-03-01

    The aim of this study was to identify city areas with similar air pollution characteristics and determine which sites may be providing redundant information. Positive matrix factorization (PMF) was applied in this study to assess the mass concentrations of sulfur dioxide (SO2) and particulate matter with an aerodynamic diameter less than 10 microm (PM010), collected in the air quality monitoring network in the year of 2000. The analysis indicated that there were obviously seasonal variations for PM10 and SO2 in Beijing. The PM10 concentrations were higher in spring and lower in summer, but the SO2 concentrations were higher in winter and lower in summer. The results of the PMF showed that the sites of PM10 network in Beijing could be identified as three regions, which represented city areas characterized by the same specific air pollution. These three regions represented Gucheng site/Chegongzhuang site, Qianmen site/National Olympic Sports Center site/Tiantan site/Nongzhanguan site, and Ming Tombs site, respectively. Some sites in region 2 which included four sites may be redundant and can be removed. SO2 network can be divided into six regions including Chegongzhuang site/Qianmen site, Tiantan site/Nongzhanguan stie, Ming Tombs site, National Olympic Sports Center site, Dongsi site, and Gucheng site. It indicated that some sites in Beijing PM10 and SO2 monitoring networks might be redundant and could be removed or relocated to other areas.

  11. Gene expression based mouse brain parcellation using Markov random field regularized non-negative matrix factorization

    NASA Astrophysics Data System (ADS)

    Pathak, Sayan D.; Haynor, David R.; Thompson, Carol L.; Lein, Ed; Hawrylycz, Michael

    2009-02-01

    Understanding the geography of genetic expression in the mouse brain has opened previously unexplored avenues in neuroinformatics. The Allen Brain Atlas (www.brain-map.org) (ABA) provides genome-wide colorimetric in situ hybridization (ISH) gene expression images at high spatial resolution, all mapped to a common three-dimensional 200μm3 spatial framework defined by the Allen Reference Atlas (ARA) and is a unique data set for studying expression based structural and functional organization of the brain. The goal of this study was to facilitate an unbiased data-driven structural partitioning of the major structures in the mouse brain. We have developed an algorithm that uses nonnegative matrix factorization (NMF) to perform parts based analysis of ISH gene expression images. The standard NMF approach and its variants are limited in their ability to flexibly integrate prior knowledge, in the context of spatial data. In this paper, we introduce spatial connectivity as an additional regularization in NMF decomposition via the use of Markov Random Fields (mNMF). The mNMF algorithm alternates neighborhood updates with iterations of the standard NMF algorithm to exploit spatial correlations in the data. We present the algorithm and show the sub-divisions of hippocampus and somatosensory-cortex obtained via this approach. The results are compared with established neuroanatomic knowledge. We also highlight novel gene expression based sub divisions of the hippocampus identified by using the mNMF algorithm.

  12. An automatic search of Alzheimer patterns using a nonnegative matrix factorization

    NASA Astrophysics Data System (ADS)

    Giraldo, Diana L.; García-Arteaga, Juan D.; Romero, Eduardo

    2013-11-01

    This paper presents a fully automatic method that condenses relevant morphometric information from a database of magnetic resonance images (MR) labeled as either normal (NC) or Alzheimer's disease (AD). The proposed method generates class templates using Nonnegative Matrix Factorization (NMF) which will be used to develop an NC/AD classi cator. It then nds regions of interest (ROI) with discerning inter-class properties. by inspecting the di erence volume of the two class templates. From these templates local probability distribution functions associated to low level features such as intensities, orientation and edges within the found ROI are calculated. A sample brain volume can then be characterized by a similarity measure in the ROI to both the normal and the pathological templates. These characteristics feed a simple binary SVM classi er which, when tested with an experimental group extracted from a public brain MR dataset (OASIS), reveals an equal error rate measure which is better than the state-of-the-art tested on the same dataset (0:9 in the former and 0:8 in the latter).

  13. Influence of neutron activation factors on matrix tablets for site specific delivery to the colon.

    PubMed

    Ahrabi, S F; Heinämäki, J; Sande, S A; Graffner, C

    2000-05-01

    The impact of the neutron activation procedure, i.e. incorporation of samarium oxide (Sm(2)O(3)) and neutron irradiation, on the compression properties (including the crushing strength) and in vitro dissolution of potential colonic delivery systems based on matrix tablets of amidated pectin (Am.P) or two types of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation factors did not influence the compression properties of the tablets. Replacement of magnesium stearate with samarium stearate in directly compressed Am.P tablets to achieve both radiolabelling and lubrication resulted in a greater extent of concentration-dependent reduction of the crushing strength. Dissolution tests demonstrated that irradiation increased the release of the model drug ropivacaine from the tablets. The extent of this increase was unexpectedly low considering the previously observed degradation of the polymer expressed as an irradiation-induced viscosity reduction in solutions prepared from the polymers. Delayed-release coating with Eudragit L 100 protected the HPMC tablets against the release-increasing effect of irradiation until the late phases of release. Sm(2)O(3) retarded the release to a varying extent depending on particle characteristics. Incorporation of Sm(2)O(3) in the coating layer did not influence the release. However, one-third of the radioactivity leached from the coating within 60 min in 0.1 M HCl. PMID:10767600

  14. UTOPIAN: user-driven topic modeling based on interactive nonnegative matrix factorization.

    PubMed

    Choo, Jaegul; Lee, Changhyun; Reddy, Chandan K; Park, Haesun

    2013-12-01

    Topic modeling has been widely used for analyzing text document collections. Recently, there have been significant advancements in various topic modeling techniques, particularly in the form of probabilistic graphical modeling. State-of-the-art techniques such as Latent Dirichlet Allocation (LDA) have been successfully applied in visual text analytics. However, most of the widely-used methods based on probabilistic modeling have drawbacks in terms of consistency from multiple runs and empirical convergence. Furthermore, due to the complicatedness in the formulation and the algorithm, LDA cannot easily incorporate various types of user feedback. To tackle this problem, we propose a reliable and flexible visual analytics system for topic modeling called UTOPIAN (User-driven Topic modeling based on Interactive Nonnegative Matrix Factorization). Centered around its semi-supervised formulation, UTOPIAN enables users to interact with the topic modeling method and steer the result in a user-driven manner. We demonstrate the capability of UTOPIAN via several usage scenarios with real-world document corpuses such as InfoVis/VAST paper data set and product review data sets.

  15. Automated Robust Image Segmentation: Level Set Method Using Nonnegative Matrix Factorization with Application to Brain MRI.

    PubMed

    Dera, Dimah; Bouaynaya, Nidhal; Fathallah-Shaykh, Hassan M

    2016-07-01

    We address the problem of fully automated region discovery and robust image segmentation by devising a new deformable model based on the level set method (LSM) and the probabilistic nonnegative matrix factorization (NMF). We describe the use of NMF to calculate the number of distinct regions in the image and to derive the local distribution of the regions, which is incorporated into the energy functional of the LSM. The results demonstrate that our NMF-LSM method is superior to other approaches when applied to synthetic binary and gray-scale images and to clinical magnetic resonance images (MRI) of the human brain with and without a malignant brain tumor, glioblastoma multiforme. In particular, the NMF-LSM method is fully automated, highly accurate, less sensitive to the initial selection of the contour(s) or initial conditions, more robust to noise and model parameters, and able to detect as small distinct regions as desired. These advantages stem from the fact that the proposed method relies on histogram information instead of intensity values and does not introduce nuisance model parameters. These properties provide a general approach for automated robust region discovery and segmentation in heterogeneous images. Compared with the retrospective radiological diagnoses of two patients with non-enhancing grade 2 and 3 oligodendroglioma, the NMF-LSM detects earlier progression times and appears suitable for monitoring tumor response. The NMF-LSM method fills an important need of automated segmentation of clinical MRI. PMID:27417984

  16. Differential expression of extracellular matrix and growth factors by embryoid bodies in hydrodynamic and static cultures.

    PubMed

    Fridley, Krista M; Nair, Rekha; McDevitt, Todd C

    2014-12-01

    During development, cell fate specification and tissue development are orchestrated by the sequential presentation of soluble growth factors (GF) and extracellular matrix (ECM) molecules. Similarly, differentiation of stem cells in vitro relies upon the temporal presence of extracellular cues within the microenvironment. Hydrodynamic culture systems are not limited by volume restrictions and therefore offer several practical advantages for scalability over static cultures; however, hydrodynamic cultures expose cells to physical parameters not present in static culture, such as fluid shear stress and mass transfer through convective forces. In this study, the differences between static and hydrodynamic culture conditions on the expression of ECM and GF molecules during the differentiation of mouse embryonic stem cells were examined at both the gene and protein level. The expression of ECM and GF genes exhibited an early decrease in static cultures based on heat map and hierarchical clustering analysis and a relative delayed increase in hydrodynamic cultures. Although the temporal patterns of specific ECM and GF protein expression were comparable between static and hydrodynamic cultures, several notable differences in the magnitudes of expression were observed at similar time points. These results describe the establishment of an analytical framework that can be used to examine the expression patterns of ECM and GF molecules expressed by pluripotent stem cells undergoing differentiation as 3D multicellular aggregates under different culture conditions, and suggest that physical parameters of stem cell microenvironments can alter endogenous ECM and GF expression profiles that may, in turn, influence cell fate decisions. PMID:25423310

  17. Growth factor and matrix molecules preserve cell function on thermally responsive culture surfaces.

    PubMed

    von Recum, H; Kikuchi, A; Yamato, M; Sakurai, Y; Okano, T; Kim, S W

    1999-06-01

    Thermally-responsive culture surfaces were designed using copolymers of N-isopropylacrylamide, 4-(aminomethyl)styrene, and acrylic acid. These surfaces contained functional amine and carboxyl groups, which allowed biomolecules to be grafted by amide formation. Epidermal growth factor (EGF), and extracellular matrix (ECM) molecules (collagen type IV, and chondroitin sulfate) were investigated, as surface-grafted biomolecules, for their ability to stimulate cell attachment, proliferation, and function by signaling only from the basal side of cultured cells. Surface analysis of biomolecule-grafted porous inserts showed covalent binding of biomolecules to either amine or carboxyl groups. Multiple attachment to amine and/or carboxyl groups served as cross-linking points that made the polymer hydrogel permanently adherent to the culture surface. Immunofluorescence microscopy techniques gave positive identification of grafted biomolecules. Grafting of EGF improved cell proliferation versus that on nongrafted controls, or controls grafted only with ECM molecules. ECM grafting induced cell attachment on attachment-resistant surfaces. Analysis of trans-epithelial resistance, fluid transport, and polarized g-glutamyl transpeptidase activity indicated that simultaneous grafting of both EGF and ECM produced better polarized cell function than nongrafted controls, or controls grafted with only one type of biomolecule. Covalent grafting of biomolecules did not interfere with cells ability to detach from thermally responsive surfaces upon temperature decrease. PMID:10434072

  18. Discovering gene functional relationships using FAUN (Feature Annotation Using Nonnegative matrix factorization)

    PubMed Central

    2010-01-01

    Background Searching the enormous amount of information available in biomedical literature to extract novel functional relationships among genes remains a challenge in the field of bioinformatics. While numerous (software) tools have been developed to extract and identify gene relationships from biological databases, few effectively deal with extracting new (or implied) gene relationships, a process which is useful in interpretation of discovery-oriented genome-wide experiments. Results In this study, we develop a Web-based bioinformatics software environment called FAUN or Feature Annotation Using Nonnegative matrix factorization (NMF) to facilitate both the discovery and classification of functional relationships among genes. Both the computational complexity and parameterization of NMF for processing gene sets are discussed. FAUN is tested on three manually constructed gene document collections. Its utility and performance as a knowledge discovery tool is demonstrated using a set of genes associated with Autism. Conclusions FAUN not only assists researchers to use biomedical literature efficiently, but also provides utilities for knowledge discovery. This Web-based software environment may be useful for the validation and analysis of functional associations in gene subsets identified by high-throughput experiments. PMID:20946597

  19. Using Separable Nonnegative Matrix Factorization Techniques for the Analysis of Time-Resolved Raman Spectra.

    PubMed

    Luce, Robert; Hildebrandt, Peter; Kuhlmann, Uwe; Liesen, Jörg

    2016-09-01

    The key challenge of time-resolved Raman spectroscopy is the identification of the constituent species and the analysis of the kinetics of the underlying reaction network. In this work we present an integral approach that allows for determining both the component spectra and the rate constants simultaneously from a series of vibrational spectra. It is based on an algorithm for nonnegative matrix factorization that is applied to the experimental data set following a few pre-processing steps. As a prerequisite for physically unambiguous solutions, each component spectrum must include one vibrational band that does not significantly interfere with the vibrational bands of other species. The approach is applied to synthetic "experimental" spectra derived from model systems comprising a set of species with component spectra differing with respect to their degree of spectral interferences and signal-to-noise ratios. In each case, the species involved are connected via monomolecular reaction pathways. The potential and limitations of the approach for recovering the respective rate constants and component spectra are discussed. PMID:27635022

  20. Matrix factorization to time-frequency distribution for structural health monitoring

    NASA Astrophysics Data System (ADS)

    Chang, Chia-Ming; Huang, Shieh-Kung

    2016-04-01

    Structural health monitoring enables structural information to be acquired through sensing technology, and is of need to early detect problems and damages in structures. Health monitoring strategies are often realized through a combination of qualitative sensing systems and high-performance structural integrity assessment methods. Structural deviations can be then effectively identified by interpreting the raw sensor measurements using signal processing techniques. The objective of this study is to develop a new structural health monitoring method that applies a matrix factorization algorithm to a time-frequency representation of multi-channel signals measured from a structure. This method processes vibrational input and/or output responses of structures to improve raw data quality, to estimate structural responses, to derive signal features, and to detect structural variations. For example, the proposed method can reduce the signal noise by utilizing first few principle vectors to reconstruct the measured signals. For frequency-domain responses, this method can smooth the phase to obtain a better input-output relationship of a structure. Additionally, the method removes abnormal signals in time series, allowing better understanding of structural behavior. Due to communication loss, this method is able to recover lost data from other channel measurements in a structure. Moreover, the proposed method transforms the signal components into a specific domain and then yield meaningful characteristics. All these features are numerically verified using experimental data, and the proposed method permits more detailed investigation of structural behavior.

  1. Community detection enhancement using non-negative matrix factorization with graph regularization

    NASA Astrophysics Data System (ADS)

    Liu, Xiao; Wei, Yi-Ming; Wang, Jian; Wang, Wen-Jun; He, Dong-Xiao; Song, Zhan-Jie

    2016-06-01

    Community detection is a meaningful task in the analysis of complex networks, which has received great concern in various domains. A plethora of exhaustive studies has made great effort and proposed many methods on community detection. Particularly, a kind of attractive one is the two-step method which first makes a preprocessing for the network and then identifies its communities. However, not all types of methods can achieve satisfactory results by using such preprocessing strategy, such as the non-negative matrix factorization (NMF) methods. In this paper, rather than using the above two-step method as most works did, we propose a graph regularized-based model to improve, specialized, the NMF-based methods for the detection of communities, namely NMFGR. In NMFGR, we introduce the similarity metric which contains both the global and local information of networks, to reflect the relationships between two nodes, so as to improve the accuracy of community detection. Experimental results on both artificial and real-world networks demonstrate the superior performance of NMFGR to some competing methods.

  2. [Assessing PM10 and SO2 networks using positive matrix factorization in Beijing city].

    PubMed

    Gao, Tao; Xie, Shao-dong; Bo, Yu; Zhao, Yue

    2010-03-01

    The aim of this study was to identify city areas with similar air pollution characteristics and determine which sites may be providing redundant information. Positive matrix factorization (PMF) was applied in this study to assess the mass concentrations of sulfur dioxide (SO2) and particulate matter with an aerodynamic diameter less than 10 microm (PM010), collected in the air quality monitoring network in the year of 2000. The analysis indicated that there were obviously seasonal variations for PM10 and SO2 in Beijing. The PM10 concentrations were higher in spring and lower in summer, but the SO2 concentrations were higher in winter and lower in summer. The results of the PMF showed that the sites of PM10 network in Beijing could be identified as three regions, which represented city areas characterized by the same specific air pollution. These three regions represented Gucheng site/Chegongzhuang site, Qianmen site/National Olympic Sports Center site/Tiantan site/Nongzhanguan site, and Ming Tombs site, respectively. Some sites in region 2 which included four sites may be redundant and can be removed. SO2 network can be divided into six regions including Chegongzhuang site/Qianmen site, Tiantan site/Nongzhanguan stie, Ming Tombs site, National Olympic Sports Center site, Dongsi site, and Gucheng site. It indicated that some sites in Beijing PM10 and SO2 monitoring networks might be redundant and could be removed or relocated to other areas. PMID:20358808

  3. UTOPIAN: user-driven topic modeling based on interactive nonnegative matrix factorization.

    PubMed

    Choo, Jaegul; Lee, Changhyun; Reddy, Chandan K; Park, Haesun

    2013-12-01

    Topic modeling has been widely used for analyzing text document collections. Recently, there have been significant advancements in various topic modeling techniques, particularly in the form of probabilistic graphical modeling. State-of-the-art techniques such as Latent Dirichlet Allocation (LDA) have been successfully applied in visual text analytics. However, most of the widely-used methods based on probabilistic modeling have drawbacks in terms of consistency from multiple runs and empirical convergence. Furthermore, due to the complicatedness in the formulation and the algorithm, LDA cannot easily incorporate various types of user feedback. To tackle this problem, we propose a reliable and flexible visual analytics system for topic modeling called UTOPIAN (User-driven Topic modeling based on Interactive Nonnegative Matrix Factorization). Centered around its semi-supervised formulation, UTOPIAN enables users to interact with the topic modeling method and steer the result in a user-driven manner. We demonstrate the capability of UTOPIAN via several usage scenarios with real-world document corpuses such as InfoVis/VAST paper data set and product review data sets. PMID:24051765

  4. Source identification of PM10 pollution in subway passenger cabins using positive matrix factorization

    NASA Astrophysics Data System (ADS)

    Park, Duckshin; Oh, Miseok; Yoon, Younghun; Park, Eunyoung; Lee, Kiyoung

    2012-03-01

    Monitoring the air quality in subway passenger cabins is important because of the large number of passengers and potentially high levels of air pollution. This report characterized PM10 levels in subway cabins in Seoul, Korea, and identified PM10 sources using elemental analysis and receptor modeling. PM10 levels in subway cabins were continuously measured using a light scattering monitor during rush and non-rush hours. A total of 41 measurements were taken during rush and non-rush hours, and the measurements were repeated in all four seasons. Filter samples were also collected for elemental composition analysis. Major PM10 sources were identified using positive matrix factorization (PMF). The in-cabin PM10 concentrations were the highest in the winter at 152.8 μg m-3 during rush hours and 90.2 μg m-3 during non-rush hours. While PM10 levels were higher during rush hours than during non-rush hours in three seasons (excluding summer), these levels were not associated with number of passenger. Elemental analysis showed that the PM10 was composed of 52.5% inorganic elements, 10.2% anions, and 37.3% other. Fe was the most abundant element and significantly correlated (p < 0.01) with Mn (r = 0.97), Ti (r = 0.91), Cr (r = 0.88), Ni (r = 0.89), and Cu (r = 0.88). Fe, Mn, Cr, and Cu are indicators of railroad-related PM10 sources. The PM10 sources characterized by PMF were soil and road dust sources (27.2%), railroad-related sources (47.6%), secondary nitrate sources (16.2%), and a chlorine factor mixed with a secondary sulfate source (9.1%). Overall, railroad-related sources contributed the most PM10 to subway cabin air.

  5. Spectral unmixing using nonnegative matrix factorization with smoothed L0 norm constraint

    NASA Astrophysics Data System (ADS)

    Yang, Zuyuan; Chen, Xi; Zhou, Guoxu; Xie, Shengli

    2009-10-01

    Spectral unmixing (SU) is a hot topic in remote sensing image interpretation, where the linear mixing model (LMM) is discussed widely for its validity and simplicity [1]. SU often includes two facts as follows: 1) endmembers extraction; 2) abundances estimation. Mathematically, in the SU model, the collections, the endmember signatures, and the abundances are nonnegative [1]. Therefore, nonnegative matrix factorization (NMF) has a great potential to solve SU, especially for LMM [2]. In fact, NMF (or NMF like) algorithms have been widely discussed in SU, such as NMF based on minimum volume constraint (NMF-MVC) [1], NMF based on minimum distance constraint (NMF-MDC) [3], and so on. These methods have advantages and disadvantages, respectively. In light of that the abundances are often sparse and sparse NMF tends to result more determinate factors, NMF with sparseness constraint has attracted more and more attentions [4-6].To solve SU using sparse NMF practically, one problem should be addressed firstly, that is how to select the functions to measure the sparseness feature. Since the abundance suffers from sum-to-one constraint physically, the widely used measure based on L1 norm constraint may be degenerate [7, 8]. As the smoothed L0 norm of the signals can reflect the sparseness intuitively and it is easy to be optimized, we focus on NMF with smoothed L0 norm constraint (NMF-SL0) in this work [9]. The rest of this paper is organized as follows. In Section II, typical SU and NMF models are presented. Section III describes the L0-based sparse NMF for solving SU, together with the gradient based optimization algorithm NMF-SL0. Simulations using synthetic mixtures and real hyperspectral images are presented in Section IV. Finally, conclusions are summarized in Section V.

  6. SOURCE APPORTIONMENT OF PM 2.5 AND CARBON IN SEATTLE USING CHEMICAL MASS BALANCE AND POSITIVE MATRIX FACTORIZATION

    EPA Science Inventory

    Three years of PM2.5 speciated data were collected and chemically analyzed using the IMPROVE protocol at the Beacon Hill site in Seattle. The data were analyzed by the Chemical Mass Balance Version 8 (CMB8) and Positive Matrix Factorization (PMF) source apportionment models. T...

  7. EFFECT OF GROWTH FACTOR-FIBRONECTIN MATRIX INTERACTION ON RAT TYPE II CELL ADHESION AND DNA SYTHESIS

    EPA Science Inventory

    ABSTRACT

    Type II cells attach, migrate and proliferate on a provisional fibronectin-rich matrix during alveolar wall repair after lung injury. The combination of cell-substratum interactions via integrin receptors and exposure to local growth factors are likely to initiat...

  8. Optical factors determined by the T-matrix method in turbidity measurement of absolute coagulation rate constants.

    PubMed

    Xu, Shenghua; Liu, Jie; Sun, Zhiwei

    2006-12-01

    Turbidity measurement for the absolute coagulation rate constants of suspensions has been extensively adopted because of its simplicity and easy implementation. A key factor in deriving the rate constant from experimental data is how to theoretically evaluate the so-called optical factor involved in calculating the extinction cross section of doublets formed during aggregation. In a previous paper, we have shown that compared with other theoretical approaches, the T-matrix method provides a robust solution to this problem and is effective in extending the applicability range of the turbidity methodology, as well as increasing measurement accuracy. This paper will provide a more comprehensive discussion of the physical insight for using the T-matrix method in turbidity measurement and associated technical details. In particular, the importance of ensuring the correct value for the refractive indices for colloidal particles and the surrounding medium used in the calculation is addressed, because the indices generally vary with the wavelength of the incident light. The comparison of calculated results with experiments shows that the T-matrix method can correctly calculate optical factors even for large particles, whereas other existing theories cannot. In addition, the data of the optical factor calculated by the T-matrix method for a range of particle radii and incident light wavelengths are listed.

  9. Matrix-Stiffness-Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis.

    PubMed

    Chen, Wan-Chun; Lin, Hsi-Hui; Tang, Ming-Jer

    2015-09-01

    The proliferation of mouse proximal tubular epithelial cells in ex vivo culture depends on matrix stiffness. Combined analysis of the microarray and experimental data revealed that Krüppel-like factor (Klf)5 was the most up-regulated transcription factor accompanied by the down-regulation of Klf4 when cells were on stiff matrix. These changes were reversed by soft matrix via extracellular signal-regulated kinase (ERK) inactivation. Knockdown of Klf5 or forced expression of Klf4 inhibited stiff matrix-induced cell spreading and proliferation, suggesting that Klf5/Klf4 act as positive and negative regulators, respectively. Moreover, stiff matrix-activated ERK increased the protein level and nuclear translocation of mechanosensitive Yes-associated protein 1 (YAP1), which is reported to prevent Klf5 degradation. Finally, in vivo model of unilateral ureteral obstruction revealed that matrix stiffness-regulated Klf5/Klf4 is related to the pathogenesis of renal fibrosis. In the dilated tubules of obstructed kidney, ERK/YAP1/Klf5/cyclin D1 axis was up-regulated and Klf4 was down-regulated. Inhibition of collagen crosslinking by lysyl oxidase inhibitor alleviated unilateral ureteral obstruction-induced tubular dilatation and proliferation, preserved Klf4, and suppressed the ERK/YAP1/Klf5/cyclin D1 axis. This study unravels a novel mechanism how matrix stiffness regulates cellular proliferation and highlights the importance of matrix stiffness-modulated Klf5/Klf4 in the regulation of renal physiologic functions and fibrosis progression.

  10. An advanced algorithm for construction of Integral Transport Matrix Method operators using accumulation of single cell coupling factors

    SciTech Connect

    Powell, B. P.; Azmy, Y. Y.

    2013-07-01

    The Integral Transport Matrix Method (ITMM) has been shown to be an effective method for solving the neutron transport equation in large domains on massively parallel architectures. In the limit of very large number of processors, the speed of the algorithm, and its suitability for unstructured meshes, i.e. other than an ordered Cartesian grid, is limited by the construction of four matrix operators required for obtaining the solution in each sub-domain. The existing algorithm used for construction of these matrix operators, termed the differential mesh sweep, is computationally expensive and was developed for a structured grid. This work proposes the use of a new algorithm for construction of these operators based on the construction of a single, fundamental matrix representing the transport of a particle along every possible path throughout the sub-domain mesh. Each of the operators is constructed by multiplying an element of this fundamental matrix by two factors dependent only upon the operator being constructed and on properties of the emitting and incident cells. The ITMM matrix operator construction time for the new algorithm is demonstrated to be shorter than the existing algorithm in all tested cases with both isotropic and anisotropic scattering considered. While also being a more efficient algorithm on a structured Cartesian grid, the new algorithm is promising in its geometric robustness and potential for being applied to an unstructured mesh, with the ultimate goal of application to an unstructured tetrahedral mesh on a massively parallel architecture. (authors)

  11. Factors influencing the Mode I interlaminar fracture toughness of a rubber toughened thermoplastic matrix composite

    NASA Technical Reports Server (NTRS)

    Parker, D. S.; Yee, A. F.

    1989-01-01

    The use of a rubber modified thermoplastic resin has been investigated as a method to improve the Mode I interlaminar fracture toughness of a unidirectional continuous carbon fiber composite. Test results show that the improvement in the fracture toughness is less than expected due to rubber particle agglomeration, solvent and molding induced crystallization of the matrix and poor fiber/matrix adhesion. The plastic zone in composites utilizing tough matrices can extend well beyond a single interfibrillar spacing. However, the development of the plastic zone is limited due to the failure of the fiber/matrix interface. In order to fully evaluate the potential of tough composites using toughened matrices, any improvement made in the matrix toughness must be coupled with improvements in the fiber/matrix adhesion.

  12. Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells

    SciTech Connect

    Sassoli, Chiara; Nosi, Daniele; Tani, Alessia; Chellini, Flaminia; Mazzanti, Benedetta; Quercioli, Franco; Zecchi-Orlandini, Sandra; Formigli, Lucia

    2014-05-01

    Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7{sup +} satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of α-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration. - Highlights: • MSC-CM contains paracrine factors that up-regulate MMP expression and function in different skeletal muscle cells. • MSC-CM promotes myoblast and satellite cell migration, proliferation and differentiation. • MSC-CM negatively interferes with fibroblast-myoblast transition in primary skeletal fibroblasts. • Paracrine factors from MSCs modulate the fibrotic response and improve the endogenous mechanisms of muscle regeneration.

  13. Elevated serum brain natriuretic peptide and matrix metalloproteinases 2 and 9 in Wilson's disease.

    PubMed

    Cheng, Nan; Wang, Honghao; Dong, Jianjian; Pan, Suyue; Wang, Xun; Han, Yongsheng; Han, Yongzhu; Yang, Renmin

    2015-08-01

    Wilson's disease (WD) is a disease of copper metabolism characterized by excessive copper deposition in the body. It is reported abnormal copper metabolism has been associated with cardiovascular disease. BNP and MMP2/9 were biomarkers of congestive heart failure (CHF). There is rare study to explore whether serum concentrations of BNP, MMP2, and or MMP9 are altered in patients with WD. In this study we determine whether serum concentrations of brain natriuretic peptide (BNP) and matrix metalloproteinases (MMP) 2 and 9 are increased in patients with WD. Serum BNP, MMP2 and MMP9 were measured by an ELISA in 34 patients with hepatic WD, in 68 patients with neurological WD, and in 33 healthy controls. We found serum BNP levels were higher in patients with neurological WD than in healthy controls (p = 0.033). Serum MMP2 levels were higher in patients with hepatic (p = 0.009) and neurologic (p = 0.0004) WD than in controls. Serum MMP9 levels were higher in patients with neurologic WD than in patients with hepatic WD (p = 0.002) and controls (p = 0.00005), and were higher in patients with hepatic WD than in controls (p = 0.03). Serum BNP levels were negatively correlated with ceruloplasmin (p = 0.017, r = -0.215), while serum (p = 0.019, r = -0.221) and MMP9 (p = 0.011, r = -0.231) in patients with WD were negatively correlated with ceruloplasmin. BNP, MMP2, and MMP9 may reflect the deposition of copper in the heart.

  14. Matrix Metalloproteinases in Alzheimer's Disease and Concurrent Cerebral Microbleeds.

    PubMed

    Duits, Flora H; Hernandez-Guillamon, Mar; Montaner, Joan; Goos, Jereon D C; Montañola, Alex; Wattjes, Mike P; Barkhof, Frederik; Scheltens, Philip; Teunissen, Charlotte E; van der Flier, Wiesje M

    2015-01-01

    Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer's disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral micro-bleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β(1-42) (Aβ42), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p <  0.05), and higher CSF MMP10 levels compared to controls (p <  0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p <  0.05), and CSF MMP10 with tau (St.B 0.38, p <  0.001) and p-tau (St.B 0.40, p <  0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients. PMID:26402072

  15. Olfactory ensheathing cells (OECs) degrade neurocan in injured spinal cord by secreting matrix metalloproteinase-2 in a rat contusion model.

    PubMed

    Yui, Sho; Fujita, Naoki; Chung, Cheng-Shu; Morita, Maresuke; Nishimura, Ryohei

    2014-11-01

    The mechanism by which olfactory ensheathing cells (OECs) exert their potential to promote functional recovery after transplantation into spinal cord injury (SCI) tissue is not fully understood, but the relevance of matrix metalloproteinases (MMPs) has been suggested. We evaluated the expression of MMPs in OECs in vitro and the MMP secretion by OECs transplanted in injured spinal cord in vivo using a rat SCI model. We also evaluated the degradation of neurocan, which is one of the axon-inhibitory chondroitin sulfate proteoglycans, using SCI model rats. The in vitro results showed that MMP-2 was the dominant MMP expressed by OECs. The in vivo results revealed that transplanted OECs secreted MMP-2 in injured spinal cord and that the expression of neurocan was significantly decreased by the transplantation of OECs. These results suggest that OECs transplanted into injured spinal cord degraded neurocan by secreting MMP-2.

  16. Synergism of matrix stiffness and vascular endothelial growth factor on mesenchymal stem cells for vascular endothelial regeneration.

    PubMed

    Wingate, Kathryn; Floren, Michael; Tan, Yan; Tseng, Pi Ou Nancy; Tan, Wei

    2014-09-01

    Mesenchymal stem cells (MSCs) hold tremendous potential for vascular tissue regeneration. Research has demonstrated that individual factors in the cell microenvironment such as matrix elasticity and growth factors regulate MSC differentiation to vascular lineage. However, it is not well understood how matrix elasticity and growth factors combine to direct the MSC fate. This study examines the combined effects of matrix elasticity and vascular endothelial growth factor (VEGF) on both MSC differentiation into endothelial lineage and MSC paracrine signaling. MSCs were seeded in soft nanofibrous matrices with or without VEGF, and in Petri dishes with or without VEGF. Only MSCs seeded in three-dimensional soft matrices with VEGF showed significant increases in the expression of endothelial markers (vWF, eNOS, Flt-1, and Flk-1), while eliminating the expression of smooth muscle marker (SM-α-actin). MSCs cultured in VEGF alone on two-dimensional dishes showed increased expression of both early-stage endothelial and smooth muscle markers, indicating immature vascular differentiation. Furthermore, MSCs cultured in soft matrices with VEGF showed faster upregulation of endothelial markers compared with MSCs cultured in VEGF alone. Paracrine signaling studies found that endothelial cells cultured in the conditioned media from MSCs differentiated in the soft matrix and VEGF condition exhibited increased migration and formation of capillary-like structures. These results demonstrate that VEGF and soft matrix elasticity act synergistically to guide MSC differentiation into mature endothelial phenotype while enhancing paracrine signaling. Therefore, it is critical to control both mechanical and biochemical factors to safely regenerate vascular tissues with MSCs.

  17. Synergism of Matrix Stiffness and Vascular Endothelial Growth Factor on Mesenchymal Stem Cells for Vascular Endothelial Regeneration

    PubMed Central

    Wingate, Kathryn; Floren, Michael; Tan, Yan; Tseng, Pi Ou Nancy

    2014-01-01

    Mesenchymal stem cells (MSCs) hold tremendous potential for vascular tissue regeneration. Research has demonstrated that individual factors in the cell microenvironment such as matrix elasticity and growth factors regulate MSC differentiation to vascular lineage. However, it is not well understood how matrix elasticity and growth factors combine to direct the MSC fate. This study examines the combined effects of matrix elasticity and vascular endothelial growth factor (VEGF) on both MSC differentiation into endothelial lineage and MSC paracrine signaling. MSCs were seeded in soft nanofibrous matrices with or without VEGF, and in Petri dishes with or without VEGF. Only MSCs seeded in three-dimensional