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Metalloproteinase Inhibitor (metalloproteinase + inhibitor)

Distribution by Scientific Domains
Chemistry53%
Medical Sciences33%
Life Sciences13%

Kinds of Metalloproteinase Inhibitor

  • matrix metalloproteinase inhibitor
    		•

    Selected Abstracts

    Hydrogen Peroxide Activated Matrix Metalloproteinase Inhibitors: A Prodrug Approach,

    ANGEWANDTE CHEMIE, Issue 38 2010
    Dr. Jody
    Zwei Jobs gleichzeitig: Ein Metalloproteinasen-Inhibitor, den reaktive Sauerstoffspezies (ROS) aktivieren, wurde mit dem Ziel entworfen, die Blut-Hirn-Schranke (BHS) bei Auftreten eines ischämischen Reperfusionsschadens zu schützen. Damit kann eine einzelne Verbindung gleich zwei Bedrohungen für die BHS ausschalten, indem sie schädigende ROS neutralisiert und BHS-abbauende Metalloproteinasen hemmt. [source]

    Synthesis and SAR of ,-Sulfonylcarboxylic Acids as Potent Matrix Metalloproteinase Inhibitors.

    CHEMINFORM, Issue 37 2006
    Yue-Mei Zhang
    Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]

    Tetrahydroisoquinoline Based Sulfonamide Hydroxamates as Potent Matrix Metalloproteinase Inhibitors.

    CHEMINFORM, Issue 17 2004
    Dawei Ma
    Abstract For Abstract see ChemInform Abstract in Full Text. [source]

    ChemInform Abstract: Arylsulfonyl Hydroxamic Acids: Potent and Selective Matrix Metalloproteinase Inhibitors.

    CHEMINFORM, Issue 37 2001
    Andrew D. Baxter
    Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

    Synthesis, SAR, and Biological Evaluation of ,-Sulfonylphosphonic Acids as Selective Matrix Metalloproteinase Inhibitors

    CHEMMEDCHEM, Issue 3 2009
    Maria Teresa Rubino Dr.
    Abstract Selective MMP inhibitors: Eleven ,-sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP-2, -8, -13, and -14, with an interesting selectivity profile versus MMP-9. Eleven simple , -sulfonylphosphonates, new analogues of previously reported , -sulfonylaminophosphonates, were prepared and tested as MMP inhibitors. The IC50 values of most of these compounds are in the nanomolar range against MMP-2, -8, -13, and -14. Compound 11 proved to be the most effective inhibitor of MMP-2 (IC50=60,nM), with interesting selectivity versus the antitarget enzymes MMP-3 and MMP-9. The mode of binding of the new phosphonates in the active site of MMP-2 was studied, and variations in inhibition was explained by means of molecular modeling. [source]

    Absence of tissue inhibitor of metalloproteinases 3 disrupts alveologenesis in the mouse

    DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2009
    Sean E. Gill
    Tissue inhibitors of metalloproteinases (TIMPs) regulate extracellular matrix (ECM) degradation by matrix metalloproteinases (MMPs) throughout lung development. We examined lungs from TIMP3 null mice and found significant air space enlargement compared with wild type (WT) animals during a time course spanning early alveologenesis (post-partum days 1, 5, 9 and 14). Trichrome staining revealed a similar pattern of collagen distribution in the walls of nascent alveoli; however, the alveolar walls of TIMP3 mutant mice appeared to be thinner than controls. Assessment of MMP2 and MMP9 activities by gelatin zymography demonstrated a significant elevation in the active form of MMP2 at post-partum days 1 and 5. Treatment of null pregnant dams with a broad spectrum synthetic metalloproteinase inhibitor, GM6001, on embryonic day 16.5 enhanced the formation of primitive alveoli during the saccular stage of lung development as evidenced by a partial, but significant, rescue of alveolar size in post-partum day 1 animals. We propose that increased MMP activity in the absence of TIMP3 enhances ECM proteolysis, upsetting proper formation of primitive alveolar septa during the saccular stage of alveologenesis. Therefore, TIMP3 indirectly regulates alveolar formation in the mouse. To our knowledge, ours is the first study to demonstrate that in utero manipulation of the TIMP/MMP proteolytic axis, to specifically inhibit proteolysis, significantly affects lung development. [source]

    A microfluidic device for characterizing the invasion of cancer cells in 3-D matrix

    ELECTROPHORESIS, Issue 24 2009
    Tingjiao Liu
    Abstract A microfluidic device was developed for the study of directed invasion of cancer cells in 3-D matrix with concentration gradient. This device consists of two parallel perfusion channels connected by two cell culture chambers. To mimic extracellular matrix (ECM), gelled basement membrane extract (BME) was used to support 3-D distribution of breast cancer cells (MCF7) in cell culture chambers. A stable linear concentration gradient of epidermal growth factor (EGF) was generated across the chambers by continuous perfusion. Using the device, we investigated MCF7 cell invasion induced by different concentrations of EGF in 3-D matrix. It was found that cancer cells responded to EGF stimulation with forming cellular protrusions and migrating towards high EGF concentration. We further investigated the anti-invasion effect of GM 6001, a matrix metalloproteinase inhibitor. We identified that matrix metalloproteinase inhibition repressed both cellular protrusion formation and cell migration in 3-D matrix. These findings suggest that EGF is able to induce MCF7 cell invasion in 3-D extracellular matrix and this effect is dependent on proteolytic activity. This device is relatively simple to construct and operate. It should be a useful platform for elucidating the mechanism of cancer invasion and screening anti-invasion drugs for cancer therapy. [source]

    Matrix metalloproteinase inhibitor reduces apoptosis induction of bone marrow cells in MDS-RA

    EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2004
    Kosei Arimura
    Abstract:,Background and objectives:,We examined the involvement of apoptosis with myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo-hypercellular bone marrow. Materials and methods:,Bone marrow smears from 31 patients with MDS-refractory anemia (RA) and five normal controls were stained using the in situ end labeling (ISEL) method. Next, the inhibitory effects of a caspase-3 inhibitor, matrix metalloproteinase inhibitor (MMPI), anti-tumor necrosis factor (TNF)- , or anti-Fas antibody upon the apoptosis induction in overnight cultures of bone marrow cells from the patients were examined. Further, TNF- ,, transforming growth factor (TGF)- , and soluble Fas ligand (sFasL) concentrations in culture supernatants of the cells were assessed by enzyme-linked immunosorbent assay (ELISA). Results:,The incidence of ISEL-positive cells among MDS patients was significantly higher than in normal controls (50.8 ± 14.0% vs. 11.3 ± 2.4%; P < 0.0001). A caspase-3 inhibitor reduced significantly the ISEL-positive rates (32.6 ± 15.2% vs. 50.2 ± 16.5%; P < 0.0001). Anti-TNF- , or anti-Fas antibody reduced the ISEL-positive rates significantly (28.2 ± 6.0%, 29.2 ± 5.8%, vs. 44.2 ± 3.4%, P < 0.001, P = 0.001, respectively). KB-R7785 also significantly decreased the ISEL-positive rates (18.0 ± 9.3% vs. 43.6 ± 14.0%; P < 0.0001). The concentration of TNF- , was significantly reduced by KB-R7785 (P < 0.05), whereas that of TGF- , was not. Concentration of sFasL was under detectable level in the present assay system. The derivatives of KB-R7785 that can be administrated orally showed inhibitory effect on apoptosis induction as well. Conclusions:,These findings suggest that MMPIs inhibits the apoptosis induction of MDS bone marrow cells via the inhibition of TNF- , and probably sFasL secretion, and that MMPIs can be used to control the abnormal induction of apoptosis in MDS. [source]

    Functional analysis of DM64, an antimyotoxic protein with immunoglobulin-like structure from Didelphis marsupialis serum

    FEBS JOURNAL, Issue 24 2002
    Surza L. G. Rocha
    Bothrops snake venoms are known to induce local tissue damage such as hemorrhage and myonecrosis. The opossum Didelphis marsupialis is resistant to these snake venoms and has natural venom inhibitors in its plasma. The aim of this work was to clone and study the chemical, physicochemical and biological properties of DM64, an antimyotoxic protein from opossum serum. DM64 is an acidic protein showing 15% glycosylation and with a molecular mass of 63 659 Da when analysed by MALDI-TOF MS. It was cloned and the amino acid sequence was found to be homologous to DM43, a metalloproteinase inhibitor from D. marsupialis serum, and to human ,1B-glycoprotein, indicating the presence of five immunoglobulin-like domains. DM64 neutralized both the in vivo myotoxicity and the in vitro cytotoxicity of myotoxins I (mt-I/Asp49) and II (mt-II/Lys49) from Bothrops asper venom. The inhibitor formed noncovalent complexes with both toxins, but did not inhibit the PLA2 activity of mt-I. Accordingly, DM64 did not neutralize the anticoagulant effect of mt-I nor its intracerebroventricular lethality, effects that depend on its enzymatic activity, and which demonstrate the dissociation between the catalytic and toxic activities of this Asp49 myotoxic PLA2. Furthermore, despite its similarity with metalloproteinase inhibitors, DM64 presented no antihemorrhagic activity against Bothrops jararaca or Bothrops asper crude venoms, and did not inhibit the fibrinogenolytic activity of jararhagin or bothrolysin. This is the first report of a myotoxin inhibitor with an immunoglobulin-like structure isolated and characterized from animal blood. [source]

    BJ46a, a snake venom metalloproteinase inhibitor

    FEBS JOURNAL, Issue 10 2001
    Isolation, characterization, cloning, insights into its mechanism of action
    Fractionation of the serum of the venomous snake Bothrops jararaca with (NH4)2SO4, followed by phenyl-Sepharose and C4 -reversed phase chromatographies, resulted in the isolation of the anti-hemorrhagic factor BJ46a. BJ46a is a potent inhibitor of the SVMPs atrolysin C (class P-I) and jararhagin (P-III) proteolytic activities and B. jararaca venom hemorrhagic activity. The single-chain, acidic (pI 4.55) glycoprotein has a molecular mass of 46 101 atomic mass units determined by MALDI-TOF MS and 79 kDa by gel filtration and dynamic laser light scattering, suggesting a homodimeric structure. mRNA was isolated from the liver of one specimen and transcribed into cDNA. The cDNA pool was amplified by PCR, cloned into a specific vector and used to transform competent cells. Clones containing the complete coding sequence for BJ46a were isolated. The deduced protein sequence was in complete agreement with peptide sequences obtained by Edman degradation. BJ46a is a 322-amino-acid protein containing four putative N-glycosylation sites. It is homologous to the proteinase inhibitor HSF (member of the fetuin family, cystatin superfamily) isolated from the serum of the snake Trimeresurus flavoviridis, having 85% sequence identity. This is the first report of a complete cDNA sequence for an endogenous inhibitor of snake venom metalloproteinases (SVMPs). The sequence reveals that the only proteolytic processing required to obtain the mature protein is the cleavage of the signal peptide. Gel filtration analyses of the inhibitory complexes indicate that inhibition occurs by formation of a noncovalent complex between BJ46a and the proteinases at their metalloproteinase domains. Furthermore, the data shows that the stoichiometry involved in this interaction is of one inhibitor monomer to two enzyme molecules, suggesting an interesting mechanism of metalloproteinase inhibition. [source]

    Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse

    HEPATOLOGY RESEARCH, Issue 8 2009
    Alisan Kahraman
    Aim:, Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury. Methods:, C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage. Results:, BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals (P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (,-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals (P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug (P < 0.05). Conclusion:, The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury. [source]

    Establishment of a matrix-associated transepithelial resistance invasion assay to precisely measure the invasive potential of synovial fibroblasts

    ARTHRITIS & RHEUMATISM, Issue 9 2009
    Christina Wunrau
    Objective Synovial fibroblasts (SFs) contribute to several aspects of the pathogenesis of rheumatoid arthritis (RA) and have been implicated most prominently in the progressive destruction of articular cartilage. Targeting the invasive phenotype of RASFs has therefore gained increasing attention, but the precise measurement of their invasive capacity and the evaluation of potential treatment effects constitute a challenge that needs to be addressed. This study used a novel in vitro invasion assay based on the breakdown of transepithelial electrical resistance to determine the course of fibroblast invasion into extracellular matrix. Methods A matrix-associated transepithelial resistance invasion (MATRIN) assay was used to assess SFs from patients with RA in comparison with SFs from patients with osteoarthritis (OA). The SFs were grown on a commercially available collagen mix that was placed onto the upper side of a Transwell polycarbonate membrane. In addition, freshly isolated cartilage extracts were studied to assess the conditions in vivo. Under this membrane, a monolayer of MDCK-C7 cells was seeded to create a high electrical resistance. Results Invasion of fibroblasts into the matrix affected the integrity of the MDCK-C7 monolayer and led to a measurable decrease and subsequent breakdown of electrical resistance. Unlike in the assay with OASFs, which did not achieve a breakdown of resistance up to 72 hours, RASFs exhibited a pronounced invasiveness in this assay, with a 50% breakdown after 42 hours. Treatment of fibroblasts with either a matrix metalloproteinase inhibitor or antibodies against ,1 integrin significantly reduced the invasiveness of RASFs. Conclusion The MATRIN assay is a valuable and sensitive biologic assay system that can be used to determine precisely the invasive potential of RASFs in vitro, and thus would be suitable for screening anti-invasion compounds. [source]

    Functional analysis of DM64, an antimyotoxic protein with immunoglobulin-like structure from Didelphis marsupialis serum

    FEBS JOURNAL, Issue 24 2002
    Surza L. G. Rocha
    Bothrops snake venoms are known to induce local tissue damage such as hemorrhage and myonecrosis. The opossum Didelphis marsupialis is resistant to these snake venoms and has natural venom inhibitors in its plasma. The aim of this work was to clone and study the chemical, physicochemical and biological properties of DM64, an antimyotoxic protein from opossum serum. DM64 is an acidic protein showing 15% glycosylation and with a molecular mass of 63 659 Da when analysed by MALDI-TOF MS. It was cloned and the amino acid sequence was found to be homologous to DM43, a metalloproteinase inhibitor from D. marsupialis serum, and to human ,1B-glycoprotein, indicating the presence of five immunoglobulin-like domains. DM64 neutralized both the in vivo myotoxicity and the in vitro cytotoxicity of myotoxins I (mt-I/Asp49) and II (mt-II/Lys49) from Bothrops asper venom. The inhibitor formed noncovalent complexes with both toxins, but did not inhibit the PLA2 activity of mt-I. Accordingly, DM64 did not neutralize the anticoagulant effect of mt-I nor its intracerebroventricular lethality, effects that depend on its enzymatic activity, and which demonstrate the dissociation between the catalytic and toxic activities of this Asp49 myotoxic PLA2. Furthermore, despite its similarity with metalloproteinase inhibitors, DM64 presented no antihemorrhagic activity against Bothrops jararaca or Bothrops asper crude venoms, and did not inhibit the fibrinogenolytic activity of jararhagin or bothrolysin. This is the first report of a myotoxin inhibitor with an immunoglobulin-like structure isolated and characterized from animal blood. [source]

    Human laminin-332 degradation by Candida proteinases

    JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2008
    P. Pärnänen
    Background:, Human laminin-332 (Lm-332) degradation by 12 Candida strains and effects of synthetic proteinase inhibitors [Ilomastat (ILM), EDTA, chemically modified tetracycline-3(CMT-3), CMT-308, synthetic peptide CTT-2, and Pefabloc] were studied. Materials and methods:, Laminin-332 was incubated with sonicated cell fractions and 10 times concentrated cell-free fractions of reference and clinical strains of C. albicans, C. dubliniensis, C. guilliermondii, C. glabrata, C. krusei, and C. tropicalis. Proteolysis, pH effects, and inhibitors were analyzed by fluorography and zymography. Results:, Cell fractions of all species except C. guilliermondii and cell-free fractions of C. albicans, and C. dubliniensis showed 20,70 kDa gelatinases at pH 5.0 and 6.0. At pH 7.6, C. glabrata, C. krusei, and C. tropicalis cell fractions and C. tropicalis cell-free fractions showed 55,70 kDa gelatinases. CMT-3, CMT-308, and CTT-2 inhibited Candida gelatinases slightly better than Pefabloc, ILM, and EDTA. No Candida fractions degraded Lm-332 at pH 7.6, but at pH 5.0, 100 kDa bands were generated by cell fractions of C. dubliniensis and C. tropicalis; C. albicans and C. glabrata clinical strains; and C. guilliermondii reference strain. C. krusei reference strain yielded three 100,130 kDa bands. C. albicans, C. dubliniensis, and C. tropicalis reference and clinical strain's cell-free fractions generated 100 kDa band. Conclusions:, Laminin-332 degradation is pH-dependent and differences exist between studied Candida strains. Lm-332 degradation can exert functional disturbances on basement membrane integrity, possibly aiding Candida cell invasion into tissues. Certain synthetic matrix metalloproteinase inhibitors (CMTs, CTT) can inhibit Candida proteinases and may be therapeutically useful in future. [source]