No description available.

No description available.

The Metzincins are a superfamily of zinc-dependent endopeptidases associated with the regulation of the extracellular matrix (ECM). Their members include A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs), A Disintegrin and Metalloproteinases (ADAMs), and the matrix metalloproteinases (MMPs). Metzincins exhibit diverse functions associated with both physiological and pathological states that include the proteolytic degradation of the ECM, regulation of various growth factors, cell surface receptors, and chemokines, and mediation of biological functions such as extravasation, survival, and proliferation. In pathological conditions such as cancer associated with chronic inflammation and multiple sclerosis associated with neurodegeneration, dysregulation of Metzincin activities are a hallmark of disease progression and severity. Hence, Metzincins are therapeutic targets for various disease states and research into optimal Metzincin inhibitor design is an ongoing exploit. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

No description available.

No description available.

The Matrix Metalloproteinase (MMP) family are conventionally considered as key enzymes contributing to cancer-cell invasion through remodelling of the extracellular matrix (ECM). In contrast, MMP-8 has been shown to exert an anti-cancer role. In normal breast, MMP-8 expression is restricted to tumour suppressor myoepithelial cells (MECs), which form the interface between glandular epithelium and the ECM. In ductal carcinoma in situ (DCIS), MECs are altered; a consistent change is up-regulation of αvβ6-integrin, which is associated with loss of suppressor activity. Preliminary observations indicated that there is also loss of MMP-8 expression in DCIS-MEC. The aim of this study is to investigate the impact of loss of MEC derived MMP-8 on MEC function and how this might modulate tumour progression. To generate a model of DCIS MEC, an αvβ6 over-expressing cell line (Myo-β6) was generated from normal MECs (Myo-Puro). These cells were found to lose MMP-8 expression. To dissect gain-of-function effect, MMP-8 was re-introduced into Myo-β6 (MMP-8 WT). A proteolytic inactive form of MMP-8 was used to dissect the dependence of function on proteolysis. In-vitro analysis demonstrated that MMP-8 WT but not inactive MMP-8 significantly up-regulates MEC adhesion (p=0.0001) and spread (p=0.0003) on ECM, but reduces migration towards ECM proteins including Collagen-I (p=0.006) and fibronectin (p=0.01). Furthermore MMP-8 WT results in reduced numbers of filopodia/retraction fibres (p=0.01) and reduced protrusion length (p=0.0001) on MEC cell surface. MMP-8 promotes the localisation of α6β4-integrin to hemidesmosomal adhesive structures (p=0.003), and inhibits MEC gelatinase (p=0.002) and TGF-β activity. Conversely, knock-down of endogenous MMP-8 in Myo-Puro MECs promotes migration and filopodia/retraction fibre formation (p=0.05), increases gelatinase activity (p=0.007) and TGF-β signalling. To analyse the paracrine effect of MEC-derived MMP-8 on breast cancer cell invasion, MDA MB 231 or SUM159 cells were co-cultured with modified Myo-β6 cells in Boyden chamber invasion assays. A significant reduction in breast cancer cell invasion was observed only in the presence of MMP-8 WT (p=0.004) but not with inactive MMP-8. In contrast, MMP-8 knock-down in Myo-Puro MECs significantly enhanced breast cancer cell invasion (p=0.001). In order to recapitulate the DCIS stromal micro-ecology, 3D-organotypic cultures were constructed. In these systems there was a significant reduction in invasion only in the presence of MMP-8 WT MECs (p<0.001). Conversely, in the absence of Myo-Puro-derived MMP-8 breast cancer cell invasion was significantly up-regulated (p=0.007). These results suggest that MMP-8 does contribute to MEC tumour suppressor function via mechanisms dependent upon its proteolytic activity. These data support the hypothesis that loss of MMP-8 may contribute to the progression of DCIS to invasive disease.

No description available.

Coacervation is a mild process for developing protein NPs. Bovine serum albumin (BSA) NPs formed via this technique were stabilized using poly-L-Lysine (PLL); short interfering ribonucleic acid (siRNA) was used as a model drug for encapsulation. Specific and non-specific degradation of these coated and uncoated BSA NPs were carried using matrix metalloproteinase-2 (MMP-2) and trypsin, respectively. The particles were characterized with atomic force microscopy, zeta-potential, and photon correlation spectroscopy measurements. There was a significant increase in the zeta potential of BSA NPs upon coating. Trypsin digested the uncoated and coated BSA NPs and resulted in higher BSA release from the particles. However, MMP-2 treatment did not result in higher release of BSA from coated NPs despite the cleavability of coated polymer by MMP-2. This study described a method for obtaining BSA NPs in a controllable size range. Such particles showed degradability in the presence of trypsin and could be promising for targeted drug delivery applications. / Chemical Engineering

Thesis (Ph.D.)--Virginia Commonwealth University, 2010. / Prepared for: Dept. of Anatomy and Neurobiology. Title from title-page of electronic thesis. Bibliography: leaves 159-193.

O objetivo do presente estudo foi avaliar os níveis das metaloproteinases da matriz MMP-9, MMP-3 e MMP-13, e das quimiocinas MCP-1, MIP-1&#946; e RANTES, no fluido gengival de dentes sob força ortodôntica. Foram recrutados 14 pacientes (3 homens e 11 mulheres) que foram submetidos à movimentação ortodôntica dos caninos superiores. Amostras do fluido gengival foram coletadas com tiras de Periopaper em diferentes tempos. O volume do FG foi determinado com o uso do Periotron e os niveis das MMPs e das quimiocinas quantificados usando-se uma multianálise imunoenzimática com microesferas. Os resultados mostraram que existe um aumento significativo no volume do FG na área de pressão em quase todos os tempos analisados, quando comparados às áreas de tensão. Os níveis da MMP-9 foram muito superiores aos das MMP-13 e MMP-3. Na análise da evolução do tempo pode ser observada uma alteração significativa nos níveis da quantidade total de MMP-9, MMP-13 e MMP-3 e na concentração de MMP-13 e MMP-3 durante o período de movimentação dentária no lado de pressão. A elevação dos níveis de expressão destas MMPs 1 hora após a aplicação da força ortodôntica sugere que estas enzimas estejam envolvidas na remodelação periodontal induzida. As quimiocinas MCP-1, MIP-1&#946; e RANTES foram detectadas no sulco gengival em todos os diferentes intervalos de tempo analisados, nas áreas de tensão e de pressão. Porém, diversas amostras estavam abaixo do nível de detecção do ensaio e, os níveis dessas quimiocinas no fluido gengival não parecem ser alterados pelas forças ortodônticas. / The goal of the present study was to evaluate the levels of the matrix metalloproteinases MMP-9, MMP-3 and MMP-13 and of the chemokines MCP-1, MIP-1&#946; and RANTES in the gingival crevicular fluid of teeth under orthodontic forces. Fourteen subjects (3 males and 11 females) were enrolled and subjected to orthodontic tooth movement of their maxillary canines. Samples of gingival crevicular fluid were collected from both tension and pressure sides using Periopaper strips at different time points. The volume of GCF was determined using a Periotron and the levels of MMPs and chemokines quantified using a multiplex microbead immunoassay. The results demonstrated that the levels of MMP-9 were higher than the levels of MMP-13 and MMP-3. Statistically significant fluctuations during the orthodontic tooth movement could be detected for the total amount of MMP-9, MMP-13 and MMP-3 and for the concentration of MMP-13 and MMP-3 at the pressure side. The elevation in the levels of these MMPs, 1 hour after the application of the orthodontic force, suggests that these enzymes are involved in the induced periodontal remodeling. The chemokines MCP-1, MIP-1&#946; and RANTES were detected in the GCF in both tension and pressure sides at different time points. However, several samples were below the level of detection of the assay and the levels of theses mediators in GCF did not seem to be altered by the orthodontic forces.