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Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities.
Khan IS, Odom M, Ehtesham M, Colvin D, Quarles CC, McLaughlin B, Singer RJ
(2016) J Neurosurg 125: 152-9
MeSH Terms: Animals, Brain Ischemia, Bridged Bicyclo Compounds, Heterocyclic, Disease Models, Animal, Injections, Intra-Arterial, Male, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Rats, Stroke
Show Abstract · Added April 25, 2016
OBJECT Matrix metalloprotease-9 (MMP-9) plays a critical role in infarct progression, blood-brain barrier (BBB) disruption, and vasogenic edema. While systemic administration of MMP-9 inhibitors has shown neuroprotective promise in ischemic stroke, there has been little effort to incorporate these drugs into endovascular modalities. By modifying the rodent middle cerebral artery occlusion (MCAO) model to allow local intraarterial delivery of drugs, one has the ability to mimic endovascular delivery of therapeutics. Using this model, the authors sought to maximize the protective potential of MMP-9 inhibition by intraarterial administration of an MMP-9 inhibitor, norcantharidin (NCTD). METHODS Spontaneously hypertensive rats were subjected to 90-minute MCAO followed immediately by local intraarterial administration of NCTD. The rats' neurobehavioral performances were scored according to the ladder rung walking test results and the Garcia neurological test for as long as 7 days after stroke. MRI was also conducted 24 hours after the stroke to assess infarct volume and BBB disruption. At the end of the experimental protocol, rat brains were used for active MMP-9 immunohistochemical analysis to assess the degree of MMP-9 inhibition. RESULTS NCTD-treated rats showed significantly better neurobehavioral scores for all days tested. MR images also depicted significantly decreased infarct volumes and BBB disruption 24 hours after stroke. Inhibition of MMP-9 expression in the ischemic region was depicted on immunohistochemical analysis, wherein treated rats showed decreased active MMP-9 staining compared with controls. CONCLUSIONS Intraarterial NCTD significantly improved outcome when administered at the time of reperfusion in a spontaneously hypertensive rat stroke model. This study suggests that supplementing endovascular revascularization with local neuroprotective drug therapy may be a viable therapeutic strategy.
1 Communities
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10 MeSH Terms
Uncoupling angiogenesis and inflammation in peripheral artery disease with therapeutic peptide-loaded microgels.
Zachman AL, Wang X, Tucker-Schwartz JM, Fitzpatrick ST, Lee SH, Guelcher SA, Skala MC, Sung HJ
(2014) Biomaterials 35: 9635-48
MeSH Terms: Angiogenesis Inducing Agents, Animals, Anti-Inflammatory Agents, Cell Line, Drug Carriers, Human Umbilical Vein Endothelial Cells, Inflammation, Injections, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Neovascularization, Physiologic, Oligopeptides, Peripheral Arterial Disease, Polyesters, Tumor Necrosis Factor-alpha
Show Abstract · Added October 30, 2014
Peripheral artery disease (PAD) is characterized by vessel occlusion and ischemia in the limbs. Treatment for PAD with surgical interventions has been showing limited success. Moreover, recent clinical trials with treatment of angiogenic growth factors proved ineffective as increased angiogenesis triggered severe inflammation in a proportionally coupled fashion. Hence, the overarching goal of this research was to address this issue by developing a biomaterial system that enables controlled, dual delivery of pro-angiogenic C16 and anti-inflammatory Ac-SDKP peptides in a minimally-invasive way. To achieve the goal, a peptide-loaded injectable microgel system was developed and tested in a mouse model of PAD. When delivered through multiple, low volume injections, the combination of C16 and Ac-SDKP peptides promoted angiogenesis, muscle regeneration, and perfusion recovery, while minimizing detrimental inflammation. Additionally, this peptide combination regulated inflammatory TNF-α pathways independently of MMP-9 mediated pathways of angiogenesis in vitro, suggesting a potential mechanism by which angiogenic and inflammatory responses can be uncoupled in the context of PAD. This study demonstrates a translatable potential of the dual peptide-loaded injectable microgel system for PAD treatment.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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16 MeSH Terms
Matrix metalloproteinase-9 inhibition improves proliferation and engraftment of myogenic cells in dystrophic muscle of mdx mice.
Hindi SM, Shin J, Ogura Y, Li H, Kumar A
(2013) PLoS One 8: e72121
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Graft Survival, Macrophages, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Mice, Knockout, Muscle, Skeletal, Muscular Dystrophy, Duchenne, Myoblasts, Phenotype, Primary Cell Culture, Receptors, Notch, Wnt Signaling Pathway
Show Abstract · Added March 3, 2014
Duchenne muscular dystrophy (DMD) caused by loss of cytoskeletal protein dystrophin is a devastating disorder of skeletal muscle. Primary deficiency of dystrophin leads to several secondary pathological changes including fiber degeneration and regeneration, extracellular matrix breakdown, inflammation, and fibrosis. Matrix metalloproteinases (MMPs) are a group of extracellular proteases that are involved in tissue remodeling, inflammation, and development of interstitial fibrosis in many disease states. We have recently reported that the inhibition of MMP-9 improves myopathy and augments myofiber regeneration in mdx mice (a mouse model of DMD). However, the mechanisms by which MMP-9 regulates disease progression in mdx mice remain less understood. In this report, we demonstrate that the inhibition of MMP-9 augments the proliferation of satellite cells in dystrophic muscle. MMP-9 inhibition also causes significant reduction in percentage of M1 macrophages with concomitant increase in the proportion of promyogenic M2 macrophages in mdx mice. Moreover, inhibition of MMP-9 increases the expression of Notch ligands and receptors, and Notch target genes in skeletal muscle of mdx mice. Furthermore, our results show that while MMP-9 inhibition augments the expression of components of canonical Wnt signaling, it reduces the expression of genes whose products are involved in activation of non-canonical Wnt signaling in mdx mice. Finally, the inhibition of MMP-9 was found to dramatically improve the engraftment of transplanted myoblasts in skeletal muscle of mdx mice. Collectively, our study suggests that the inhibition of MMP-9 is a promising approach to stimulate myofiber regeneration and improving engraftment of muscle progenitor cells in dystrophic muscle.
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18 MeSH Terms
Synthesis and in vitro efficacy of MMP9-activated NanoDendrons.
Samuelson LE, Scherer RL, Matrisian LM, McIntyre JO, Bornhop DJ
(2013) Mol Pharm 10: 3164-74
MeSH Terms: Animals, Cell Line, Tumor, Dipeptides, Doxorubicin, Drug Delivery Systems, Humans, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Paclitaxel, Prodrugs, Rats
Show Abstract · Added March 7, 2014
Chemotherapeutics such as doxorubicin (DOX) and paclitaxel (PXL) have dose-limiting systemic toxicities, including cardiotoxicity and peripheral neuropathy. Delivery strategies to minimize these undesirable effects are needed and could improve efficacy, while reducing patient morbidity. Here, DOX and PXL were conjugated to a nanodendron (ND) through an MMP9-cleavable peptide linker, producing two new therapies, ND2(DOX) and ND2(PXL), designed to improve delivery specificity to the tumor microenvironment and reduce systemic toxicity. Comparative cytotoxicity assays were performed between intact ND-drug conjugates and the MMP9 released drug in cell lines with and without MMP9 expression. While ND2(DOX) was found to lose cytotoxicity due to the modification of DOX for conjugation to the ND; ND2(PXL) was determined to have the desired properties for a prodrug delivery system. ND2(PXL) was found to be cytotoxic in MMP9-expressing mouse mammary carcinoma (R221A-luc) (53%) and human breast carcinoma (MDA-MB-231) (66%) at a concentration of 50 nM (in PXL) after 48 h. Treating ND2(PXL) with MMP9 prior to the cytotoxicity assay resulted in a faster response; however, both cleaved and intact versions of the drug reached the same efficacy as the unmodified drug by 96 h in the R221A-luc and MDA-MB-231 cell lines. Further studies in modified Lewis lung carcinoma cells that either do (LLC(MMP9)) or do not (LLC(RSV)) express MMP9 demonstrate the selectivity of ND2(PXL) for MMP9. LLC(MMP9) cells were only 20% viable after 48 h of treatment, while LLC(RSV) were not affected. Inclusion of an MMP inhibitor, GM6001, when treating the LLC(MMP9) cells with ND2(PXL) eliminated the response of the MMP9 expressing cells (LLC(MMP9)). The data presented here suggests that these NDs, specifically ND2(PXL), are nontoxic until activated by MMP9, a protease common in the microenvironment of tumors, indicating that incorporation of chemotherapeutic or cytostatic agents onto the ND platform have potential for tumor-targeted efficacy with reduced in vivo systemic toxicities.
1 Communities
2 Members
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11 MeSH Terms
Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome.
Siller SS, Broadie K
(2012) Neural Plast 2012: 124548
MeSH Terms: Animals, Disease Models, Animal, Drosophila, Fragile X Syndrome, Humans, Matrix Metalloproteinase Inhibitors, Matrix Metalloproteinases, Mice, Minocycline, Protease Inhibitors
Show Abstract · Added March 29, 2017
Fragile X syndrome (FXS) is the most common known genetic form of intellectual disability and autism spectrum disorders. FXS patients suffer a broad range of other neurological symptoms, including hyperactivity, disrupted circadian activity cycles, obsessive-compulsive behavior, and childhood seizures. The high incidence and devastating effects of this disease state make finding effective pharmacological treatments imperative. Recently, reports in both mouse and Drosophila FXS disease models have indicated that the tetracycline derivative minocycline may hold great therapeutic promise for FXS patients. Both models strongly suggest that minocycline acts on the FXS disease state via inhibition of matrix metalloproteinases (MMPs), a class of zinc-dependent extracellular proteases important in tissue remodeling and cell-cell signaling. Recent FXS clinical trials indicate that minocycline may be effective in treating human patients. In this paper, we summarize the recent studies in Drosophila and mouse FXS disease models and human FXS patients, which indicate that minocycline may be an effective FXS therapeutic treatment, and discuss the data forming the basis for the proposed minocycline mechanism of action as an MMP inhibitor.
1 Communities
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10 MeSH Terms
MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis.
Rebustini IT, Myers C, Lassiter KS, Surmak A, Szabova L, Holmbeck K, Pedchenko V, Hudson BG, Hoffman MP
(2009) Dev Cell 17: 482-93
MeSH Terms: Animals, Blotting, Western, Cell Proliferation, Collagen Type IV, Epithelial Cells, Fluorescent Antibody Technique, Heparin, Heparin-binding EGF-like Growth Factor, Immunoprecipitation, Integrin beta1, Intercellular Signaling Peptides and Proteins, Matrix Metalloproteinase 14, Matrix Metalloproteinase 15, Matrix Metalloproteinase Inhibitors, Mice, Mice, Knockout, Morphogenesis, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Submandibular Gland
Show Abstract · Added December 10, 2013
Proteolysis is essential during branching morphogenesis, but the roles of MT-MMPs and their proteolytic products are not clearly understood. Here, we discover that decreasing MT-MMP activity during submandibular gland branching morphogenesis decreases proliferation and increases collagen IV and MT-MMP expression. Specifically, reducing epithelial MT2-MMP profoundly decreases proliferation and morphogenesis, increases Col4a2 and intracellular accumulation of collagen IV, and decreases the proteolytic release of collagen IV NC1 domains. Importantly, we demonstrate the presence of collagen IV NC1 domains in developing tissue. Furthermore, recombinant collagen IV NC1 domains rescue branching morphogenesis after MT2-siRNA treatment, increasing MT-MMP and proproliferative gene expression via beta1 integrin and PI3K-AKT signaling. Additionally, HBEGF also rescues MT2-siRNA treatment, increasing NC1 domain release, proliferation, and MT2-MMP and Hbegf expression. Our studies provide mechanistic insight into how MT2-MMP-dependent release of bioactive NC1 domains from collagen IV is critical for integrating collagen IV synthesis and proteolysis with epithelial proliferation during branching morphogenesis.
1 Communities
2 Members
0 Resources
23 MeSH Terms
Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background.
Martin MD, Carter KJ, Jean-Philippe SR, Chang M, Mobashery S, Thiolloy S, Lynch CC, Matrisian LM, Fingleton B
(2008) Cancer Res 68: 6251-9
MeSH Terms: Animals, Female, Lung Neoplasms, Male, Mammary Neoplasms, Experimental, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Mice, Inbred C57BL, Protease Inhibitors, Stromal Cells
Show Abstract · Added March 5, 2014
Matrix metalloproteinases (MMP) are a family of enzymes with a myriad of functions. Lately, we have come to realize that broad-spectrum inhibition of these enzymes, as was tried unsuccessfully in multiple phase III trials in cancer patients, is likely unwise given the protumorigenic and antitumorigenic functions of various family members. Here, we used the multistage mammary tumor model MMTV-PyVT to investigate roles for either MMP7 or MMP9 in tumor progression. We found no effect of genetic ablation of MMP7 or MMP9 on the multifocal tumors that developed in the mammary glands. Lack of MMP7 also had no effect on the development of lung metastases, suggesting that MMP7 is irrelevant in this model. In contrast, MMP9 deficiency was associated with an 80% decrease in lung tumor burden. The predominant cellular source of MMP9 was myeloid cells, with neutrophils being the largest contributor in tumor-bearing lungs. Experimental metastasis assays corroborated the role of host-derived MMP9 in lung metastasis and also facilitated determination of a time frame most relevant for the MMP9-mediated effect. The lung tumors from MMP9-deficient mice showed decreased angiogenesis. Surprisingly, the antimetastatic outcome of MMP9 ablation seemed to be dependent on strain. Only mice that had genetic background derived from C57BL/6 showed reduced metastasis, whereas mice fully of the FVB/N background showed no significant effect. These strain-specific responses were also observed in a study using a highly selective pharmacologic inhibitor of MMP9 and thus suggest that responses to MMP inhibition are controlled by genetic differences.
1 Communities
1 Members
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11 MeSH Terms
MMPs as therapeutic targets--still a viable option?
Fingleton B
(2008) Semin Cell Dev Biol 19: 61-8
MeSH Terms: Animals, Clinical Trials as Topic, Drug Delivery Systems, Enzyme Inhibitors, Humans, Matrix Metalloproteinase Inhibitors, Matrix Metalloproteinases, Metabolic Diseases, Models, Animal, Treatment Outcome
Show Abstract · Added March 5, 2014
Matrix metalloproteinases (MMPs) appear to be ideal drug targets--they are disease-associated, extracellular enzymes with a dependence on zinc for activity. This apparently straightforward target, however, is much more complex than initially realized. Although disease associated, the roles for particular enzymes may be healing rather than harmful making broad-spectrum inhibition unwise; targeting the catalytic zinc with specificity is difficult, since other related proteases as well as non-related proteins can be affected by some chelating groups. While the failure of early-generation MMP inhibitors dampened enthusiasm for this type of drug, there has recently been a wealth of studies examining the basic biology of MMPs which will greatly inform new drug trials in this field.
1 Communities
1 Members
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10 MeSH Terms
Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia.
Clark ES, Whigham AS, Yarbrough WG, Weaver AM
(2007) Cancer Res 67: 4227-35
MeSH Terms: Actins, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Membrane, Cortactin, Extracellular Matrix, Head and Neck Neoplasms, Humans, Isoenzymes, Matrix Metalloproteinase 14, Matrix Metalloproteinase Inhibitors, Matrix Metalloproteinases
Show Abstract · Added March 5, 2014
Invadopodia are branched actin-rich structures associated with extracellular matrix (ECM) degradation that collectively form the invasive machinery of aggressive cancer cells. Cortactin is a prominent component and a specific marker of invadopodia. Amplification of cortactin is associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), possibly because of its activity in invadopodia. Although the role of cortactin in invadopodia has been attributed to signaling and actin assembly, it is incompletely understood. We made HNSCC cells deficient in cortactin by RNA interference knockdown methods. In these cortactin knockdown cells, invadopodia were reduced in number and lost their ability to degrade ECM. In the reverse experiment, overexpression of cortactin dramatically increased ECM degradation, far above and beyond the effect on formation of actin/Arp3-positive invadopodia puncta. Secretion of matrix metalloproteinases (MMP) MMP-2 and MMP-9, as well as plasma membrane delivery of MT1-MMP correlated closely with cortactin expression levels. MMP inhibitor treatment of control cells mimicked the cortactin knockdown phenotype, with abolished ECM degradation and fewer invadopodia, suggesting a positive feedback loop in which degradation products from MMP activity promote new invadopodia formation. Collectively, these data suggest that a major role of cortactin in invadopodia is to regulate the secretion of MMPs and point to a novel mechanism coupling dynamic actin assembly to the secretory machinery, producing enhanced ECM degradation and invasiveness. Furthermore, these data provide a possible explanation for the observed association between cortactin overexpression and enhanced invasiveness and poor prognosis in HNSCC patients.
1 Communities
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12 MeSH Terms
Warm hepatic ischemia-reperfusion promotes growth of colorectal carcinoma micrometastases in mouse liver via matrix metalloproteinase-9 induction.
Nicoud IB, Jones CM, Pierce JM, Earl TM, Matrisian LM, Chari RS, Gorden DL
(2007) Cancer Res 67: 2720-8
MeSH Terms: Adenocarcinoma, Animals, Cell Line, Tumor, Colorectal Neoplasms, Doxycycline, Enzyme Induction, Female, Ischemia, Liver, Liver Neoplasms, Experimental, Male, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Mice, Inbred C57BL, RNA, Messenger, Reperfusion, Reperfusion Injury, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation
Show Abstract · Added January 10, 2014
Surgical resection remains the best treatment for colorectal metastases isolated to the liver; however, 5-year survival rates following liver resection are only 40% to 50%, with liver recurrence being a significant reason for treatment failure. The ischemia-reperfusion (I/R) injury incurred during liver surgery can lead to cellular dysfunction and elevations in proinflammatory cytokines and matrix metalloproteinases (MMP). In rodents, I/R injury to the liver has been shown to accelerate the outgrowth of implanted tumors. The mechanism for increased tumor growth in the setting of liver I/R injury is unknown. To investigate the effect of I/R on tumor growth, an experimental model was used whereby small hepatic metastases form after 28 days. Mice subjected to 30 min of 70% liver ischemia at the time of tumor inoculation had significantly larger tumor number and volume, and had elevated MMP9 serum and liver tissue MMP9 as evidenced by zymography and quantitative real-time PCR. Mice treated with doxycycline, a broad-spectrum MMP inhibitor, had reduced MMP9 levels and significantly smaller tumor number and volume in the liver. MMP9-null mice were used to determine if the effects of doxycycline were due to the absence of stromal-derived MMP9. The MMP9-null mice, with or without doxycycline treatment, had reduced tumor number and volume that was equivalent to wild-type mice treated with doxycycline. These findings indicate that hepatic I/R-induced elevations in MMP9 contribute to the growth of metastatic colorectal carcinoma in the liver and that postresection MMP9 inhibition may be clinically beneficial in preventing recurrence following hepatic surgery.
1 Communities
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20 MeSH Terms