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Inflammatory Responses Acquired Following Environmental Exposures Are Involved in Pathogenesis of Musculoskeletal Pain
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Ritchie C. Shoemaker, James C. Ryan
MSH also exerts a damping effect on production of matrix metalloproteinase 9 (MMP-9), a protein made following cleavage of MMP-14, which is induced by the effects of cytokines in endothelial cells and white blood cells. We use MMP-9 because of the inability to accurately measure the total burden of Th1 and Th2 cytokines. The problem here is that cells that produce Th1/Th2 cytokines can bind given cytokines (autocrine effects) or cells nearby can also bind the cytokine (paracrine effects). When we measure IL1 beta or IL6 in the blood, the result is only the endocrine function of those cytokines. MMP-9 has additional important effects in chronic pain, namely delivery from inflammatory elements out of blood across cell membrane of endothelial cells through the basement membrane into the sub-intimal space. This delivery mechanism can create havoc in lung, brain, muscle, tendon and nerve [25].
Potential Targets for Imaging Atherosclerosis
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
David N. Smith, Mehran M. Sadeghi, Jeffrey R. Bender
Inflammatory disease states associated with elevated AT II and TNF-α induce EC and macrophages to release MMPs (80). The activated macrophage is the primary source of local MMP secretion, largely mediated through local inflammation-derived cytokine byproducts (e.g., prostaglandins and TNF-α) (81). OxLDL induces MMP-14 expression in macrophages and EC. MMP-14 anchors to the cell membrane to promote pericellular degradation, as well to activate other collagenases, particularly 2 and 13 (82–86). MMPs localize in the vulnerable plaque shoulder regions, which are thought to be more susceptible to rupture and initiation of acute events (87). In these regions, cyclooxygenase and its products (e.g., PGE) induce MMPs to increase plaque instability (88).
Bioresponsive Nanoparticles
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Drashti Pathak, Deepa H. Patel
TME also have upregulated levels of enzymes such as matrix metalloproteinase (MMP), which is predominantly a Fabrication of DOX-loaded PEI-NI-based nanoparticle co-assembled with HA-Ce6, (b) CD 44-mediated endocytosis and release of DOX in response to hypoxia generated by laser irradiation involved in tumor development and proliferation. The nanoprobe was constructed through the self-assembly of hexahistidine-tagged (His-Tagged) fluorescent protein and nickel ferrite nanoparticles. The nickel ferrite nanoparticles functioned as protein binders of His-Tagged fluorescent protein and fluorescent quencher. The nanoprobe was reported to be turned on by the presence of MMP-2, leading to enhanced cellular uptake and the restoration of fluorescence, thereby enabling the visualization of nanoparticles within tumor tissue. Ma et al. reported the fabrication of polymeric conjugate for mitochondrial targeting for paclitaxel (PTX) delivery. The polymeric conjugate consists of a PAMAM-based dendrimer core into which triphenylphosphine and PTX were conjugated through an amino bond and disulfide bonds, respectively. To enhance the circulation time of the polymeric conjugate in the blood, PEG was conjugated via the MMP-2 sensitive peptide (GPLGIAGQ). The conjugates accumulate in tumor tissue through the EPR effect. Once the conjugate enters tumor cells, the PEG layer is detached from PAMAM by cleavage of MMP-2 sensitive peptide by the action of MMP-2. The conjugate would then target the mitochondria via triphenylphosphine and PTX would be released in the cytoplasm. Ansari et al. have reported the synthesis of theranostic nanoparticles that possess enzyme-specific drug release and in vivo magnetic resonance imaging (MRI). The nanoparticles were synthesized through the conjugation of ferumoxytol (FDA approved iron oxide nanoparticles) to MMP-14 activatable peptide conjugated to azademetylcolchicine (ICT) (CLIO-ICT). Upon reaching the tumor, the CLIO-ICT would be converted from non-toxic form to toxic form by the action of MMP-14 thereby, releasing potent ICT. This type of nanoparticles also enables the real-time monitoring of accumulation and localization of drug at the tumor site through MRI imaging. Another type of enzyme whose levels are known to be upregulated in various cancer subtypes is β-galactosidase (β-gal). Sharma et al. have developed theragnostic prodrug for the treatment of colon cancer using receptor-mediated targeting and enzyme responsive activation. In this study, β-gal was used for both targeting asialoglycoprotein (ASGP) receptors and activation of prodrug.
Development of a naringenin microemulsion as a prospective ophthalmic delivery system for the treatment of corneal neovascularization: in vitro and in vivo evaluation
Published in Drug Delivery, 2022
Yu Ma, Jingjing Yang, Yali Zhang, Chunyan Zheng, Zhen Liang, Ping Lu, Fei Song, Yuwei Wang, Junjie Zhang
The results showed that topical administration of 0.5% NAR-ME significantly reduced the levels of VEGF-A and MMP14 in cornea tissue, and the CNV area was also greatly reduced. Numerous reports have shown that NAR can inhibit VEGF-A-induced angiogenesis through different pathways (Li et al., 2016; Dmytrenko et al., 2017; Pafumi et al., 2017). A similar observation has been documented by Oguido et al. (2017). MMP14 has been implicated in angiogenesis as not only a proangiogenic factor but also an antiangiogenic factor, and both up- and downregulation of MMP14 has been observed in a variety of disease models of angiogenesis. However, MMP14 is generally regarded as proangiogenic because it is upregulated during angiogenesis in endothelial tissue, and deficiency of MMP14 leads to a loss of the ability of endothelial cells to form new vessels (Han et al., 2015, 2019). Thus, NAR-ME may inhibit CNV by reducing the expression of proangiogenic growth factors such as VEGF-A and MMP14.
Endothelial dysfunction: a therapeutic target in bacterial sepsis?
Published in Expert Opinion on Therapeutic Targets, 2021
Jean-Louis Vincent, Can Ince, Peter Pickkers
Therapeutic targeting of the angiopoietin-Tie pathway has resulted in beneficial effects in some animal models of sepsis [67,74,75]. Matrix metalloprotease (MMP)-14 can mediate Tie2 ectodomain shedding, so that pharmacological MMP-14 blockade may have endothelial protective effects predominantly by attenuation of Tie2 cleavage [76]. The anti-fungal agent bifonazole may improve vascular barrier function by decreasing the release of Angpt-2 [77]. In a murine model of peritonitis, administration of a pan-caspase inhibitor limited capillary leakage, suggesting a deleterious role of endothelial cell apoptosis [78]. Inhibition of vascular endothelial growth factor (VEGF) may also be an option. This approach did not improve outcome in an animal model of sepsis [79], but a recent study indicated that dual inhibition of Angpt-2 and VEGF improved outcomes in a murine sepsis model [80]. It is still possible, however, that this dual inhibition strategy does not provide additional benefit compared to therapeutics that only inhibit Angpt-2.
Chondrocyte protein co-synthesis network analysis links ECM mechanosensing to metabolic adaptation in osteoarthritis
Published in Expert Review of Proteomics, 2021
Aspasia Destouni, Konstantinos C. Tsolis, Anastassios Economou, Ioanna Papathanasiou, Charalampos Balis, Evanthia Mourmoura, Aspasia Tsezou
The network of proteins that are unique to OA comprises a total of 303 nodes expanding the core interactome by 129 proteins (Figure 5b). Chaperonin CCT2 was the top node followed by beta-catenin (CTNNB1) (Figure 5b). Two ribosomal proteins, Ribosomal Protein S4 X-Linked (RPS4X) and Ribosomal Protein Lateral Stalk Subunit P0 (RPLP0), were added to the top node list, as their immediate interactors were uniquely identified in OA chondrocytes and comprised translation initiation and elongation factors and ribosomal subunits. Elevated levels of β-catenin are associated with cartilage degeneration and increased WNT signaling in mature chondrocytes and exacerbate hallmarks of OA manifestation, such as chondrocyte hypertrophy and increased matrix metalloproteinase expression [47,48]. In the OA interactome CTNNB1 was linked to MMP14, which is secreted by invading osteoblasts in the hypertrophic zone of cartilage. This interaction probably indicates that MMP14 signals to promote cartilage canal formation and secondary ossification center initiation [49].