Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a "tetrapartite" synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit ("pentapartite" synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein-protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments.
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PMID:Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System. 3053 57

The objective of this work was to engineer self-assembled nanoparticles (NPs) for on-demand release of bone morphogenetic protein-2 (BMP2) and vascular endothelial growth factor (VEGF) in response to enzymes secreted by the migrating human mesenchymal stem cells (hMSCs) and human endothelial colony forming cells (ECFCs) to induce osteogenesis and vasculogenesis. Gene expression profiling experiments revealed that hMSCs and ECFCs, encapsulated in osteogenic/vasculogenic hydrogels, expressed considerable levels of plasminogen, urokinase plasminogen activator and its receptor uPAR, and tissue plasminogen activator. Therefore, the plasmin-cleavable lysine-phenylalanine-lysine-threonine (KFKT) was used to generate enzymatically cleavable NPs. The acetyl-terminated, self-assembling peptide glycine-(phenylalanine)3GFFF-ac and the plasmin-cleavable GGKFKTGG were reacted with the cysteine-terminated CGGK(Fmoc/MTT) peptide through the MTT and Fmoc termini, respectively. The difunctional peptide was conjugated to polyethylene glycol diacrylate (PEGDA) with molecular weights (MW) ranging from 0.5 to 7.5 kDa, and the chain ends of the PEG-peptide conjugate were terminated with succinimide groups. After self-assembly in aqueous solution, BMP2 was grafted to the self-assembled, plasmin-cleavable PEG-based (PxSPCP) NPs for on-demand release. The NPs' stability in aqueous solution and that of the grafted BMP2 were strongly dependent on PEG MW. P2SPCP NPs showed high particle size stability, BMP2 grafting efficiency, grafted protein stability, and high extent of osteogenic differentiation of hMSCs. The localized and on-demand release of BMP2 from PxSPCP NPs coencapsulated with hMSCs in the linear polyethylene glycol-co-lactide acrylate patterned hydrogel with microchannels encapsulating hMSCs + ECFCs and VEGF-conjugated nanogels resulted in the highest extent of osteogenic and vasculogenic differentiation of the encapsulated cells compared to directly added BMP2/VEGF. The on-demand release of BMP2 from PxSPCP NPs not only enhances osteogenesis and vasculogenesis but also potentially reduces many undesired side effects of BMP2 therapy in bone regeneration.
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PMID:Plasmin-Cleavable Nanoparticles for On-Demand Release of Morphogens in Vascularized Osteogenesis. 3128 51


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