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Reproductive Sciences (Thousand Oaks,... Mar 2022As a key mechanism in fibrinolysis and tissue remodeling, the plasminogen activator system has been suggested in the process of endometrial shedding and tissue...
As a key mechanism in fibrinolysis and tissue remodeling, the plasminogen activator system has been suggested in the process of endometrial shedding and tissue remodeling. Previous studies have explored the role of estrogen, progesterone, and androgen receptors as well as elements of the renin-angiotensin-aldosterone system in shaping the morphology of the endometrium. This study investigates the distribution and concentrations of the mineralocorticoid receptor, glucocorticoid receptor, tissue plasminogen activator, urokinase plasminogen activator, and plasminogen activator inhibitor-1 within the endometrial stroma, glandular, and endothelial cells of the primate endometrium during artificial menstrual cycles. Our immunohistochemistry quantification shows mineralocorticoid and glucocorticoid receptors are ubiquitously distributed within the macaque endometrium with their patterns of expression following similar fluctuations to urokinase and tissue plasminogen activators particularly within the endometrial vasculature. These proteins are present in endometrial vasculature in high levels during the proliferative phase, decreasing levels during the secretory phase followed by rising levels in the menstrual phase. These similarities could suggest overlapping pathways and interactions between the plasminogen activator system and the steroid receptors within the endometrium. Given the anti-inflammatory properties of glucocorticoids and the role of plasminogen activators in endometrial breakdown, the glucocorticoid receptor may be contributing to stabilizing the endometrium by regulating plasminogen activators during the proliferative phase and menstruation. Furthermore, given the anti-mineralocorticoid properties of certain anti-androgenic progestins and their reduced unscheduled uterine bleeding patterns, the mineralocorticoid receptor may be involved in unscheduled endometrial bleeding.
Topics: Animals; Endometrium; Female; Macaca mulatta; Menstrual Cycle; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Tissue Plasminogen Activator
PubMed: 34796470
DOI: 10.1007/s43032-021-00797-8 -
Advanced Healthcare Materials Nov 2022The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present...
The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase-type plasminogen activator (uPA) and coated with a low-fouling peptide that is incorporated within a metal-phenolic network (MPN). The peptide-containing MPN (pep-MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep-MPN-coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane-dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA-loaded pep-MPN-coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half-life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane-dependent release of uPA within pep-MPN-coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.
Topics: Mice; Animals; Fibrinolytic Agents; Drug Carriers; Polyphenols; Urokinase-Type Plasminogen Activator; Thrombosis; Lipids; Peptides
PubMed: 36037807
DOI: 10.1002/adhm.202201151 -
Cells May 2020The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis... (Review)
Review
The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis and progression of various human diseases including kidney, brain, and other diseases. Tissue plasminogen activator (tPA), a serine protease regulating homeostasis of blood coagulation, fibrinolysis, and matrix degradation, has been shown to act as a cytokine to trigger profound receptor-mediated intracellular events, modulate the NF-κB pathway, and mediate organ dysfunction and injury. In this review, we focus on the current understanding of NF-κB and tPA signaling in the development and progression of kidney disease. Their roles in the nervous and cardiovascular system are also briefly discussed.
Topics: Animals; Humans; Inflammation; Kidney Diseases; Macrophages; NF-kappa B; Signal Transduction; Tissue Plasminogen Activator
PubMed: 32485860
DOI: 10.3390/cells9061348 -
International Journal of Molecular... Mar 2021Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the... (Review)
Review
Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.
Topics: Cardiovascular Diseases; Cell Movement; Fibrinolysis; Fibrosis; Humans; Neoplasm Proteins; Neoplasms; Plasminogen Activator Inhibitor 1; Proteolysis; Urokinase-Type Plasminogen Activator
PubMed: 33800359
DOI: 10.3390/ijms22052721 -
Journal of Translational Medicine Mar 2022Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at... (Review)
Review
Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at high levels in malignant tumours. uPAR is closely related to the invasion and metastasis of malignant tumours, plays important roles in the degradation of extracellular matrix (ECM), tumour angiogenesis, cell proliferation and apoptosis, and is associated with the multidrug resistance (MDR) of tumour cells, which has important guiding significance for the judgement of tumor malignancy and prognosis. Several uPAR-targeted antitumour therapeutic agents have been developed to suppress tumour growth, metastatic processes and drug resistance. Here, we review the recent advances in the development of uPAR-targeted antitumor therapeutic strategies, including nanoplatforms carrying therapeutic agents, photodynamic therapy (PDT)/photothermal therapy (PTT) platforms, oncolytic virotherapy, gene therapy technologies, monoclonal antibody therapy and tumour immunotherapy, to promote the translation of these therapeutic agents to clinical applications.
Topics: Humans; Neoplasms; Prognosis; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Urokinase-Type Plasminogen Activator
PubMed: 35303878
DOI: 10.1186/s12967-022-03329-3 -
Blood Jul 2021
Topics: Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 34236426
DOI: 10.1182/blood.2021011268 -
ACS Nano Apr 2023Thrombolysis with tissue plasminogen activator (tPA) provides the most common therapy for ischemic stroke onset within the past 4.5 h. However, enhanced neutrophil...
Thrombolysis with tissue plasminogen activator (tPA) provides the most common therapy for ischemic stroke onset within the past 4.5 h. However, enhanced neutrophil infiltration and secondary blood-brain barrier injury caused by tPA administration have limited its therapeutic application, and tPA treatment is often accompanied by hemorrhagic transformation. To overcome the limitations of thrombolysis by tPA, maximize the therapeutic efficacy, and improve the safety, herein, we report a cryo-shocked platelet-based cell-hitchhiking drug delivery system, which consists of cryo-shocked platelet (CsPLT) and reactive oxygen species (ROS)-responsive liposomes loaded with thrombolytic tPA and anti-inflammation drug aspirin (ASA). CsPLT and liposomes were facilely conjugated via host-guest interactions. Under the guidance of CsPLT, it selectively accumulated in the thrombus site and quickly released the therapeutic payloads in response to the high ROS. tPA subsequently exhibited localized thrombolytic activity to suppress the expansion of thrombus, while ASA assisted in the inactivation of reactive astrogliosis, microglial/macrophage, and obstruction of neutrophil infiltration. This cryo-shocked platelet-hitchhiking tPA/ASA delivery system not only improves the thrombus-targeting efficiency of the two drugs for highly localized thrombolytic effects and anti-inflammation actions and platelets inactivation but also provides insights to the development of targeted drug delivery systems for thromboembolic disease treatment.
Topics: Humans; Tissue Plasminogen Activator; Reactive Oxygen Species; Liposomes; Nanomedicine; Fibrinolytic Agents; Aspirin; Thrombosis; Stroke
PubMed: 36971410
DOI: 10.1021/acsnano.2c11865 -
Neuroscience Mar 2024The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by... (Review)
Review
The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.
Topics: Humans; Tissue Plasminogen Activator; Fibrinolysin; Ischemic Stroke; Endothelial Cells; Brain Ischemia; Brain; Fibrinolytic Agents
PubMed: 37574107
DOI: 10.1016/j.neuroscience.2023.08.011 -
Neuroscience Letters Jan 2022The serine protease tissue plasminogen activator (tPA), encoded by the gene Plat, exerts a wide range of proteolysis-dependent and proteolysis-independent functions. In...
The serine protease tissue plasminogen activator (tPA), encoded by the gene Plat, exerts a wide range of proteolysis-dependent and proteolysis-independent functions. In the developing brain, tPA is involved in neuronal development via the modulation of the proteolytic degradation of the extracellular matrix (ECM). Both lack of and excessive tPA are associated with neurodevelopmental disorders and with brain pathology. Astrocytes play a major role in neurite outgrowth of developing neurons as they are major producers of ECM proteins and ECM proteases. In this study we investigated the expression of Plat in developing and mature hippocampal and cortical astrocytes of Aldh1l1-EGFP-Rpl10a mice in vivo following Translating Ribosome Affinity Purification (TRAP) and the role of tPA in modulating astrocyte-mediated neurite outgrowth in an in vitro astrocyte-neuron co-culture system. We show that Plat is highly enriched in astrocytes in the developing, but not in the mature, hippocampus and cortex. Both the silencing of tPA expression in astrocytes and astrocyte exposure to recombinant tPA reduce neuritogenesis in co-cultured hippocampal neurons. These results suggest that astrocyte tPA is involved in modulating neuronal development and that tight control of astrocyte tPA expression is important for normal neuronal development, with both experimentally elevated and reduced levels of this proteolytic enzyme impairing neurite outgrowth. These results are consistent with the hypothesis that the ECM, by serving as adhesive substrate, enables neurite outgrowth, but that controlled proteolysis of the ECM is needed for growth cone advancement.
Topics: Animals; Astrocytes; Brain; Cells, Cultured; Cerebral Cortex; Hippocampus; Neuronal Outgrowth; Plasminogen Activators; Pyramidal Cells; Rats; Rats, Sprague-Dawley
PubMed: 34968722
DOI: 10.1016/j.neulet.2021.136422 -
Medical Hypotheses May 2020Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The...
Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The disease originates from the loss of dopamine-producing neurons in the substantia nigra in the brain, resulting in unregulated activity of the basal ganglia. Αlpha-synuclein (α-syn) is a protein found to aggregate in the substantia nigra region of patients with PD, forming Lewy Body inclusions; its aggregation may contribute to neuronal cell death in PD. This work hypothesizes about the synergistic relationship between α-syn aggregation and neuroinflammation to up-regulate expression of the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1). The protease, plasmin, has been shown to cleave extracellular α-syn (including its monomeric, oligomeric, and fibrillary forms), resulting in less aggregation and Lewy Body formation. The zymogen plasminogen is converted to its active serine protease form, plasmin, either by tissue plasminogen activator (tPA) or by urokinase plasminogen activator (uPA) bound to urokinase receptor (uPAR). Both tPA and uPA/uPAR are inhibited by PAI-1. Thus, when PAI-1 levels increase, less plasmin is generated, which would lead to reduced proteolysis of α-syn. Expression of PAI-1 is increased both in inflammatory environments and in the presence of extracellular α-syn aggregates. This scenario suggests a pathological amplification loop: increased extracellular α-syn aggregation activates an inflammatory response from microglia and astrocytes, increasing PAI-1 levels, and decreasing the generation of plasmin. With reduced plasmin, less α-syn can be cleaved, and aggregation continues, sustaining the pathological process. Understanding this putative pathogenic loop could provide insight into the means by which neurodegeneration progresses in PD, and it may offer possible novel therapeutic strategies.
Topics: Aged; Humans; Lewy Bodies; Parkinson Disease; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-Synuclein
PubMed: 32035284
DOI: 10.1016/j.mehy.2020.109602