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Cells Mar 2024Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis... (Review)
Review
Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis frequently result in bone destruction. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-17 are known to influence bone loss by promoting the differentiation and activation of osteoclasts. Fibrinolytic factors, such as plasminogen (Plg), plasmin, urokinase-type plasminogen activator (uPA), its receptor (uPAR), tissue-type plasminogen activator (tPA), α2-antiplasmin (α2AP), and plasminogen activator inhibitor-1 (PAI-1) are expressed in osteoclasts and osteoblasts and are considered essential in maintaining bone homeostasis by regulating the functions of both osteoclasts and osteoblasts. Additionally, fibrinolytic factors are associated with the regulation of inflammation and the immune system. This review explores the roles of fibrinolytic factors in bone destruction caused by inflammation.
Topics: Humans; Urokinase-Type Plasminogen Activator; Inflammation; Osteoclasts; Osteoblasts; Bone and Bones
PubMed: 38534360
DOI: 10.3390/cells13060516 -
Journal of Controlled Release :... Oct 2022Sonothrombolysis with recombinant tissue plasminogen activator (rtPA) and microbubbles has been widely studied to enhance thrombolytic potential. Here, we report...
Sonothrombolysis with recombinant tissue plasminogen activator (rtPA) and microbubbles has been widely studied to enhance thrombolytic potential. Here, we report different sonothrombolysis strategy in nanoparticles using microbubbles cavitation. We found that different particles in shape exhibited different reactivity toward the cavitation, leading to a distinct sonothrombolytic potential. Two different gold nanoparticles in shape were functionalized with the rtPA: rtPA-functionalized gold nanospheres (NPt) and gold nanostars (NSt). NPt could not accelerate the thrombolytic potential with a sole acoustic stimulus. Importantly, NSt enhanced the potential with acoustic stimulus and microbubble-mediated cavitation, while NPt were not reactive to cavitation. Coadministration of NSt and microbubbles resulted in a dramatic reduction of the infarcts in a photothrombotic model and recovery in the cerebral blood flow. Given the synergistic effect and in vivo feasibility of this strategy, cavitation-assisted sonothrombolysis by asymmetrical NSt might be useful for treating acute ischemic stroke.
Topics: Fibrinolytic Agents; Gold; Humans; Ischemic Stroke; Metal Nanoparticles; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 36096365
DOI: 10.1016/j.jconrel.2022.09.008 -
Clinical and Applied... 2022The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is... (Review)
Review
The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-β-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.
Topics: Antiphospholipid Syndrome; Blood Coagulation; Endothelial Cells; Female; Humans; Placenta; Pregnancy; Tissue Plasminogen Activator
PubMed: 35317658
DOI: 10.1177/10760296221088576 -
Journal of Thrombosis and Haemostasis :... Apr 2024Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This...
BACKGROUND
Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis.
OBJECTIVES
To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment.
METHODS
Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.
RESULTS
Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10; rs1421067 (CHD9), P = 1.81 × 10; and rs34780449, near ROBO1 gene, P = 1.64 × 10. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).
CONCLUSION
We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
Topics: Humans; Tissue Plasminogen Activator; von Willebrand Factor; Genome-Wide Association Study; Nerve Tissue Proteins; Receptors, Immunologic; Stroke; Fibrinogen; Hemostatics; Risk Factors
PubMed: 38103737
DOI: 10.1016/j.jtha.2023.11.027 -
International Journal of Molecular... Dec 2021Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to...
Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of -Methyl-d-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.
Topics: Animals; Cell Death; Cell Survival; Fetus; Mice; Neurons; Primary Cell Culture; Protein Isoforms; Proto-Oncogene Proteins c-met; Receptor Cross-Talk; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Tissue Plasminogen Activator
PubMed: 34948279
DOI: 10.3390/ijms222413483 -
BMC Ophthalmology Sep 2022Diabetic retinopathy (DR) is a serious complication of longstanding type 2 diabetes mellitus (T2DM), a leading cause of blindness and visual disability in the world. The...
BACKGROUND
Diabetic retinopathy (DR) is a serious complication of longstanding type 2 diabetes mellitus (T2DM), a leading cause of blindness and visual disability in the world. The aim of this study is to compare the activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in tears and serum of patients with DR and those without DR.
METHOD
Among the T2DM patients enrolled in this study, 26 patients had DR (n = 26) while 29 were without DR (n = 29). The blood and tear samples were obtained from all participants. The level of PAI-1 and tPA were measured in both the serum and tears. Anthropometric measurements, HbA1c, renal and lipid profile were also obtained.
RESULTS
Patients with DR had significantly longer disease duration and higher systolic blood pressure compared to those without DR. Serum PAI-1 level was significantly higher in patients with DR compared to those without DR, 32.72 (IQR 32.52) vs 21.37 (IQR 14.93) ng/mL, respectively (p < 0.05). However, tear PAI-1 were comparable in both groups. Serum and tear tPA levels in both groups were also comparable (p > 0.05). Among patients with DR, there were no significant correlations between tear and serum of both biomarkers. Patients without DR showed a moderate positive correlation between serum and tear tPA levels with a coefficient of 0.363, albeit no statistical significance. Patients with DR demonstrated a significant positive correlation between levels of tears PAI-1 and BMI (r = 0.555, p = 0.026). In the group without DR, there was a statistically significant positive correlation between serum level of PAI-1 with urine albumin creatinine ratio (UACR) (r = 0.501, p = 0.013).
CONCLUSION
The present study demonstrated a significantly greater serum PAI-1 levels in patients with DR compared to those without DR. No significant correlations between tears and serum PAI-1 and tPA were observed. Thus, the role of tear biomarkers remains relevant for further investigations.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator
PubMed: 36057550
DOI: 10.1186/s12886-022-02550-4 -
Fluids and Barriers of the CNS Oct 2022In the vascular compartment, the serine protease tissue-type plasminogen activator (tPA) promotes fibrinolysis, justifying its clinical use against vasculo-occlusive...
BACKGROUND
In the vascular compartment, the serine protease tissue-type plasminogen activator (tPA) promotes fibrinolysis, justifying its clinical use against vasculo-occlusive diseases. Accumulating evidence shows that circulating tPA (endogenous or exogenous) also controls brain physiopathological processes, like cerebrovascular reactivity, blood-brain barrier (BBB) homeostasis, inflammation and neuronal fate. Whether this occurs by direct actions on parenchymal cells and/or indirectly via barriers between the blood and the central nervous system (CNS) remains unclear. Here, we postulated that vascular tPA can reach the brain parenchyma via the blood-cerebrospinal fluid barrier (BCSFB), that relies on choroid plexus (CP) epithelial cells (CPECs).
METHODS
We produced various reporter fusion proteins to track tPA in primary cultures of CPECs, in CP explants and in vivo in mice. We also investigated the mechanisms underlying tPA transport across the BCSFB, with pharmacological and molecular approaches.
RESULTS
We first demonstrated that tPA can be internalized by CPECs in primary cultures and in ex vivo CPs explants. In vivo, tPA can also be internalized by CPECs both at their basal and apical sides. After intra-vascular administration, tPA can reach the cerebral spinal fluid (CSF) and the brain parenchyma. Further investigation allowed discovering that the transcytosis of tPA is mediated by Low-density-Lipoprotein Related Protein-1 (LRP1) expressed at the surface of CPECs and depends on the finger domain of tPA. Interestingly, albumin, which has a size comparable to that of tPA, does not normally cross the CPs, but switches to a transportable form when grafted to the finger domain of tPA.
CONCLUSIONS
These findings provide new insights on how vascular tPA can reach the brain parenchyma, and open therapeutic avenues for CNS disorders.
Topics: Albumins; Animals; Blood-Brain Barrier; Brain; Choroid Plexus; Lipoproteins; Mice; Tissue Plasminogen Activator
PubMed: 36243724
DOI: 10.1186/s12987-022-00378-0 -
Scientific Reports May 2023Atherosclerosis (AS) is a major contributor to a variety of negative clinical outcomes, including stroke and myocardial infarction. However, the role and therapeutic...
Atherosclerosis (AS) is a major contributor to a variety of negative clinical outcomes, including stroke and myocardial infarction. However, the role and therapeutic value of hypoxia-related genes in AS development has been less discussed. In this study, Plasminogen activator, urokinase receptor (PLAUR) was identified as an effective diagnostic marker for AS lesion progression by combining WGCNA and random forest algorithm. We validated the stability of the diagnostic value on multiple external datasets including humans and mice. We identified a significant correlation between PLAUR expression and lesion progression. We mined multiple single cell-RNA sequencing (sc-RNA seq) data to nominate macrophage as the key cell cluster for PLAUR mediated lesion progression. We combined cross-validation results from multiple databases to predict that HCG17-hsa-miR-424-5p-HIF1A, a competitive endogenous RNA (ceRNA) network, may regulate hypoxia inducible factor 1 subunit alpha (HIF1A) expression. The DrugMatrix database was used to predict alprazolam, valsartan, biotin A, lignocaine, and curcumin as potential drugs to delay lesion progression by antagonizing PLAUR, and AutoDock was used to verify the binding ability of drugs and PLAUR. Overall, this study provides the first systematic identification of the diagnostic and therapeutic value of PLAUR in AS and offers multiple treatment options with potential applications.
Topics: Humans; Mice; Animals; Receptors, Urokinase Plasminogen Activator; Plasminogen Activators; Urokinase-Type Plasminogen Activator; Hypoxia; Atherosclerosis
PubMed: 37237021
DOI: 10.1038/s41598-023-35548-z -
Journal of Thrombosis and Thrombolysis Feb 2022Stroke is the third leading cause of death in the United States and the leading cause of adult disability. Despite enormous research efforts including many clinical...
Stroke is the third leading cause of death in the United States and the leading cause of adult disability. Despite enormous research efforts including many clinical trials, tissue plasminogen activator (tPA) remains the only FDA-approved treatment for acute ischemic stroke. Unfortunately, only 1-3% of stroke patients in the US receive this therapy because of the narrow time window and severe side effects for using tPA. The most deadly and damaging side effect is the risk of intracranial bleeding or hemorrhage. For that reason, the dose of tPA and its overall administration are under tight control, which may compromise the effect of thrombolysis. Studies have been focused on improving the effectiveness of tPA for higher rate of reperfusion, and the safety for less adverse bleeding episode. We studied how metal ions (zinc & iron) affect tPA-induced thrombolysis in vitro and in vivo, and proposed a method to improve the rate of thrombolysis. The amount of hemoglobin in the blood clot lysis was measured by a spectrophotometer. The tPA-induced thrombolysis was measured in vivo in femoral artery. Our results showed that Zn, Fe and Fe inhibited tPA-induced thrombolysis, with Zn and Fe being the most effective. Metal ion chelating agent EDTA when it was co-applied with tPA significantly enhanced the tPA-induced thrombolysis. The chelation alone did not have noticeable thrombolytic effect. In in vivo study of tPA-induced thrombosis following femoral artery thrombosis, the co-application of tPA and EDTA achieved significant higher rate of reperfusion than that by tPA treatment alone, suggesting that ion chelation facilitates tPA-induced thrombolysis and potentially improves the safety of tPA application by reducing the necessary dose of tPA application. Our results suggest that the co-application of a chelator and tPA improves the efficacy and, potentially, safety of tPA application, by reducing the necessary dose of tPA for thrombolysis.
Topics: Adult; Chelating Agents; Fibrinolytic Agents; Humans; Ions; Ischemic Stroke; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 34757546
DOI: 10.1007/s11239-021-02600-6 -
Molecular Cancer Oct 2023Vascular invasion is a major route for intrahepatic and distant metastasis in hepatocellular carcinoma (HCC) and is a strong negative prognostic factor. Circular RNAs...
BACKGROUND
Vascular invasion is a major route for intrahepatic and distant metastasis in hepatocellular carcinoma (HCC) and is a strong negative prognostic factor. Circular RNAs (circRNAs) play important roles in tumorigenesis and metastasis. However, the regulatory functions and underlying mechanisms of circRNAs in the development of vascular invasion in HCC are largely unknown.
METHODS
High throughput sequencing was used to screen dysregulated circRNAs in portal vein tumor thrombosis (PVTT) tissues. The biological functions of candidate circRNAs in the migration, vascular invasion, and metastasis of HCC cells were examined in vitro and in vivo. To explore the underlying mechanisms, RNA sequencing, MS2-tagged RNA affinity purification, mass spectrometry, and RNA immunoprecipitation assays were performed.
RESULTS
circRNA sequencing followed by quantitative real-time PCR (qRT-PCR) revealed that circRNA pleckstrin and Sect. 7 domain containing 3 (circPSD3) was significantly downregulated in PVTT tissues. Decreased circPSD3 expression in HCC tissues was associated with unfavourable characteristics and predicted poor prognosis in HCC. TAR DNA-binding protein 43 (TDP43) inhibited the biogenesis of circPSD3 by interacting with the downstream intron of pre-PSD3. circPSD3 inhibited the intrahepatic vascular invasion and metastasis of HCC cells in vitro and in vivo. Serpin family B member 2 (SERPINB2), an endogenous bona fide inhibitor of the urokinase-type plasminogen activator (uPA) system, is the downstream target of circPSD3. Mechanistically, circPSD3 interacts with histone deacetylase 1 (HDAC1) to sequester it in the cytoplasm, attenuating the inhibitory effect of HDAC1 on the transcription of SERPINB2. In vitro and in vivo studies demonstrated that circPSD3 is a promising inhibitor of the uPA system.
CONCLUSIONS
circPSD3 is an essential regulator of vascular invasion and metastasis in HCC and may serve as a prognostic biomarker and therapeutic target.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; RNA, Circular; Urokinase-Type Plasminogen Activator; RNA; Plasminogen Activator Inhibitor 2; Gene Expression Regulation, Neoplastic
PubMed: 37884951
DOI: 10.1186/s12943-023-01882-z