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Biomaterials Dec 2023Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous...
Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous injection of tissue plasminogen activator-like proteins are the bleeding complication and the dose related neurotoxicity. Indeed, the drug has to be injected in high concentrations due to its short half-life, the presence of its natural blood inhibitor (PAI-1) and the fast hepatic clearance (0.9 mg/kg in humans, 10 mg/kg in mouse models). Overall, there is a serious need for a dose-reduced targeted treatment to overcome these issues. We present in this article a new acoustic cavitation-based method for polymer MBs synthesis, three times faster than current hydrodynamic-cavitation method. The generated MBs are ultrasound responsive, stable and biocompatible. Their functionalization enabled the efficient and targeted treatment of stroke, without side effects. The stabilizing shell of the MBs is composed of Poly-Isobutyl Cyanoacrylate (PIBCA), copolymerized with fucoidan. Widely studied for its targeting properties, fucoidan exhibit a nanomolar affinity for activated endothelium and activated platelets (P-selectins). Secondly, the thrombolytic agent (rtPA) was loaded onto microbubbles (MBs) with a simple adsorption protocol. Hence, the present study validated the in vivo efficiency of rtPA-loaded Fuco MBs to be over 50 % more efficient than regular free rtPA injection for stroke resolution. In addition, the relative injected rtPA grafted onto targeting MBs was 1/10th of the standard effective dose (1 mg/kg in mouse). As a result, no hemorrhagic event, BBB leakage nor unexpected tissue distribution were observed.
Topics: Humans; Animals; Mice; Tissue Plasminogen Activator; Microbubbles; Polymers; Fibrinolytic Agents; Stroke
PubMed: 37952499
DOI: 10.1016/j.biomaterials.2023.122385 -
Journal of Ethnopharmacology Jan 2024YangXueQingNaoWan (YXQNW), a compound Chinese medicine, has been widely used for dizziness, irritability, insomnia, and dreaminess caused by blood deficiency and liver...
ETHNOPHARMACOLOGICAL RELEVANT
YangXueQingNaoWan (YXQNW), a compound Chinese medicine, has been widely used for dizziness, irritability, insomnia, and dreaminess caused by blood deficiency and liver hyperactivity in China. However, whether YXQNW can inhibit cerebral microvascular exudation and cerebral hemorrhage (CH) caused by blood brain barrier (BBB) damage after tissue plasminogen activator (tPA) still unknown.
AIM OF THE RESEARCH
To observe the effect of YXQNW on cerebral microvascular exudation and CH after tPA and investigate its mechanism in protecting BBB.
MATERIALS AND METHODS
Male C57BL/6 N mice suffered from ischemia stroke by mechanical detachment of carotid artery thrombi with the stimulation of ferric chloride. Then mice were treated with tPA (10 mg/kg) and/or YXQNW (0.72 g/kg) at 4.5 h. Cerebral blood flow (CBF), infarct size, survival rate, neurological scores, gait analysis, Evans blue extravasation, cerebral water content, fluorescein isothiocyanate-labeled albumin leakage, hemorrhage, junction and basement membrane proteins expression, leukocyte adhesion and matrix metalloproteinases (MMPs) expression were evaluated 24 h after tPA. Proteomics was used to identify target proteins.
RESULTS
YXQNW inhibited cerebral infarction, neurobehavioral deficits, decreased survival, Evans blue leakage, albumin leakage, cerebral water content and CH after tPA thrombolysis; improved CBF, low-expression and degradation of junction proteins, basement membrane proteins, Arhgap21 and its downstream α-catenin and β-catenin proteins expression; and suppressed the increase of adherent leukocytes and the release of MMP-9 derived from macrophage.
CONCLUSION
YXQNW relieved BBB damage and attenuated cerebral microvascular exudation and CH after tPA thrombolysis. The effect of YXQNW on cerebral microvascular exudation was associated with the inhibition of the low-expression of junction proteins, especially AJs mediated by Rho GTPase-activating protein 21 (Arhgap21), while the effect on CH was associated with the inhibition of leukocyte adhesion, the release of MMP-9 derived from macrophage, and low-expression and degradation of collagen IV and laminin in the vascular basement membrane.
Topics: Male; Mice; Animals; Tissue Plasminogen Activator; Blood-Brain Barrier; Matrix Metalloproteinase 9; Evans Blue; Brain Ischemia; Mice, Inbred C57BL; Cerebral Hemorrhage; Cerebral Infarction; Ischemic Stroke; Thrombolytic Therapy; Albumins; Stroke
PubMed: 37572928
DOI: 10.1016/j.jep.2023.117024 -
Clinical Infectious Diseases : An... Mar 2024Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor...
BACKGROUND
Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor (suPAR) and olfactomedin 4, and mast cell mediators, chymase and tryptase, have not been measured longitudinally across the dengue phases. The utility of these proteins as prognostic biomarkers for severe dengue has also not been assessed in an older adult population.
METHODS
We prospectively enrolled 99 adults with dengue-40 dengue fever, 46 dengue with warning signs and 13 severe dengue, along with 30 controls. Plasma levels of suPAR, olfactomedin 4, chymase and tryptase were measured at the febrile, critical and recovery phases in dengue patients.
RESULTS
The suPAR levels were significantly elevated in severe dengue compared to the other dengue severities and controls in the febrile (P < .001), critical (P < .001), and recovery (P = .005) phases. In the febrile phase, suPAR was a prognostic biomarker of severe dengue, with an AUROC of 0.82. Using a cutoff derived from Youden's index (5.4 ng/mL) and an estimated prevalence of severe dengue (16.5%) in our healthcare institution, the sensitivity was 71.4% with a specificity of 87.9% in the febrile phase, and the positive and negative predictive values were 54.7% and 95.8%, respectively. Olfactomedin 4 was elevated in dengue patients but not in proportion to disease severity in the febrile phase (P = .04) There were no significant differences in chymase and tryptase levels between dengue patients and controls.
CONCLUSIONS
In adult dengue, suPAR may be a reliable prognostic biomarker for severe dengue in the febrile phase.
Topics: Humans; Aged; Receptors, Urokinase Plasminogen Activator; Biomarkers; Prognosis; Chymases; Tryptases; Severe Dengue; Glycoproteins; Extracellular Matrix Proteins
PubMed: 37823481
DOI: 10.1093/cid/ciad637 -
The New England Journal of Medicine Feb 2024
Topics: Humans; Brain Ischemia; Fibrinolytic Agents; Stroke; Tenecteplase; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 38329103
DOI: 10.1056/NEJMe2314930 -
Neurological Research Sep 2023This article aimed to analyze the relationship between obesity and the efficacy of acute ischaemic stroke patients treated with IVT. (Review)
Review
OBJECTIVES
This article aimed to analyze the relationship between obesity and the efficacy of acute ischaemic stroke patients treated with IVT.
BACKGROUND
Stroke causes morbidity and mortality in large numbers of individuals annually. Intravenous thrombolysis (IVT)with recombinant tissue plasminogen activator (r-tPA) is currently the only approved by the FDA for treatment of acute ischaemic stroke. Researchers have focused on studying the mechanisms associated with ischaemic stroke. Obesity is an established vascular risk factor with increasing prevalence and a huge impact on public health worldwide. It is an independent predictor for ischaemic stroke with a 4% risk increase for each unit augmentation in body mass index (BMI). Therefore, obese patients will constitute an increasing subgroup of candidates for IVT. However, its impact on prognosis in acute ischaemic stroke patients with intravenous thrombolysis did not reach a consensus conclusion.
METHODS
Systematic literature search of PUBMED databases published before August 2020, was performed to identify studies addressing the role of obesity in acute ischaemic stroke patients treated with IVT. Studies included randomized clinical trials, observational studies, guideline statements, and review articles.
CONCLUSIONS
Obesity may be related to long-term prognosis of large group of AIS patients treated with IVT. It depends on the scale of clinical study samples, follow-up time, and evaluation criteria.
Topics: Humans; Brain Ischemia; Fibrinolytic Agents; Ischemic Stroke; Obesity; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 34112057
DOI: 10.1080/01616412.2021.1939486 -
International Journal of Molecular... Sep 2023Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different...
Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA ( = 99) in Sweden were included, complemented by matched subjects with MI-CAD ( = 99) and controls ( = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively ( = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.
Topics: Humans; Coronary Artery Disease; Tissue Plasminogen Activator; Helicobacter pylori; MINOCA; Case-Control Studies; Seroepidemiologic Studies; Myocardial Infarction; Biomarkers
PubMed: 37762446
DOI: 10.3390/ijms241814143 -
Journal of Cellular and Molecular... Feb 2024Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease...
Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.
PubMed: 38386354
DOI: 10.1111/jcmm.18013 -
Clinical Neurology and Neurosurgery Oct 2023Alteplase is the standard medical therapy for acute ischemic stroke (AIS) patients who present within 4.5 h of symptom onset. Tenecteplase is a modified alteplase... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alteplase is the standard medical therapy for acute ischemic stroke (AIS) patients who present within 4.5 h of symptom onset. Tenecteplase is a modified alteplase variant with pharmacological and practical advantages over alteplase. Many trials have investigated the efficacy and safety of tenecteplase against alteplase. This systematic review and meta-analysis aimed to compare the efficacy and safety of tenecteplase to alteplase across randomized controlled trials.
METHOD
Medline, Embase, and Cochrane CENTRAL were used to search the related articles until February 20, 2023. Randomized controlled trials (RCTs) that compared the effectiveness and safety of tenecteplase against alteplase for AIS patients were included. Screening, risk of bias assessment, and data extraction were performed following PRISMA guidelines. Data were pooled using a random-effect model.
RESULTS
Ten RCTs were included, with a total of 5123 patients. There was no significant difference between the two interventions in modified rankin scale 0-1 (mRS 0-1) (RR= 1.04, 95% CI [0.99-1.10], P = 0.11, I =0%) and early neurological improvement (RR= 1.06, 95% CI [0.97-1.15], P = 0.21, I =35). There was no difference in the rates of symptomatic intracranial hemorrhage (RR= 1.18, 95% CI [0.84-1.65], P = 0.35, I = 0%). Tenecteplase was associated with significantly higher complete recanalization rate compared to alteplase (RR= 1.17, 95% CI [1.00-1.36], P = 0.05, I =0%). For large vessel occlusion (LVO) patients assigned to tenecteplase, there was a significant improvement in mRS 0-1 (RR= 1.28, 95% CI [1.07-1.52], P = 0.006, I =0%).
CONCLUSION
Based on our meta-analysis, tenecteplase has similar efficacy and safety to alteplase, with a more promising effect in patients with LVO.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Fibrinolytic Agents; Stroke; Brain Ischemia; Randomized Controlled Trials as Topic; Ischemic Stroke; Treatment Outcome
PubMed: 37713743
DOI: 10.1016/j.clineuro.2023.107961 -
Functional & Integrative Genomics Aug 2023It is well-established that breast cancer is a highly prevalent malignancy among women, emphasizing the need to investigate mechanisms underlying its pathogenesis and...
It is well-established that breast cancer is a highly prevalent malignancy among women, emphasizing the need to investigate mechanisms underlying its pathogenesis and metastasis. In this study, the Gene Expression Omnibus (GEO) database was utilized to conduct differential expression analysis in breast cancer and adjacent tissues. Upregulated genes were selected for prognostic analysis of breast cancer. The expression of urokinase plasminogen activator receptor (uPAR), also known as PLAUR, was assessed using RT-qPCR and western blot. Immunofluorescence staining was employed to determine PLAUR localization. Various cellular processes were analyzed, including proliferation, migration, invasion, apoptosis, and cell cycle. Bioinformatics analysis was used to predict transcription factors of PLAUR, which were subsequently validated in a double luciferase reporter gene experiment. Rescue experiments confirmed the impact of PLAUR on the proliferation, apoptosis, and migration of MDA-MB-231 cells. Furthermore, the effects of PLAUR were evaluated in an orthotopic tumor transplantation and lung metastasis nude mouse model. Our findings substantiated the critical involvement of PLAUR in the progression of triple-negative breast cancer (TNBC) in vitro and among TNBC patients with a poor prognosis. Additionally, we demonstrated Yin Yang-1 (YY1) as a notable transcriptional regulator of PLAUR, whose activation could transcriptionally enhance the proliferation and invasion capabilities of TNBC cells. We also identified the downstream mechanism of PLAUR associated with PLAU, focal adhesion kinase (FAK), and AKT. Overall, these findings offer a novel perspective on PLAUR as a potential therapeutic target for TNBC.
Topics: Animals; Female; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Signal Transduction; Triple Negative Breast Neoplasms; YY1 Transcription Factor; Receptors, Urokinase Plasminogen Activator
PubMed: 37552345
DOI: 10.1007/s10142-023-01193-y -
Blood Advances Nov 2023Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding...
Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value.
Topics: Humans; Fibrinolysis; Fibrin Clot Lysis Time; alpha-2-Antiplasmin; Fibrinolysin; Leukemia, Promyelocytic, Acute; Prospective Studies; Lymphoma; Thrombosis; Hematologic Neoplasms; Antifibrinolytic Agents; Urokinase-Type Plasminogen Activator; Amyloidosis; Plasminogen
PubMed: 37756519
DOI: 10.1182/bloodadvances.2023011379