RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Thrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. AIM OF THE STUDY: This work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. MATERIALS AND METHODS: Systematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. RESULTS: A total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3ß-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than -5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. CONCLUSION: Our integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.
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Fibrinolíticos , Metabolómica , Simulación del Acoplamiento Molecular , Farmacología en Red , Ratas Sprague-Dawley , Trombosis , Animales , Fibrinolíticos/farmacología , Fibrinolíticos/química , Fibrinolíticos/aislamiento & purificación , Ratas , Masculino , Trombosis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/químicaRESUMEN
BACKGROUND: While surgery still remains the gold standard treatment for mechanical prosthetic valve thrombosis (MPVT) by many guidelines, the ultraslow low-dose thrombolytic regimen has been reported as a promising alternative. METHODS: In this prospective single-center cohort, patients with acute MPVT were treated with an ultraslow low-dose thrombolytic regimen consisting of 25 mg infusion of recombinant tissue-type plasminogen activator (rtPA) over 25 h. The regimen could be repeated in case of failure until resolution/occurrence of adverse events or a maximum cumulative dose of 150 mg. The primary outcome was the complete MPVT resolution rate; other outcomes included first-dose success rate, major bleeding, thromboembolic events, mortality, and total thrombolytic dose/duration. RESULTS: Between April 2018 to January 2024, 135 episodes of acute MPVT were treated with an ultraslow low-dose thrombolytic regimen in 118 patients. In 118/135 (87.4 %) episodes, right-sided prosthetic valve was involved. Complete success was achieved in 88.1 % of cases, with 39.5 % responding after the first dose. The median total dose was 50 mg over a median of 30 h. Only one fatal intracranial hemorrhage occurred (0.7 %), with no other bleeding or thromboembolic complications. CONCLUSION: The ultraslow low-dose thrombolytic regimen appears to exhibit high efficacy and acceptable safety in treating acute MPVT. Further large clinical trials are essential for validating these preliminary findings.
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Fibrinolíticos , Prótesis Valvulares Cardíacas , Terapia Trombolítica , Trombosis , Humanos , Femenino , Masculino , Estudios Prospectivos , Terapia Trombolítica/métodos , Prótesis Valvulares Cardíacas/efectos adversos , Persona de Mediana Edad , Trombosis/tratamiento farmacológico , Trombosis/etiología , Fibrinolíticos/administración & dosificación , Fibrinolíticos/uso terapéutico , Anciano , Estudios de Cohortes , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Resultado del Tratamiento , Enfermedad AgudaAsunto(s)
Hidroxicloroquina , Lupus Eritematoso Sistémico , Inhibidores de Agregación Plaquetaria , Trombosis , Humanos , Hidroxicloroquina/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Trombosis/tratamiento farmacológico , Trombosis/etiología , Femenino , Adulto , Masculino , Antirreumáticos/uso terapéutico , Persona de Mediana EdadRESUMEN
AIMS: Cancer-related thrombosis (CAT) is a common complication in cancer patients, significantly impacting their quality of life and survival prospects. Nattokinase (NK) has potent thrombolytic properties, however, its efficacy is limited by low oral bioavailability and the risk of severe allergic reactions with intravenous use. Heparin (HP) is a widely used anticoagulant in clinical settings. This study aimed to overcome the intravenous toxicity of NK and explore its effect on CAT in advanced tumors. MAIN METHODS: In this study, NK-HP electrostatic complexes were constructed, and their safety and thrombolytic efficacy were verified through guinea pig allergy tests, mouse tail vein tests, and both in vivo and in vitro thrombolysis experiments. Additionally, an S180 advanced tumor model was developed and combined with sialic acid-modified doxorubicin liposomes (DOX-SAL) to investigate the impact of NK-HP on CAT and its antitumor effects in advanced tumors. KEY FINDINGS: We observed that NK-HP can eliminate the intravenous injection toxicity of NK, has strong thrombolytic performance, and can prevent thrombosis formation. Intravenous injection of NK-HP can enhance the antitumor effect of DOX-SAL by reducing the fibrin content in advanced tumors and increasing the levels of the cross-linked protein degradation product D-dimer. SIGNIFICANCE: This study developed a method to eliminate the intravenous injection toxicity of NK, proposing a promising therapeutic strategy for CAT treatment, particularly for CAT in advanced tumors, and improving the efficacy of nano-formulations in anti-tumor therapy.
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Heparina , Neoplasias , Subtilisinas , Trombosis , Animales , Subtilisinas/administración & dosificación , Ratones , Trombosis/tratamiento farmacológico , Inyecciones Intravenosas , Heparina/administración & dosificación , Neoplasias/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacología , Electricidad Estática , Cobayas , Masculino , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Liposomas , HumanosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Every year, cardiovascular diseases (CVDs) account for about 17.9 million deaths, making them the primary cause of both morbidity and mortality. Conventional drugs, which are often prescribed to treat cardiovascular diseases, are costly and have adverse effects. Consequently, dietary modifications and other medications are needed. Traditional use of Solanum indicum as cardiotonic to treat hypertension and anticoagulant potency has been reported but poorly evaluated scientifically. AIM OF THE STUDY: This study investigated the in vivo anticoagulant activity and mechanism of anticoagulation of quercetin (QC), a bioactive compound isolated from S. indicum (SI) hydroethanolic fruit extract. MATERIALS AND METHODS: Bioassay-guided fractionation (anticoagulant activity) extracted QC from hydroethanolic SI extract. QC was extensively characterized biochemically and pharmacologically. The interaction between QC and thrombin was investigated using spectrofluorometric and isothermal calorimetric methods. Cytotoxicity, antiplatelet, and thrombolytic studies were carried out in vitro. The Swiss albino mice were used to assess the in vivo, anticoagulant, and antithrombotic activities of QC. RESULTS: QC exhibits anticoagulant activity via (i) uncompetitive inhibition of thrombin but not FXa with a Ki value of 33.11 ± 4.2 µM and (ii) a partial inhibition of thrombin-catalyzed platelet aggregation with an IC50 value of 13.2 ± 1.2 µM. The experimental validation of the in silico study's prediction of QC's binding to thrombin was confirmed by spectrofluorometric and isothermal calorimetric analyses. QC was nontoxic to mammalian, non-hemolytic cells and demonstrated thrombolytic activity by activating plasminogen. QC demonstrated in vivo anticoagulant efficacy, preventing k-carrageen-induced thrombus formation in mice's tails. In the acute circulatory stasis paradigm in mice, QC reduces thromboxane B2 (TXB2) and endothelin-1 (ET-1) while increasing nitric oxide synthase (eNOS) and 6-keto prostaglandin F1α (6-keto-PGF1 α). CONCLUSION: Effective in vivo anticoagulant and antithrombotic properties of S. indicum's bioactive component QC point to the plant's potential use as a herbal anticoagulant medication for preventing and treating cardiovascular diseases linked to thrombosis.
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Anticoagulantes , Fibrinolíticos , Extractos Vegetales , Agregación Plaquetaria , Quercetina , Solanum , Animales , Quercetina/farmacología , Quercetina/aislamiento & purificación , Ratones , Fibrinolíticos/farmacología , Fibrinolíticos/aislamiento & purificación , Solanum/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Anticoagulantes/farmacología , Anticoagulantes/aislamiento & purificación , Humanos , Agregación Plaquetaria/efectos de los fármacos , Masculino , Plantas Medicinales/química , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Frutas/química , Trombina , Simulación del Acoplamiento Molecular , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Coagulación Sanguínea/efectos de los fármacosRESUMEN
Thrombotic diseases, emerging as a global public health hazard with high mortality and disability rates, pose a significant threat to human health and longevity. Although current antithrombotic therapies are effective in treating these conditions, they often carry a substantial risk of bleeding, highlighting the urgent need for safer therapeutic alternatives. Recent evidence has increasingly pointed to a connection between elastase activity and thrombosis. In the current study, we investigated the antithrombotic effects of ShSPI, an elastase inhibitor peptide derived from the venom of Scolopendra hainanum. Results showed that ShSPI significantly attenuated carrageenan-induced thrombosis in vivo. Furthermore, ShSPI effectively inhibited the carrageenan-induced decrease in serum superoxide dismutase (SOD) activity and increase in prothrombin time, fibrinogen level, and endothelial nitric oxide synthase (eNOS) activity. In addition, ShSPI reduced intracerebral thrombosis and improved functional outcomes following ischemic stroke in a transient middle cerebral artery occlusion (tMCAO) mouse model. Collectively, these findings suggest that ShSPI is a promising candidate for the development of novel thrombotic therapies.
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Accidente Cerebrovascular Isquémico , Trombosis , Animales , Ratones , Trombosis/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Masculino , Modelos Animales de Enfermedad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Superóxido Dismutasa/metabolismo , Ratones Endogámicos C57BL , Carragenina , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéuticoRESUMEN
Thrombosis is the primary cause of death in patients with cancer. Resveratrol inhibits platelet activation, a crucial pathophysiological basis of thrombosis, in healthy individuals. However, its effects and mechanisms of action in patients with colon cancer remain unknown. Here, we investigated the effect of resveratrol on platelet adhesion and aggregation in patients with colon cancer. Through numerous in vitro and in vivo analyses, including flow cytometry, western blotting, ELISA, and immunofluorescence and colon cancer rat models, we demonstrated that resveratrol reduced thrombosis in patients with colon cancer by inhibiting the phosphorylation of the MAPK and activating the cyclic-GMP/vasodilator-stimulated phosphoprotein pathway. These findings demonstrate the potential of resveratrol in reducing thrombosis in patients with colon cancer and could be used to develop novel therapeutic strategies for this condition.
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Moléculas de Adhesión Celular , Neoplasias del Colon , GMP Cíclico , Fosfoproteínas , Activación Plaquetaria , Resveratrol , Trombosis , Resveratrol/farmacología , Resveratrol/uso terapéutico , Trombosis/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/complicaciones , Humanos , Animales , Activación Plaquetaria/efectos de los fármacos , Masculino , Ratas , GMP Cíclico/metabolismo , Moléculas de Adhesión Celular/metabolismo , Fosfoproteínas/metabolismo , Femenino , Estilbenos/farmacología , Estilbenos/uso terapéutico , Ratas Sprague-Dawley , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Proteínas de MicrofilamentosRESUMEN
Thrombotic cardiovascular diseases are a prevalent factor contributing to both physical impairment and mortality. Thrombolysis and ischemic mitigation have emerged as leading contemporary therapeutic approaches for addressing the consequences of ischemic injury and reperfusion damage. Herein, an innovative cellular-cloaked spermatozoon-driven microcellular submarine (SPCS), comprised of multimodal motifs, was designed to integrate nano-assembly thrombolytics with an immunomodulatory ability derived from innate magnetic hyperthermia. Rheotaxis-based navigation was utilized to home to and cross the clot barrier, and finally accumulate in ischemic vascular organs, where the thrombolytic motif was "switched-on" by the action of thrombus magnetic red blood cell-driven magnetic hyperthermia. In a murine model, the SPCS system combining innate magnetic hyperthermia demonstrated the capacity to augment delivery efficacy, produce nanotherapeutic outcomes, exhibit potent thrombolytic activity, and ameliorate ischemic tissue damage. These findings underscore the multifaceted potential of our designed approach, offering both thrombolytic and ischemia-mitigating effects. Given its extended therapeutic effects and thrombus-targeting capability, this biocompatible SPCS system holds promise as an innovative therapeutic agent for enhancing efficacy and preventing risks after managing thrombosis.
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Isquemia , Espermatozoides , Trombosis , Animales , Masculino , Ratones , Isquemia/terapia , Espermatozoides/efectos de los fármacos , Trombosis/tratamiento farmacológico , Terapia Trombolítica/métodos , Hipertermia Inducida/métodos , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Fibrinolíticos/química , Humanos , Ratones Endogámicos C57BLRESUMEN
According to the importance of time in treatment of thrombosis disorders, faster than current treatments are required. For the first time, this research discloses a novel strategy for rapid dissolution of blood clots by encapsulation of a fibrinolytic (Reteplase) into a Thrombin sensitive shell formed by polymerization of acrylamide monomers and bisacryloylated peptide as crosslinker. Degradability of the peptide units in exposure to Thrombin, creates the Thrombin-sensitive Reteplase nanocapsules (TSRNPs) as a triggered release system. Accelerated thrombolysis was achieved by combining three approaches including: deep penetration of TSRNPs into the blood clots, changing the clot dissolution mechanism by altering the distribution pattern of TSRNPs to 3D intra-clot distribution (based on the distributed intra-clot thrombolysis (DIT) model) instead of peripheral and unidirectional distribution of unencapsulated fibrinolytics and, enzyme-stimulated release of the fibrinolytic. Ex-vivo study was carried out by an occluded tube model that mimics in-vivo brain stroke as an emergency situation where faster treatment in short time is a golden key. In in vivo, efficacy of the developed formulation was confirmed by PET scan and laser Doppler flowmetry (LDF). As the most important achievements, 40.0 ± 0.7 (n = 3) % and 37.0 ± 0.4 (n = 3) % reduction in the thrombolysis time (faster reperfusion) were observed by ex-vivo and in-vivo experiments, respectively. Higher blood flow and larger digestion mass of clot at similar times in comparison to non-encapsulated Reteplase were observed that means more effective thrombolysis by the developed strategy.
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Fibrinolíticos , Trombina , Terapia Trombolítica , Activador de Tejido Plasminógeno , Fibrinolíticos/administración & dosificación , Fibrinolíticos/química , Fibrinolíticos/farmacología , Animales , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/administración & dosificación , Trombina/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Péptidos/química , Péptidos/administración & dosificación , Polímeros/química , Trombosis/tratamiento farmacológico , Masculino , Liberación de Fármacos , Nanopartículas/químicaRESUMEN
A 48-year-old man with a history of mitral valve replacement (MVR) in March 2019 for rheumatic heart disease (RHD) and ischemic stroke in August 2019 presented with a history of sudden onset angina of 6 hours duration. He admits to defaulting oral anticoagulant (OAC) intake for the last 50 days. On arrival, he had atrial fibrillation with hemodynamic instability [blood pressure (BP) 70/40 mm Hg, saturation of peripheral oxygen (SpO2) 80% at room air and heart rate approx 140/minute], which was managed with intravenous diltiazem and hemodynamic stability achieved (BP 116/72 mm Hg, heart rate 86/minute). Urgent transthoracic echocardiogram (TTE) and fluoroscopy confirmed obstructive prosthetic mitral valve thrombosis. Though available recommendations suggest surgical intervention for the left-sided valve involvement in a stable patient, in view of the nonavailability of a surgical facility, the patient was thrombolyzed with Alteplase, a recombinant tissue plasminogen activator (rtPA). Since the patient was stable, a "long fibrinolytic protocol" of Alteplase 10 mg bolus, 50 mg during the 1st hour, and 20 mg each during the 2nd and 3rd hour (total of 100 mg) was given. Subsequent TTE revealed a mean gradient of 5 mm Hg, and cine fluoroscopy showed improved mitral valve motion, thereby indicating successful thrombolysis. The patient felt symptomatically relieved within 6 hours and is presently on OAC therapy with strict drug compliance.
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Fibrinolíticos , Prótesis Valvulares Cardíacas , Válvula Mitral , Trombosis , Activador de Tejido Plasminógeno , Humanos , Masculino , Persona de Mediana Edad , Activador de Tejido Plasminógeno/uso terapéutico , Fibrinolíticos/uso terapéutico , Fibrinolíticos/administración & dosificación , Trombosis/tratamiento farmacológico , Trombosis/etiología , Prótesis Valvulares Cardíacas/efectos adversos , Válvula Mitral/cirugía , Terapia Trombolítica/métodos , Cardiopatía Reumática/complicaciones , Cardiopatía Reumática/tratamiento farmacológico , EcocardiografíaRESUMEN
The use of antithrombotic agents is increasing in infants, children and adolescents. The more recent routine inclusion of children in FDA-monitored clinical trials has propelled the rapid accumulation of safety and efficacy data on these agents in pediatric patients. Antithrombotic agents in current use include indirect or antithrombin-dependent anticoagulants, intravenous direct thrombin inhibitors, direct oral anticoagulants (DOACs) targeting thrombin or factor Xa, antiplatelet agents and thrombolytic therapies. Each class of antithrombotic agent has distinct mechanisms of action, clearance routes, half-lives, safety and dosing. Anticoagulant efficacy is dependent upon the specific clinical indication and stability of the pediatric patient. Duration of anticoagulant course is also dependent upon the clinical indication as well as rate of thrombus resolution. This manuscript reviews the mechanism of action, route of administration, route of clearance and plasma half-life for the antithrombotic agents in current use in children. Use of anticoagulation in the context of thrombolytic therapy is discussed.
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Anticoagulantes , Humanos , Niño , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Adolescente , Lactante , Preescolar , Resultado del Tratamiento , Factores de Edad , Coagulación Sanguínea/efectos de los fármacos , Trombosis/tratamiento farmacológico , Trombosis/sangre , Terapia Trombolítica/efectos adversos , Recién Nacido , Fibrinolíticos/efectos adversos , Fibrinolíticos/administración & dosificación , Hemorragia/inducido químicamente , Factores de Riesgo , Administración OralAsunto(s)
COVID-19 , Fibrinolíticos , Guías de Práctica Clínica como Asunto , Humanos , COVID-19/complicaciones , Fibrinolíticos/uso terapéutico , Fibrinolíticos/administración & dosificación , SARS-CoV-2 , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , Trombosis/sangreAsunto(s)
COVID-19 , Fibrinolíticos , Guías de Práctica Clínica como Asunto , Humanos , COVID-19/complicaciones , COVID-19/sangre , Fibrinolíticos/uso terapéutico , Fibrinolíticos/efectos adversos , Fibrinolíticos/administración & dosificación , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , Trombosis/sangreRESUMEN
The development of thrombolytic drug carriers capable of thrombus-targeting, prolonged circulation time, intelligent responsive release, and the ability to inhibit thrombotic recurrences remains a promising but significant challenge. To tackle this, an artificial polysaccharide microvesicle drug delivery system (uPA-CS/HS@RGD-ODE) was constructed. It is composed of cationic chitosan and anionic heparin assembled in a layer by layer structure, followed by surface modification using RGD peptide and 2-(N-oxide-N,N-diethylamino) ethylmethacrylate (ODE) before encapsulation of urokinase-type plasminogen activator (uPA). The effect of chitosan on the basic performances of uPA-CS/HS@RGD-ODE was estimated. The in vitro results suggest the uPA carrier, CS/HS@RGD-ODE, displayed outstanding targeting specific to activated platelets (61 %) and microenvironment-responsiveness at pH 6.5, facilitating thrombus-targeting and a controlled drug release, respectively. Most importantly, in vivo experiment suggests ODE from uPA-CS/HS@RGD-ODE substantially extends the half-life of uPA (120 min), as uPA-CS/HS@RGD-ODE can adhere onto erythrocytes and deliver uPA under cover of erythrocytes enabling a prolonged circulation time in the bloodstream. Further tail vein and abdominal aorta thrombosis models confirmed uPA-CS/HS@RGD-ODE exhibited superior targeting and thrombolysis capabilities compared to systemic administration of free uPA. To the knowledge of authors, this may be the first study to develop new drug carriers for delivery of thrombolytic drugs under the cover of erythrocytes for extended drug half-lives.
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Quitosano , Portadores de Fármacos , Eritrocitos , Fibrinolíticos , Trombosis , Activador de Plasminógeno de Tipo Uroquinasa , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Quitosano/química , Quitosano/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Portadores de Fármacos/química , Fibrinolíticos/química , Fibrinolíticos/farmacología , Trombosis/tratamiento farmacológico , Liberación de Fármacos , Terapia Trombolítica/métodos , Heparina/química , Heparina/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Humanos , Semivida , Ratones , Sistemas de Liberación de Medicamentos/métodos , Masculino , Polisacáridos/química , Polisacáridos/farmacologíaRESUMEN
There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs' long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi.
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Terapia Trombolítica , Trombosis , Activador de Tejido Plasminógeno , Animales , Activador de Tejido Plasminógeno/uso terapéutico , Humanos , Trombosis/diagnóstico por imagen , Trombosis/tratamiento farmacológico , Masculino , Ratas , Terapia Trombolítica/métodos , Trampas Extracelulares/metabolismo , Porcinos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/farmacología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Fibrina/metabolismo , Nanomedicina Teranóstica/métodos , Resistencia a Medicamentos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
ETHNO-PHARMACOLOGICAL RELEVANCE: Huangqi Gegen decoction (HGD), which comprises Astragali Radix (AR) and Puerariae Radix (PR), is widely used to treat thrombosis in China. However, the mechanism underlying its synergistic effect in thrombosis treatment remains unclear. AIM OF THE STUDY: Following PR administration, low plasma exposure was reported for its primary ingredients. In this regard, this study examined the effect of AR on PR's antithrombotic efficacy with respect to the impact of Astragalus Polysaccharide (APS) on the oral delivery of Puerarin (PUE). MATERIALS AND METHODS: To evaluate the synergistic effect of HGD, a thrombus mice model was established via intraperitoneal injection of carrageenan. After treatment, histopathological observations were made, and the proportion of thrombus length in the tail, as well as the plasma APTT, PT, INR, and FIB levels, were detected. Molecular docking was employed to assess the PR ingredients that could inhibit the HMGB1/NF-κB/NLRP3 pathway. The Pharmacokinetics of PR ingredients in rats were also compared between the PR and HGD groups. Moreover, the effect of APS on the solubility, intestinal absorption, and pharmacokinetics of PUE was evaluated. Furthermore, the impact of APS on the antithrombotic efficacy of PUE was assessed. RESULTS: In mice, AR enhanced the antithrombotic effect of PR. This improved PR effect was associated with isoflavones-induced downregulation of the HMGB1/NF-κB/NLRP3 pathway. The synergistic effect resulting from the compatibility of HGD components was primarily achieved by improving the plasma exposure of PR isoflavones. Specifically, APS enhanced PUE's water solubility through the formation of self-assembly Nanoparticles, increasing its intestinal absorption and oral bioavailability, which, in turn, suppressed the HMGB1/NF-κB/NLRP3 pathway, thus improving its antithrombotic effect. CONCLUSIONS: Our findings revealed that APS improved PUE's plasma exposure, enhancing its inhibitory effect on the HMGB1/NF-κB/NLRP3 pathway. This mechanism presents a key aspect of the synergistic effect of HGD compatibility in thrombosis treatment.
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Planta del Astrágalo , Sinergismo Farmacológico , Medicamentos Herbarios Chinos , Isoflavonas , Polisacáridos , Trombosis , Animales , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Isoflavonas/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Polisacáridos/farmacología , Polisacáridos/administración & dosificación , Masculino , Administración Oral , Trombosis/tratamiento farmacológico , Ratones , Planta del Astrágalo/química , Fibrinolíticos/farmacología , Fibrinolíticos/administración & dosificación , Pueraria/química , Modelos Animales de Enfermedad , Simulación del Acoplamiento Molecular , Astragalus propinquus/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
INTRODUCTION: Balancing the prevention of thrombosis with bleeding risk when combining anticoagulants and platelet antagonists remains a concern among clinicians, particularly in patients with acute coronary syndrome (ACS) who are treated with potent antiplatelet therapy. This may be because the available antiplatelet and anticoagulants are unable to uncouple physiological hemostasis and pathological thrombosis. Therefore, their use is associated with an unavoidable elevated risk of bleeding. AREAS COVERED: Evidence available from studies evaluating FXIa inhibitors and milvexian was collected from a selective literature search. In this review, the authors describe the potential role of FXI/XIa in experimental thrombosis, evidence for FXIa inhibition in the treatment of clinical thrombotic events, and highlight the current evidence supporting the role of milvexian, a novel FXIa inhibitor, in patients with ACS. EXPERT OPINION: The ongoing LIBREXIA-ACS trial is a large-scale study currently investigating milvexian in patients with ACS. This study may support the proof of concept of differentiating physiological hemostasis and pathological thrombosis and achieving maximum antithrombotic efficacy with minimum bleeding risk when used on top of dual antiplatelet therapy with potent P2Y12 receptor blockers.
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Síndrome Coronario Agudo , Factor XIa , Hemorragia , Inhibidores de Agregación Plaquetaria , Trombosis , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Hemorragia/inducido químicamente , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Factor XIa/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Animales , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversosRESUMEN
Thrombosis is the formation of abnormal blood clots in the blood vessels that obstruct blood flow and lead to thrombosis. Current treatments for thrombosis are associated with serious side effects. Therefore there is a need for alternative natural therapy. A fibrinolytic protease was isolated from fresh leaves of Moringa oleifera Lam. and characterized for its potential to solubilize blood clots and hydrolyse fibrin under in-vitro conditions. The isolated protease showed a single protein band on native-PAGE. It showed optimum fibrinolytic activity at pH 8.0, 37 oC with 50 µg protein. The fibrinolytic activity of isolated protease was also confirmed by fibrin zymography. Km and Vmax of isolated protease were determined by the Lineweaver Burk plot. The isolated protease could solubilize 96.41% of blood clots by 96 h under in-vitro conditions. In-vitro fibrin hydrolysis and blood clot solubilization activities shown by an isolated protease from leaves of Moringa oleifera Lam. suggest its fibrinolytic potential to dissolve blood clots. Being a natural molecule and from a dietary plant it can be explored as an alternative natural therapy against thrombosis.
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Fibrina , Moringa oleifera , Péptido Hidrolasas , Proteínas de Plantas , Moringa oleifera/química , Fibrina/metabolismo , Fibrina/química , Péptido Hidrolasas/química , Péptido Hidrolasas/metabolismo , Hidrólisis , Proteínas de Plantas/química , Proteínas de Plantas/farmacología , Proteínas de Plantas/aislamiento & purificación , Fibrinolíticos/química , Fibrinolíticos/farmacología , Fibrinolíticos/aislamiento & purificación , Humanos , Trombosis/tratamiento farmacológico , Hojas de la Planta/química , Fibrinólisis/efectos de los fármacos , SolubilidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS) are the major effective components of Panax notoginseng (burk) F.H.Chen which is one of the classic promoting blood circulation herbs in traditional Chinese medicine. PNS is widely used in China for the treatment of cerebral ischemic stroke. Pathological low shear stress is a causal factor in endothelial inflammation and thrombosis. However, the mechanism of PNS against low shear related endothelial inflammation is still unclear. AIM TO THE STUDY: This study aims to investigate the effects of PNS against endothelial inflammation induced by low shear stress and to explore the underlying mechanical and biological mechanisms. MATERIALS AND METHODS: Mouse model of carotid partial ligation for inducing low endothelial shear stress was established, the pharmacodynamic effect and mechanism of PNS against endothelial inflammation induced by low shear stress through Piezo1 were explored. Yoda1-evoked Piezo1 activation and expression in human umbilical vein endothelial cells (HUVECs) were determined at static condition. Microfluidic channel systems were used to apply shear stress on HUVECs and Piezo1 siRNA HUVECs to determine PECAM-1, p-YAP and VCAM-1 expression. And platelet rich plasma (PRP) was introduced to low shear treated endothelial cells surface to observe the adhesion and activation by fluorescence imaging and flowcytometry. RESULTS: PNS attenuated endothelial inflammation and improved blood flow in a reasonable dose response pattern in carotid partial ligation mouse model by influencing Piezo1 and PECAM-1 expression, while suppressing yes-associated protein (YAP) nuclear translocation. We found Piezo1 sensed abnormal shear stress and transduced these mechanical signals by different pathways in HUVECs, and PNS relieved endothelial inflammation induced by low shear stress through Piezo1. We also found Piezo1 signalling has interaction with PECAM-1 under low shear stress, which were involved in platelets adhesion to endothelial cells. Low shear stress increased YAP nuclear translocation and increased VCAM-1 expression in HUVECs which might activate platelets. PNS inhibited low shear induced Piezo1 and PECAM-1 expression and YAP nuclear translocation in HUVECs, furthermore inhibited platelet adhesion and activation on dysfunctional endothelial cells induced by low shear stress. CONCLUSION: PNS ameliorated endothelial inflammation and thrombosis induced by low shear stress through modulation of the Piezo1 channel, PECAM-1 expression, and YAP nuclear translocation. PNS might serve as a potential therapeutic candidate for ameliorating endothelial inflammation induced by abnormal blood shear stress.