A5015160740- Platelet Disorders and Treatments
- Antiplatelet Therapy and Cardiovascular Diseases
- Blood Coagulation and Thrombosis Mechanisms
- Cell Adhesion Molecules Research
- Chronic Myeloid Leukemia Treatments
- Protein Tyrosine Phosphatases
- Receptor Mechanisms and Signaling
- Hemoglobinopathies and Related Disorders
- Complement system in diseases
- Synthesis and Characterization of Heterocyclic Compounds
- Adipokines, Inflammation, and Metabolic Diseases
- Computational Drug Discovery Methods
- Asthma and respiratory diseases
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Chemical Synthesis and Analysis
- Cardiovascular Disease and Adiposity
- Ion Channels and Receptors
- Cancer Risks and Factors
- Atrial Fibrillation Management and Outcomes
- Adipose Tissue and Metabolism
- Multiple Myeloma Research and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Respiratory and Cough-Related Research
- Venous Thromboembolism Diagnosis and Management
- Cytokine Signaling Pathways and Interactions
Universidade de Santiago de Compostela
2021-2024
Maastricht University
2019-2024
Center for Research in Molecular Medicine and Chronic Diseases
2021-2024
Instituto de Investigación Sanitaria de Santiago
2022-2023
Cardiovascular Institute Hospital
2023
Spanish National Centre for Cardiovascular Research
2019
Hepatocellular carcinoma (HCC) is the sixth most common cancer type and fourth leading cause of cancer-related death. This appears with higher incidence in men during obesity; however, specific mechanisms underlying this correlation are unknown. Adipose tissue, a key organ metabolic syndrome, shows evident gender disparities production adipokines. Levels important adipokine adiponectin decrease puberty, as well obese state. Here, we show that levels responsible for increased liver risk...
Abstract Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, clinical scientists to discuss origin potential consequences of thrombo-inflammation etiology, diagnostics, management patients with disease, including myocardial infarction, stroke, peripheral artery disease. This article presents state-of-the-art...
Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement the signaling collagen receptor glycoprotein (GP)VI, enforced integrin α2β1. Protein tyrosine kinase Syk central in GPVI-induced pathway, leading to elevated cytosolic Ca2+. We aimed determine Syk-mediated thrombogenic activity several peptides and (fibrillar) type I III collagens. High-shear perfusion blood over microspots these...
Red blood cells (RBCs) and platelets contribute to the coagulation capacity in bleeding thrombotic disorders. The thrombin generation (TG) process is considered reflect interactions between plasma various cells. Using a new high-throughput method capturing complete TG curve, we were able compare whole autologous platelet-rich platelet-poor redefine cell contributions clotting process. We report faster initially higher of shorter time than upon low concentrations coagulant triggers, including...
The plasmatic von Willebrand factor (VWF) circulates in a compact form unable to bind platelets. Upon shear stress, the VWF A1 domain is exposed, allowing VWF-binding platelet glycoprotein Ib-V-IX (GPIbα chain). For better understanding of role this interaction cardiovascular disease, molecules are needed specifically interfere with opened GPIbα. Therefore, we silico designed and chemically synthetized stable cyclic peptides interfering platelet-binding per se or complexed botrocetin....
Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of on thrombus formation induced by other TK-dependent receptors, and (2) coagulating Cardiovascular disease comorbidity in patients, resulting possible aspirin are associated with increased bleeding risk, therefore we also (3) synergistic these compounds fibrin formation. Blood or...
Antiplatelet drugs targeting G-protein-coupled receptors (GPCRs), used for the secondary prevention of arterial thrombosis, coincide with an increased bleeding risk. Targeting ITAM-linked receptors, such as collagen receptor glycoprotein VI (GPVI), is expected to provide a better antithrombotic-hemostatic profile. Here, we developed and characterized ultra-high-throughput (UHT) method based on intracellular [Ca2+]i increases differentiate GPVI GPCR effects platelets. In 96-, 384-, or...
Abstract The endothelial regulation of platelet activity is incompletely understood. Here we describe novel approaches to find molecular pathways implicated on the platelet–endothelium interaction. Using high‐shear whole‐blood microfluidics, employing coagulant or non‐coagulant conditions at physiological temperature, observed that presence human umbilical vein cells (HUVEC) strongly suppressed adhesion and activation, via collagen receptor glycoprotein VI (GPVI) PAR receptors for thrombin....
Distinct platelet activation patterns are elicited by the tyrosine kinase-linked collagen receptor glycoprotein VI (GPVI) and G-protein coupled protease-activated receptors (PAR1/4) for thrombin. This is reflected in different Ca2+ responses induced GPVI agonist collagen-related peptide (CRP) PAR1/4 Using a 96 well-plate assay with human Calcium-6-loaded platelets panel of 22 pharmacological inhibitors, we assessed cytosolic signaling domains these developed an automated curve algorithm. The...
The protein tyrosine phosphatase SHP2 (PTPN11) is a negative regulator of glycoprotein VI (GPVI)-induced platelet signal under certain conditions. Clinical trials with derivatives the allosteric drug SHP099, inhibiting SHP2, are ongoing as potential therapy for solid cancers. Gain-of-function mutations PTPN11 gene observed in part patients Noonan syndrome, associated mild bleeding disorder. Assessment effects inhibition platelets from controls and syndrome patients.Washed human were...
Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) cancer inhibit platelet function, minor reported symptoms. The aim this study was to compare properties eight TKIs explore their possible repurposing as drugs. Samples whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated TKI vehicle. Measurements aggregation, activation, intracellular calcium...
Linking the genetic background of patients with bleeding diathesis and altered platelet function remains challenging. We aimed to assess how a multiparameter microspot-based measurement thrombus formation under flow can help identify disorder. For this purpose, we studied 16 presenting and/or albinism suspected dysfunction 15 relatives. Genotyping revealed novel biallelic pathogenic variant in RASGRP2 (splice site c.240-1G>A), abrogating CalDAG-GEFI expression, compound heterozygosity...
Glycoprotein (GP)VI and integrin αIIbβ3 are key signaling receptors in collagen-dependent platelet aggregation arterial thrombus formation under shear. The multiple downstream pathways still poorly understood. Here, we focused on disclosing the integrin-dependent roles of focal adhesion kinase (protein tyrosine 2, PTK2), shear-dependent collagen receptor GPR56 (ADGRG1 gene), calcium integrin-binding protein 1 (CIB1). We designed synthetized peptides that interfered with αIIb binding (pCIB...
Abstract The platelet receptors, glycoprotein VI (GPVI) and integrin α2β1 jointly control collagen-dependent thrombus formation via protein tyrosine kinases. It is unresolved to which extent the ITIM (immunoreceptor tyrosine-based inhibitory motif) receptor PECAM1 its downstream acting phosphatase PTPN11 interfere in this process. Here, we hypothesized that has a co-regulatory role PECAM1- PTPN11-dependent restraint of formation. We investigated activation under flow on collagens with...
The platelet collagen receptor glycoprotein VI (GPVI) signals to activation of phospholipase Cγ2 (PLCγ2) and phosphoinositide 3-kinases (PI3K), causing aggregation. non-receptor Src homology tyrosine phosphatases Shp1/2 modulate GPVI signaling in partly opposite ways, both which are targeted by the potential drug NSC87877. Effect measurements inhibitor NSC87877 on via using light transmission aggregometry, Ca2+ flux assay, western blotting flow cytometry. selective PI3K TGX221. Inhibition...