Lozano Almela, María Luisa

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Lozano Almela, María Luisa

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Lozano Almela, María Luisa

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Universidad de Murcia. Departamento de Medicina

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Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor
(Elsevier, 2005) Lozano Almela, María Luisa; Castillo, J.; Benavente-García, O.; Vicente, Vincente; Rivera Pozo, José; Guerrero López, José Antonio; Medicina Interna; Facultad de Medicina
Background: Dietary flavonoids are known for their antiplatelet activity resulting in cardiovascular protection, although the specific mechanisms by which this inhibition occurs has not been fully established. Objective: The aim of this study was to Investigate the interaction of nine flavonoids representative of various chemical classes, with platelet responses dependent on thromboxane A2 (TxA2) generation and on receptor antagonism, and to analyze the structural requirements for such effects. Methods: The effect of several types of flavonoids on platelet aggregation, serotonin release, andTxA2generationwasinvestigated. Competitive radioligand binding assays were used to screen for affinity of these compounds to TxA2 receptors. Results: Flavones (apigeninand luteolin) and isoflavones (genistein) abrogated arachidonic acid and collagen-induced platelet responses, such as aggregation and secretion, with a less substantial effect on TxA2 synthesis. These compounds were identified as specific ligands of the TxA2 receptor in the lmol L)1 range, this effect accounting for antiplatelet effects related to stimulation with those agonists. Tight binding of flavonoids to the human TxA2 receptor relies on structural features such as the presence of the double bond in C2–C3, and a keto group in C4. Conclusions: The inhibition by specific flavonoids of in vitro platelet responses induced by collagen or arachidonic acid seems to be related, to a great extent, to their ability to compete for binding to the TxA2receptor. Therefore, antagonism of this TxA2 receptor may represent an additional mechanism for the inhibitory effect of these compounds in platelet function.
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Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR(1) and PAR(4) in platelets
(Wiley, British Pharmacological Society, 2009-10-28) Guerrero López, José Antonio; Navarro-Núñez, I.; Rivera Pozo, José; Martínez, C.; Vicente García, Vicente; Lozano Almela, María Luisa; Medicina Interna
Background and purpose: The modulation by flavonoids of platelet responses induced by thrombin has been little investigated, and the antiplatelet activity, as well as possible inhibitory mechanisms of these compounds on thrombin signalling, has not yet been elucidated. We explored whether flavonoids affect platelet signalling pathways triggered by thrombin and by the selective activation of its protease-activated receptors (PARs) 1 and 4, and analysed the antagonism of these polyphenols at thrombin receptors. Experimental approach: We investigated the effect of a range of polyphenolic compounds on platelet aggregation, 5-HT secretion, intracellular calcium mobilization, protein kinase activity and tyrosine phosphorylation, triggered by thrombin and PAR agonist peptides (PAR-APs). The ability of these flavonoids to bind to thrombin receptors was investigated by competitive radioligand binding assays using 125I-thrombin. Key results: Quercetin, apigenin and genistein impaired platelet aggregation, as well as 5-HT release and calcium mobilization, induced by thrombin and PAR-APs. Quercetin and apigenin were inhibitors of protein kinases, but genistein exhibited a minimal ability to suppress platelet phosphorylation. Binding assays did not establish any kind of interaction between thrombin receptors and any of the flavonoids tested. Conclusions and implications: Quercetin, apigenin and genistein did not inhibit thrombin responses by interacting with thrombin receptors, but by interfering with intracellular signalling. While inhibition by genistein may be a consequence of affecting calcium mobilization, subsequent platelet secretion and aggregation, for quercetin and apigenin, inhibition of kinase activation may also be involved in the impairment of platelet responses.
Open Access
Neutrophil extracellular traps and von Willebrand factor are allies that negatively influence COVID-19 outcomes
(Wiley, 2021-01) Águila Martínez, Sonia; Fernández-Pérez, M. P.; Reguilón-Gallego, L.; de Los Reyes-García, A. M.; Miñano, A.; Bravo-Pérez, C.; García-Barberá, N.; Gómez-Verdú, J. M.; Martínez, C.; Morena Barrio, María Eugenia de la; Corral de la Calle, Javier; Bernal Morell, Enrique; Herranz Marín, María Teresa; Vicente García, Vicente; González-Conejero Hilla, Rocío; Lozano Almela, María Luisa; Medicina Interna
Open Access
Flavonoids inhibit the platelet TxA2 signalling pathway and antagonize TxA2 receptors (TP) in platelets and smooth muscle cells
(Wiley, British Pharmacological Society, 2007-04-10) Guerrero López, José Antonio; Navarro-Nuñez, Leyre; Lozano Almela, María Luisa; Martínez, Constantino; Vicente García, Vicente; Gibbins, Jonathan M.; Rivera Pozo, José; Medicina Interna; Medicina; Facultad de Medicina
Aims: Flavonoids may affect platelet function by several mechanisms, including antagonism of TxA2 receptors (TP). These TP are present in many tissues and modulate different signalling cascades. We explored whether flavonoids affect platelet TP signalling, and if they bind to TP expressed in other cell types. Methods: Platelets were treated with flavonoids, or other selected inhibitors, and then stimulated with U46619. Similar assays were performed in aspirinized platelets activated with thrombin. Effects on calcium release were analysed by fluorometry and changes in whole protein tyrosine phosphorylation and activation of ERK 1/2 by Western blot analysis. The binding of flavonoids to TP in platelets, human myometrium and TPaand TPb-transfected HEK 293T cells was explored using binding assays and the TP antagonist 3H-SQ29548. Results: Apigenin, genistein, luteolin and quercetin impaired U46619-induced calcium mobilization in a concentration-dependent manner (IC50 10–30 mm). These flavonoids caused a significant impairment of U46619-induced platelet tyrosine phosphorylation and of ERK 1/2 activation. By contrast, in aspirin-treated platelets all these flavonoids, except quercetin, displayed minor effects on thrombin-induced calcium mobilization, ERK 1/2 and total tyrosine phosphorylation. Finally, apigenin, genistein and luteolin inhibited by >50% 3H-SQ29548 binding to different cell types. Conclusions: These data further suggest that flavonoids may inhibit platelet function by binding to TP and by subsequent abrogation of downstream signalling. Binding of these compounds to TP occurs in human myometrium and in TP-transfected HEK 293T cells and suggests that antagonism of TP might mediate the effects of flavonoids in different tissues.
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Evaluation of refrigerated platelet concentrates supplemented with low doses of second messenger effectors
(Wiley, 2004-07-27) Pérez Ceballos, Elena; Rivera Pozo, José; Lozano Almela, María Luisa; Candela, M.J.; Corral de la Calle, Javier; Guerrero López, José Antonio; Vicente García, Vicente; Medicina Interna
With the goal of producing haemostatically effective platelet concentrates (PCs) with a longer shelf-life, we aimed to identify a simple combination of platelet inhibitors, with a low pharmacological load, which could avoid the unacceptable loss of platelets stored under refrigerated conditions. PCs stored with different combinations of second messenger effectors were analysed at days 5, 10 and 15 of storage and compared with those supplemented with ThromboSol – a combination of six platelet inhibitors that protects cells from cold damage. The following parameters were analysed: platelet counts, biochemical parameters (glucose, pH, bicarbonate, lactate), cell lysis (lactic dehydrogenase, LDH), membrane glycoproteins (GPs), platelet aggregation, fibrinogen binding and hypotonic shock response. We characterized the combination of amiloride and sodium nitroprusside (at 1/2 the dose included in ThromboSol). This was found to be similar to ThromboSol and superior to nontreated units in the prevention of cold-induced platelet aggregation at day 15 of storage (maintenance of 78% and 80% of initial platelet counts, respectively), preservation of GPIba (11% and 12% better maintenance of mean fluorescence intensity compared with control units, respectively), and reduced cell lysis (13% and 11% decrease in supernatant LDH, respectively). The reduced pharmacological load with the identified solution compared with ThromboSol is an argument in favour of the potential use of these agents when designing strategies to improve PC storage.
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Latent and polymeric antithrombin: Clearance and potential thrombotic risk
(Frontiers Media, 2007) Guerrero López, José Antonio; Corral de la Calle, Javier; Rivera Pozo, José; Miñano, Antonia; Alberca, Ignacio; Hernández Espinosa, David; Ordóñez, Adriana; Martínez, Constantino; Navarro-Núñez, Leyre; González-Conejero Hilla, Rocío; Lozano Almela, María Luisa; Vicente García, Vicente; Medicina Interna