Browsing by browse.metadata.contributordepartment "Medicina Interna"

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    Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure?
    (2004-12-16) González-Conejero Hilla, Rocío; Rivera Pozo, José; Corral de la Calle, Javier; Acuña, Carmen; Vicente, Vincente; Guerrero López, José Antonio; Medicina Interna; Facultad de Medicina
    Background and Purpose— The widespread use of aspirin requires clarification of the aspirin resistance phenomenon. Most studies on this field are focused on patients which may affect the action of aspirin. Methods— We evaluated the biological efficacy of aspirin in healthy subjects. Results— Agonist–induced platelet aggregation was fully abrogated by 100 mg of aspirin in all individuals. By contrast, with the platelet function analyzer-100 device, 33.3% of the subjects displayed no response. This failure was overcome by 500 mg or by in vitro treatment of blood with 30 μmol/L acetylsalicylic acid. Intake of 100 mg of aspirin efficiently reduced by 75% the level of 11-dehydro thromboxane B2 (11-dTxB2) in all cases. However, variability on the pre-aspirin level (range 72.4 to 625.9 ng/mmol creatinine) led to substantial differences in the residual amount of the metabolite between subjects treated with aspirin (range 12.9 to 118.0 ng/mmol creatinine). Finally, there was no influence of platelet glycoprotein IIb/IIIa (Pro33Leu), platelet glycoprotein Ia/IIa, (C807T), and FXIII (Val34Leu) polymorphisms on the efficacy of aspirin. However, the cyclooxygenase (Cox)-1 50T allele associated with higher level of 11-dTxB2, both before and after aspirin. Moreover, the Cox-2 −765C variant displayed a slightly higher reduction in 11-dTxB2 level on treatment with aspirin. Conclusions— Our findings suggest that full resistance of healthy subjects to aspirin is rather unlikely. However, differences in aspirin absorption, or pharmacokinetic, or other unrecognized factors may lead to lack of effect of low dose of aspirin in some subjects when using tests like platelet function analyzer-100. Whether Cox polymorphisms are thrombotic risk factor for patients under aspirin will require further research.
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    Cardiac Noradrenaline Turnover and Heat Shock Protein 27 Phosphorylation in Dyskinetic Monkeys.
    (Wiley Online Library, 2019-11) Almela, Pilar; Cuenca Bermejo, Lorena; Yuste, José E.; Estrada, Cristina; Pablos, Vicente de; Bautista Hernández, Víctor; Herrero Ezquerro, María Trinidad; Fernández Villalba, Emiliano; Laorden Carrasco, María Luisa; Anatomía Humana y Psicobiología; Medicina Interna
    ABSTRACT: Background: Autonomic dysfunction is a well-known dominant symptom in the advanced stages of Parkinson’s disease. However, the role of cardiac sympathetic nerves still needs to be elucidated. Objectives: To evaluate cardiac sympathetic response in Parkinsonian and dyskinetic monkeys. Methods: Adult male monkeys were divided into 1 of the following 3 groups: controls, 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine–treated monkeys, and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine+levodopa–treated animals. Noradrenaline, its metabolite normetanephrine, and phospho-Heat shock proten 27 (p-Hsp27) at erine 82 levels were analyzed in the left and right ventricles of the heart. Tyrosine hydroxylase immunohistochemistry was performed in the ventral mesencephalon. Results: The results were the following: (1) 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine intoxication significantly increased normetanephrine levels and decreased noradrenaline turnover in the right ventricle without changes in the left ventricle; however, (2) levodopa treatment decreased noradrenaline levels and enhanced the normetanephrine/noradrenaline ratio in parallel with a very significant increase of Hsp27 activity in both ventricles. Conclusions: Levodopa treatment could induce protective cardiac effects through the increased Hsp27 activity. © 2019 International Parkinson and Movement Disorder Society
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    Clinical Complete Response and Organ Preservation Strategies in Rectal Cancer: A Real-World Single-Center Experience Clinical Complete Response and Organ Preservation in Rectal Cancer
    (MDPI, 2026-02-27) Encarnación, J.A. ; Ibáñez, N. ; de la Fuente, I.; González, S. ; Sánchez, M.; Bautista, Y. ; Rodríguez, C.; Nadal, J.A. ; Abellán, I. ; Montoya, M.; Ono, A. ; Carbonell, G.; Frutos, L. ; Ortiz, E.; Manso, C. ; Ruiz Carreño, Paula; Marín Vera, Miguel; Quiles, B.; Abrisqueta Carrión, Jesús; Royo-Villanova Reparaz, Carlota; Alonso Romero, José Luis; Marín-Zafra, G.; Guirao, M.; Hernández, Q.; Medicina Interna; Facultades de la UMU::Facultad de Medicina
    Background: The management of rectal cancer has evolved toward response-adapted strategies, including organ preservation in selected patients achieving a clinical complete response (cCR) after neoadjuvant treatment. However, most available evidence derives from clinical trials, and data from real-world clinical practice remain limited. Methods: We conducted a retrospective observational cohort study including consecutive patients with rectal adenocarcinoma treated at a tertiary referral center between January 2021 and December 2025. Baseline clinical, tumor-related, and treatment characteristics were collected. Tumor response was assessed using clinical, endoscopic, and radiological criteria. The primary endpoint was the rate of clinical complete response and the implementation of watch-and-wait strategies. Secondary endpoints included recurrence patterns and exploratory oncologic outcomes according to baseline tumor characteristics. Results: A total of 229 patients were identified, of whom 148 were evaluable for treatment response. Clinical complete response was documented in 56 patients (37.8%), and a watch-and-wait strategy was implemented in 42 patients (28.4%). Higher cCR rates were observed in patients with stage I–II disease and in tumors measuring < 4 cm on baseline magnetic resonance imaging, with cCR rates exceeding 55% in this subgroup. Tumors ≥ 4 cm showed substantially lower response rates. Clinical complete responses were observed across both short-course radiotherapy plus chemotherapy and long-course chemoradiotherapy regimens in patients with small tumors and early-stage disease. Tumor distance from the anal verge was not consistently associated with response. With a median follow-up of 26 months in the watch-and-wait group, five recurrences were observed, including three local recurrences. Conclusions: In this real-world cohort, baseline tumor size and clinical stage were the main determinants of clinical complete response and eligibility for organ-preservation strategies in rectal cancer. Small tumors (<4 cm) showed high response rates regardless of neoadjuvant regimen. These findings support response-adapted, individualized treatment strategies and highlight the importance of tumor burden in selecting candidates for non-operative management in routine clinical practice.
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    Clinical subtypes in breast cancer patients with brain metastases from an ambispective registry of advanced breast cancer, GEICAM/2014-03 (RegistEM)
    (2026-02-20) López Tarruella, Sara ; Guerrero-Zotano, Ángel ; Antolín, Silvia ; Cruz, Josefina ; Martínez, Purificación ; Rodríguez, César A.; Falo, Catalina ; Rodríguez Lescure, Álvaro ; Adrover, Encarna ; Hernández, María ; Andrés, Raquel ; Chacón, José Ignacio ; Alonso Romero, José Luis; Miguel, Ana ; Gómez Raposo, César ; Margelí, Mireia ; González, Iria ; Guerra, José Antonio; Antón, Antonio ; Tibau, Ariadna ; Miralles, Juan José; Escudero, María José; Bezares, Susana ; Rojo, Federico ; Álvarez, Isabel ; Medicina Interna; Facultades de la UMU::Facultad de Medicina
    Background: Breast cancer frequently results in brain metastases (BCBM), leading to poor outcomes. Central nervous system (CNS) involvement entails significant challenges in advanced breast cancer (ABC) patients. Objectives: To characterize BCBM patients according to surrogate clinical BC subtypes and evaluate the interval between ABC and BCBM detection, both at ABC diagnosis (BCBM1 cohort) and for those who develop BCBM subsequently (BCBM2 cohort). Secondary objectives included analyzing the time-related outcomes by BC subtype. Design: RegistEM is an ongoing ambispective, observational study of ABC patients diagnosed since January/2016. Methods: We describe the characteristics of BCBM patients reported by January 22, 2024, categorized by BC subtype on the most recent tumor sample obtained before first-line therapy. Results: At the cutoff date, 346/1947 (18%) patients diagnosed with ABC between January/2016 and December/2019 developed BCBM, and 288/346 (83%) died. All patients were female, predominantly Caucasian (98%), with a median age of 55 years at ABC diagnosis. The distribution by subtype was 170/346 (49%) HR+/HER2−, 68/346 (20%) HR+/HER2+, 54/346 (16%) HR−/HER2+, and 51/346 (15%) HR−/HER2− (triple negative (TN)). One-fourth (85/346) were in the BCBM1 cohort, with 22/85 (26%) having BCBM as the only metastatic location; in this cohort, median time to BCBM was 38 months, with shorter intervals in HR−/HER2+ and TN subtypes (17 and 18 months, respectively). In the BCBM2 cohort (261/346), the median time to BCBM was 24 months, with the shortest interval in TN (13 months). Median survival from BCBM diagnosis was 26 months (95% confidence interval (CI), 20−35) in BCBM1 and 9 months (95% CI, 7−12) in BCBM2 (hazard ratio, 2.3; 95% CI, 1.7−3.0); TN subtype showed the poorest results (median of 6 months; 95% CI, 3−13). Conclusion: TN and HER2+ BC subtypes progressed faster to BCBM and had worse outcomes. Survival differed significantly between the two cohorts, BCBM1 and BCBM2. Continued research is essential to improve the treatment and prevention strategies.
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    Combined 1-Deoxynojirimycin and Ibuprofen treatment decreases microglial activation, phagocytosis and dopaminergic degeneration in MPTP-treated mice
    (Springer , 2020-06-21) Costa, T. C. S.; Fernández Villalba, Emiliano; Izura, V.; Lucas Ochoa, a. M.; Menezes Filho, N. J.; Santana, R.; Olivera, M. de; Araújo, F.; Estrada Esteban, C.; Silva, V.; Costa, S. L.; Herrero Ezquerro, María Trinidad; Medicina Interna; Facultades de la UMU::Facultad de Medicina
    Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions. Graphical Abstract MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.
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    Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in antithrombin deficiency.
    (Elsevier, 2013-03-10) Águila Martínez, Sonia; Martínez-Martínez, Irene; Collado, Miriam; Llamas, Pilar; Antón, Ana I.; Martínez-Redondo, Consuelo; Padilla, José; Miñano, Antonia; Morena Barrio, María Eugenia de la; García-Avello, Ángel; Vicente García, Vicente; Corral de la Calle, Javier; Medicina Interna
    Background: The characterization of natural mutants identified in patients with antithrombin deficiency has helped to identify functional domains or regions of this key anticoagulant and the mechanisms involved in the deficiency, as well as to define the clinical prognosis. Recently, we described an abnormal glycosylation in a pleiotropic mutant (K241E) that explained the impaired heparin affinity and the mild risk of thrombosis in carriers. Objectives: To evaluate the effects of different natural pleiotropic mutations on the glycosylation of antithrombin and their functional effects. Methods: Five pleiotropic mutations identified in patients with antithrombin deficiency and located at each one of the strands of the C-sheet were selected (K241E, M251I, M315K, F402L, and P429L). Recombinant mutants were generated and purified. Glycoform heterogeneity and conformational sensitivity were studied with electrophoresis, proteomic analysis, and glycomic analysis. Heparin affinity was evaluated from intrinsic fluorescence. Reactivity assays with factor Xa, thrombin and neutrophil elastase in the presence or absence of heparin were also performed. Results and Conclusions: Pleiotropic mutants, except for that with the M315K mutation, which affects a non-exposed residue, showed two glycoforms. Variant 1, with abnormal glycosylation, had reduced heparin affinity and severely affected reactivity with the target proteases. In contrast, variant 2, with similar electrophoretic mobility and heparin affinity to wild-type antithrombin, had impaired inhibitory activity that was partially compensated for by activation with heparin. Our results suggest the C-sheet of antithrombin as a new region that is relevant for proper maturation of the N-glycans. Therefore, pleiotropic mutations lead to glycosylation defects that are responsible for the reduced heparin affinity
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    Conformational activation of antithrombin by heparin involves an altered exosite interaction with protease
    (Elsevier; American Society for Biochemistry and Molecular Biology, 2014-12-05) Águila Martínez, Sonia; Izaguirre, Gonzalo; Qi, Lixin; Swanson, Richard; Roth, Ryan; Rezaie, Alireza R.; Gettins, Peter G. W.; Olson, Steven T.; Medicina Interna
    Background: Exosites are known to mediate heparin allosteric activation of antithrombin. Results: Mutagenesis revealed that an exosite differentially contributes to antithrombin reactivity with factors Xa/IXa in unactivated and heparin-activated states. Conclusion: Heparin allosteric activation of antithrombin results from alterations in an exosite interaction with protease induced by core conformational changes. Significance: The findings support our recently proposed model of antithrombin allosteric activation.
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    Data set for: Cardiac remodeling data associated with antimiR-199a treatment in a mouse model of myocardial infarction
    (2021-02-16) Lax Pérez, Antonio Manuel; Medicina Interna; Facultades de la UMU::Facultad de Medicina
    This repository contains data associated with Figure 2 from the article “The miRNA199a/SIRT1/P300/Yy1/sST2 signaling axis regulates adverse cardiac remodeling following MI” (DOI: 10.1038/s41598-021-82745-9), including the complete figure, supporting quantification data, and the original unprocessed images underlying panel h (WGA staining).
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    Data set for: Quantitative profiling of cardiac remodeling and antimiR-199a therapeutic efficacy in a murine MI model
    (2020-12-09) Antonio Lax; Medicina Interna; Facultades de la UMU::Facultad de Medicina
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    Dataset for: Experimental validation of SIRT1 as a direct target of miR-199a-5p and its restoration via antimiR-199a therapy in post-MI remodeling
    (2020-04-24) Lax Pérez, Antonio Manuel; Medicina Interna; Facultades de la UMU::Facultad de Medicina
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    Dawning of the age of genomics for platelet granule disorders: improving insight, diagnosis and management
    (Wiley, 2016-12-16) Bariana, Tadbir K.; Ouwehand, Willem H.; Guerrero López, José Antonio; Gomez, Keith; Medicina Interna
    Inherited disorders of platelet granules are clinically heterogeneous and their prevalence is underestimated because most patients do not undergo a complete diagnostic work-up. The lack of a genetic diagnosis limits the ability to tailor management, screen family members, aid with family planning, predict clinical progression and detect serious consequences, such as myelofibrosis, lung fibrosis and malignancy, in a timely manner. This is set to change with the introduction of high throughput sequencing (HTS) as a routine clinical diagnostic test. HTS diagnostic tests are now available, affordable and allow parallel screening of DNA samples for variants in all of the 80 known bleeding, thrombotic and platelet genes. Increased genetic diagnosis and curation of variants is, in turn, improving our understanding of the pathobiology and clinical course of inherited platelet disorders. Our understanding of the genetic causes of platelet granule disorders and the regulation of granule biogenesis is a work in progress and has been significantly enhanced by recent genomic discoveries from high-powered genome-wide association studies and genome sequencing projects. In the era of whole genome and epigenome sequencing, new strategies are required to integrate multiple sources of big data in the search for elusive, novel genes underlying granule disorders.
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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.
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    Disease-causing mutations in the serpin antithrombin reveal a keydomaincritical for inhibiting protease activities
    (Elsevier, American Society for Biochemistry and Molecular Biology , 2017-10-06) Águila Martínez, Sonia; Izaguirre, G.; Vicente García, Vicente; Martínez-Martínez, I.; Olson, S. T.; Corral de la Calle, Javier; Medicina Interna
    Antithrombin mainly inhibits factor Xa and thrombin. The reactive center loop (RCL) is crucial for its interactions with its protease targets and is fully inserted into the A-sheet after its cleavage, causing translocation of the covalently linked protease to the opposite end of the A-sheet. Antithrombin variants with altered RCL hinge residues behave as substrates rather than inhibitors, resulting in stoichiometries of inhibition greater than one. Other antithrombin residues have been suggested to interfere with RCL insertion or the stability of the antithrombin–protease complex, but available crystal structures or mutagenesis studies have failed to identify such residues. Here, we characterized two mutations, S365L and I207T, present in individuals with type II antithrombin deficiency and identified a new antithrombin functional domain. S365L did not form stable complexes with thrombin or factor Xa, and the I207T/I207A variants inhibited both proteases with elevated stoichiometries of inhibition. Close proximity of Ile-207 and Ser-365 to the inserted RCL suggested that the preferred reaction of these mutants as protease substrates reflects an effect on the rate of the RCL insertion and protease translocation. However, both residues lie within the final docking site for the protease in the antithrombin–protease complex, supporting the idea that the enhanced substrate reactions may result from an increased dissociation of the final complexes. Our findings demonstrate that the distal end of the antithrombin A-sheet is crucial for the last steps of protease inhibition either by affecting the rate of RCL insertion or through critical interactions with proteases at the end of the A-sheet.
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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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    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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    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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    Genetic variants of the extra-large stimulatory Gs protein alpha-subunit and risk of thrombotic and haemorrhagic disorders
    (Wiley, 2004-04-27) González-Conejero Hilla, Rocío; Corral de la Calle, Javier; Guerrero López, José Antonio; Iniesta Valera, Juan Antonio; Rivera Pozo, José; Arriba de la Fuente, Felipe de; Vicente García, Vicente; Medicina Interna
    A polymorphism of the gene encoding the extra-large stimulatory G-protein a-subunit (XLas), originally identified in three patients with a bleeding tendency, involved a 36-bp insertion and two missense changes. A paternallyinherited insertion displayed a moderate platelet Gsa over-expression, which lead to platelet hypo-reactivity. These data prompted us to investigate the genetic, functional and clinical relevance of this polymorphism in the Mediterranean population. We included 414 healthy subjects and three case/ control studies: 263 consecutive patients with a first episode of primary intracerebral haemorrhage, 195 patients with deep venous thrombosis, and 104 patients with cerebrovascular disease. Controls were selected by approximating criteria to match selected risk factors to patients. Moreover, we performed studies of platelet function. We developed a simple method to determine the methylated allele, by digestion of genomic DNA with Sma I before polymerase chain reaction amplification. We identified two new rare variants, resulting from the loss of repeat units 7 and 5. The AB genotype was present in 3Æ6% of healthy population and the prevalence of the B allele was similar among cases and controls. Accordingly, the non-methylated B allele did not modify either the expression of platelet Gsa or the platelet response to Gs-agonists. Thus, our study suggests a minor functional role of XLas polymorphism in thrombotic or in haemorrhagic disorders.
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    Identification of predictors of sarcopenia in older adults using machine learning: English Longitudinal Study of Ageing
    (MDPI, 2024-11-12) Pavón Pulido, Nieves; Domínguez, Ligia; Blasco García, Jesús Damián; Veronese, Nicola; Lucas Ochoa, Ana María; Fernández Villalba, Emiliano; González Cuello, Ana María; Barbagallo, Mario; Herrero Ezquerro, María Trinidad; GOING FWD Investigators; Medicina Interna; Facultades de la UMU::Facultad de Medicina
    Background: After its introduction in the ICD-10-CM in 2016, sarcopenia is a condition widely considered to be a medical disease with important consequences for the elderly. Considering its high prevalence in older adults and its detrimental effects on health, it is essential to identify its risk factors to inform targeted interventions. Methods: Taking data from wave 2 of the ELSA, using ML-based methods, this study investigates which factors are significantly associated with sarcopenia. The Minimum Redundancy Maximum Relevance algorithm has been used to allow for an optimal set of features that could predict the dependent variable. Such a feature is the input of a ML-based prediction model, trained and validated to predict the risk of developing or not developing a disease. Results: The presented methods are suitable to identify the risk of acquired sarcopenia. Age and other relevant features related with dementia and musculoskeletal conditions agree with previous knowledge about sarcopenia. The present classifier has an excellent performance since the “true positive rate” is 0.81 and the low “false positive rate” is 0.26. Conclusions: There is a high prevalence of sarcopenia in elderly people, with age and the presence of dementia and musculoskeletal conditions being strong predictors. The new proposed approach paves the path to test the prediction of the incidence of sarcopenia in older adults.202
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    In vivo relevance for platelet glycoprotein Ibα residue Tyr276 in thrombus formation
    (Elsevier, 2008) Guerrero López, José Antonio; Shafirstein, G.; Russell, S.; Varughese, K. I.; Kanaji, T.; Liu, J.; Gartner, T. K.; Bäumler, W.; Jarvis, G. E.; Ware, J.; Medicina Interna; Facultad de Medicina