Artículos (Bioquímica Médica y Biología Molecular e Inmunología)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10990

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Targeting iysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing
(Elsevier science; Elsevier BV, 2025-11-04) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; Millán-Huang, Marta San; Maldonado y Aibar, María Dolores; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS160: Neuroinmunoendocrinología Molecular; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.
Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
(Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier, 2025-10-29) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; San Millán-Huang, Marta; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue–positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.
Monovalent glycoconjugates of sulforaphane prevent inflammation induced by lipopolysaccharide in human dendritic cells by inhibiting NF-ĸB signalling pathway
(John Wiley and Sons Inc, 2025-11) Leiva‐Castro, Camila; Múnera‐Rodríguez, Ana Maria; Martínez Bailén, Macarena; Carmona Asenjo, Ana Teresa; López Enríquez, Soledad; Palomares Jerez, María Francisca; Química Orgánica y Farmacéutica; Química Orgánica; Bioquímica Médica y Biología Molecular e Inmunología; Ministerio de Ciencia e Innovación (MICIN). España; Universidad de Sevilla
Background and Purpose: Sulforaphane (SFN) has notable health benefits but faces challenges due to its poor solubility and delivery. This study investigates SFN-glycoconjugates effects on lipopolysaccharide (LPS)-induced inflammation in dendritic cells (DCs). With the aiming to enhance their therapeutic potential against inflammatory diseases. Novel monovalent SFN-glycoconjugates with mannose (Man) and fucose (0Fuc) were developed and tested for their anti-inflammatory and immune-modulatory properties in DCs from healthy donors under chronic LPS exposure. Experimental Approach: By leveraging therapeutic strategies, SFN-glycoconjugates significantly improved the solubility and bioavailability of SFN, thereby overcoming the limitations of traditional delivery methods. Monocyte-derived DCs were treated with SFN-glycoconjugates and subsequently exposed to a chronic inflammatory environment induced by LPS. Key Results: Our results showed that SFN-glycoconjugates enhance effectiveness in suppressing inflammation by targeting the p65 NF-κB pathway, without affecting MAPK signalling. SFN-glycoconjugates induce a tolerogenic immune response, characterized by increased IL-10 production and enhanced regulatory T- and B-cell proliferation. These effects surpass those of p65 NF-κB inhibition alone, highlighting a distinct and potent regulatory mechanism independent of MAPK pathways. Conclusion and Implications: The integration of food therapeutic strategies not only enhances the stability and delivery of bioactive compounds but also broadens their potential applications in functional foods and therapeutic approaches. In particular, SFN-glycoconjugates represent a promising option as biologically active compounds for inflammatory diseases, offering enhanced anti-inflammatory and immunomodulatory effects through optimized delivery systems and the activation of specific molecular pathways.
Corrigendum: Microbiota-derived extracellular vesicles: current knowledge, gaps, and challenges in precision nutrition
(Frontiers Media SA, 2025-05-15) Márquez Parada, Elvira; Torrecillas López, María; del-Río-Vázquez, José L.; Barrera Chamorro, Luna; González de la Rosa, Teresa; Montserrat de la Paz, Sergio; Bioquímica Médica y Biología Molecular e Inmunología; CTS1074: Inmunonutrición e Inmunometabolismo
Modulating inflammation and oxidative stress in rheumatoid arthritis: a systematic review of nutraceutical interventions
(Springer Science and Business Media LLC, 2025-09-30) Leiva-Castro, Camila; Múnera-Rodríguez, Ana M.; Torres-Joya, Gádor; Palomares, Francisca; López Enriquez, Soledad; Bioquímica Médica y Biología Molecular e Inmunología; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla; CTS1100: Inmunometabolismo e Inflamación
Rheumatoid arthritis is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. The gut microbiome has emerged as a key factor in the regulation of the immune system, and its dysbiosis has been implicated in the pathogenesis of rheumatoid arthritis. Nutraceuticals, including probiotics, omega-3 fatty acids, coen zyme Q10, vitamin D, and polyphenols, have shown potential in modulating the gut microbiota and inflammatory pathways. This review explores the interplay between nutraceuticals, gut microbiota, and immune function in rheumatoid arthritis, with attention to pharmacokinetics and safety. We discuss recent clinical evidence, elucidate molecular mechanisms of action, and highlight future research directions for integrating nutraceuticals into therapeutic strategies for rheumatoid arthritis.
Neuroavailable peptides from hempseed protein hydrolysates reduce hippocampal inflammation and glial activation in a scopolamine-induced Alzheimer’s disease
(Elsevier, 2025-09-04) Torrecillas López, María; Claro Cala, Carmen María; González de la Rosa, Teresa; Barrera Chamorro, Luna; Millan Linares, Carmen; Márquez Paradas, Elvira; del-Río-Vázquez, José L.; Montserrat de la Paz, Sergio; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); CTS1074: Inmunonutrición e Inmunometabolismo
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, synaptic dysfunction, and neuronal loss. Neuroinflammation, driven by the activation of microglia and astrocytes, is a key contributor to AD pathology, amplifying oxidative stress and amyloid-β toxicity. Modulation of neuroinflammatory pathways thus represents a promising therapeutic strategy. In this study, we evaluated the effects of a food-grade hempseed protein hydrolysate (HPH20A) on hippocampal inflammation and glial activation in a scopolamine-induced mouse model of AD. Mice were orally supplemented with HPH20A (10 mg/kg/day) for 12 weeks. Hippocampal tissue was analyzed by RT-qPCR and immunohistochemistry to assess the expression of glial and inflammatory markers. To identify peptides capable of reaching the brain, we employed a double transwell in vitro system simulating intestinal and blood-brain barrier (BBB) transport, followed by LC-TIMS-MS/MS peptidomics, in silico bioactivity prediction, and molecular docking. HPH20A supplementation significantly attenuated the expression of pro-inflammatory markers, including GFAP, IBA1, TREM2, CD68, iNOS, COX2, and IL-6, and increased the anti-inflammatory cytokine IL-10. Peptidomic analysis identified two peptides, NVDTELAHKL and DSETVKRL, consistently present across intestinal, systemic, and brain compartments. These peptides were predicted to exhibit anti-inflammatory activity and demonstrated high-affinity binding to AD-related targets (APP, TREM2, and AChE) in docking simulations. Taken together, these findings suggest that HPH20A exerts neuroprotective effects by modulating hippocampal inflammation inflammation, potentially through specific bioactive peptides capable of crossing the BBB. Our results support the potential of hempseed-derived peptides as dietary modulators of neuroinflammation in early stages of neurodegenerative disease.
Glycodendropeptides stimulate dendritic cell maturation and T cell proliferation: a potential influenza A virus immunotherapy
(Royal soc chemistry, 2015-07-07) Mascaraque, A.; Kowalczyk, W.; Fernandez, T.; Palomares, Francisca; Mayorga, C.; Andreu, D.; Rojo, J.; Bioquímica Médica y Biología Molecular e Inmunología; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Generalitat de Cataluña; Instituto de Salud Carlos III (ISCIII) Redes Temáticas y Centros de Investigación Cooperativa: RIRAAF; Junta de Andalucia; Ministerio de Economia y Competitividad (MINECO); Programa Nicolás Monardes; Proyecto ISCIII; CTS1100: Inmunometabolismo e Inflamación
Mannosylation facilitates uptake and internalization of immunogenic peptides by antigen-processing cells expressing mannose receptors at their surface, such as DC-SIGN, a lectin that plays a key role in the immune response against different pathogens. This internalization, processing and subsequent MHC presentation may result in a strong T cell stimulation. Here, we hypothesized that combining mannose glycodendrons with multivalent presentation of peptide epitopes in a likewise dendron format would yield hybrid constructs, named glycodendropeptides (GDPs), with the capacity to enhance peptide immunogenicity, hence providing a novel and versatile platform for applications in immunotherapy. Thus, GDPs of different valencies displaying the NP366–374 epitope, a conserved sequence from the influenza A virus nucleoprotein (NP), have been built by two click chemistry-based methodologies and assessed as potential flu vaccine candidates. Preliminary evaluation of the ability of these constructs to stimulate dendritic cell maturation and lymphocyte proliferation was promising, showing the highest-functionalized NP366–374 GDPs as inducing the strongest immunostimulatory effect.
Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy Case report
(Lippincott Williams & Wilkins, 2018-10) Ley-Martos, Myriam; Guerrero Montávez, Juan Miguel; Lucas-Javato, Marta; Remón-García, Cristina; Raul García-Lozano, J.; Colón, Cristóbal; Macher, Hada C.; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Fundacion Publica Andaluza Progreso y Salud; Instituto de Salud Carlos III-Fondos FEDER; CTS160: Neuroinmunoendocrinología Molecular
Rationale: Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is produced by the deficiency of the enzyme arylsulfatase B, responsible for the hydrolysis of N-acetyl-D-galactosamine, chondroitin sulfate, and dermatan sulfate. Patient concerns: A 3-year-old male with Moroccan origins is the index case. He had healthy consanguineous parents and 4 healthy brothers and sisters. The patient showed a wide spectrum of symptoms including skeletal dysplasia and short stature with elevated glycosaminoglycans (GAGs) in urine. Diagnoses, interventions, and outcomes: GAGs were quantified by spectrometry method with 1,9-dimethylen blue in 24-hour urine samples. The qualitative analysis of urine GAGs was obtained by thin-layer chromatography to determine the predominant presence of dermatan sulfate. The activities of both arylsulfatase B and beta-galactosidase as well as genetic studies were performed in dried blood spots. The genetic study was performed with deoxyribonucleic acid by massive sequencing a of lisosomal storage diseases. Results showed a new mutation c.263A > C with the severe phenotype in homozygous in the patient. The familiar study of ARSB and GLB1 genes presented some asymptomatic SNPs but with a discrete decrease in the activity of arylsulfatase B and beta-galactosidase. After an early detection by pediatricians, and both enzymatic and genetic confirmation, the patient had a good response to substitutive enzymatic treatment with galsulfase. Lessons: Mucoplysaccharidosis type VI is an autosomal recessive rare disease characterized by a lysosomal storage disorder. Although a number of mutations have been already associated to the disease, we have found a new mutation located in the arylsulfatase B enzyme gene. We have described that this mutation is the ultimate cause of a severe presentation of the disease.
The PNPLA3 genetic variant rs738409 influences the progression to cirrhosis in hiv/hepatitis c virus coinfected patients
(Public Library of Science (PLoS), 2016-12-14) Núñez-Torres, Rocío; Macías Sánchez, Juan; Mancebo, María; Frías, Mario; Dolci, Giovanni; Téllez, Francisco; Merchante Gutiérrez, Nicolás; Gómez Mateos, Jesús María; Pineda Vergara, Juan Antonio; Real Navarrete, Luis Miguel; Medicina; Bioquímica Médica y Biología Molecular e Inmunología; Junta de Andalucía; Gobierno de España; Instituto de Salud Carlos III; Ministerio de Economia, Industria y Competitividad (MINECO). España
Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3geneonliver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymor phisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hun dred andthirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut-off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determina tions without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients whounderwent liver transplant, as well as 19 non-cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 Gallele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.123.50). Also, 21 (30.4%) of 69 Gallele carriers versus 16 (15.7%) of 102 CC patients showed signifi cant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.236.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95%confidence interval = 1.0111.70). Our results strongly suggest that the rs738409 poly morphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients.
Vaccination prepartum enhances the beneficial effects of melatonin on the immune response and reduces platelet responsiveness in sheep
(BioMed Central, 2012-06-20) Regodón, Sergio; Ramos, Asunción; Míguez, María P.; Carrillo Vico, Antonio; Rosado, Juan A.; Jardín, Isaac; Bioquímica Médica y Biología Molecular e Inmunología; Junta de Extremadura; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia e Innovación (MICIN). España
Background: Melatonin regulates several physiological processes and its powerful action as antioxidant has been widely reported. Melatonin acts modulating the immune system, showing a protective effect on the cardiovascular system and improving vaccine administration as an adjuvant-like agent. Here, we have investigated the role of melatonin as an adjuvant of the Clostridium perfringens vaccine in prepartum sheep and whether melatonin modulates platelet physiology during peripartum. Results: The experiments were carried out in peripartum sheep from a farm located in an area of Mediterranean-type ecosystem. Plasma melatonin levels were determined by ELISA and sheep platelet aggregation was monitored using an aggregometer. Here we demonstrated for the first time that plasma melatonin concentration were higher in pregnant (125 pg/mL) than in non-pregnant sheep (15 pg/mL; P < 0.05). Administration of melatonin prepartum did not significantly modify platelet function but significantly improved the immune response to vaccination against C. perfringens. Conclusion: Administration of melatonin as an adjuvant provides a significant improvement in the immune response to vaccine administration prepartum against C. perfringens.
Leptin Is an Anti-Apoptotic Effector in Placental Cells Involving p53 Downregulation
(Ed. Public Library of Science (PLoS), 2014-06-12) Toro, Ayelén Rayen; Maymó, Julieta Lorena; Ibarbalz, Federico Matías; Pérez Pérez, Antonio; Maskin, Bernardo; Faletti, Alicia Graciela; Sánchez Margalet, Víctor; Varone, Cecilia Laura; Bioquímica Médica y Biología Molecular e Inmunología; ANPCyT; CONICET; CONICET fellowship; Fundacion Florencio Fiorini, Buenos Aires, Argentina; Instituto de Salud Carlos III; Universidad de Buenos Aires (UBACYT)
Leptin, a peripheral signal synthetized by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may work as an autocrine hormone. We have previously demonstrated that leptin promotes proliferation and survival of trophoblastic cells. In the present work, we aimed to study the molecular mechanisms that mediate the survival effect of leptin in placenta. We used the human placenta choriocarcinoma BeWo and first trimester Swan-71 cell lines, as well as human placental explants. We tested the late phase of apoptosis, triggered by serum deprivation, by studying the activation of Caspase-3 and DNA fragmentation. Recombinant human leptin added to BeWo cell line and human placental explants, showed a decrease on Caspase-3 activation. These effects were dose dependent. Maximal effect was achieved at 250 ng leptin/ml. Moreover, inhibition of endogenous leptin expression with 2 µM of an antisense oligonucleotide, reversed Caspase-3 diminution. We also found that the cleavage of Poly [ADP-ribose] polymerase-1 (PARP-1) was diminished in the presence of leptin. We analyzed the presence of low DNA fragments, products from apoptotic DNA cleavage. Placental explants cultivated in the absence of serum in the culture media increased the apoptotic cleavage of DNA and this effect was prevented by the addition of 100 ng leptin/ml. Taken together these results reinforce the survival effect exerted by leptin on placental cells. To improve the understanding of leptin mechanism in regulating the process of apoptosis we determined the expression of different intermediaries in the apoptosis cascade. We found that under serum deprivation conditions, leptin increased the anti-apoptotic BCL-2 protein expression, while downregulated the pro-apoptotic BAX and BID proteins expression in Swan-71 cells and placental explants. In both models leptin augmented BCL-2/BAX ratio. Moreover we have demonstrated that p53, one of the key cell cycle-signaling proteins, is downregulated in the presence of leptin under serum deprivation. On the other hand, we determined that leptin reduced the phosphorylation of Ser-46 p53 that plays a pivotal role for apoptotic signaling by p53. Our data suggest that the observed anti-apoptotic effect of leptin in placenta is in part mediated by the p53 pathway. In conclusion, we provide evidence that demonstrates that leptin is a trophic factor for trophoblastic cells
Lower expression of plasma-derived exosome miR-21 levels in HIV-1 elite controllers with decreasing CD4 T cell count
(Elsevier, 2019-09) Ruiz-de-León, M. J.; Jiménez-Sousa, M. A.; Moreno, S.; García, M.; Gutiérrez-Rivas, M.; León, A.; Vallejo, A.; ECRIS network integrated in the Spanish AIDS research network; Muñoz Pérez, María Asunción; Rafii-El-Idrissi Benhnia, Mohammed; Leal Noval, Manuel; Bioquímica Médica y Biología Molecular e Inmunología; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Beca de Investigación, Educación, Juventud y Deporte de Madrid; Beca de investigación intramuros del IIS-FJD; Programa de Investigación Miguel Servet, Instituto Español de Salud Carlos III (ISCIII); Red Española de Investigación sobre el SIDA (RIS); Instituto Español de Salud Carlos III (ISCIII); Fondo Español de Investigación Sanitaria (FIS, ISCIII)
Exosome-derived miR-21 was independently associated with CD4 T cell decline in HIV-1-infected elite controllers (OR 0.369, 95% CI 0.137-0.994, p = 0.049). Also, a negative correlation between miR-21 expression and MCP-1 level was found (r = -0.649, p = 0.020), while no correlation between soluble biomarkers or cellular immune activation was found.
Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: the GR@ACE Project
(Elsevier Inc.; WILEY, 2019-10) Moreno-Grau, Sonia; de Rojas, Itziar; Hernández, Isabel; Quintela, Inés; Montrreal, Laura; Alegret, Montserrat; Pineda Vergara, Juan Antonio; Macías Sánchez, Juan; Mir Rivera, Pablo; Real Navarrete, Luis Miguel; Ruiz, A.; GR@ACE consortium; Degesco Consortium; Alzheimer's disease neuroimaging initiative; Labrador Espinosa, Miguel Ángel; Periñan Tocino, Maria Teresa; Medicina; Bioquímica Médica y Biología Molecular e Inmunología; Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia); AGES; Neuroimagen de la Enfermedad de Alzheimer (ADNI) (Institutos Nacionales de Salud); Fundación para el Descubrimiento de Fármacos para el Alzheimer; Investigación sobre el Alzheimer en el Reino Unido; Biogen; Fundación de Investigación Biomédica; Compañía Bristol-Myers Squibb; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); Consejeria de Salud de la Junta de Andalucia; Corporacion Tecnologica de Andalucia; CurePSP Foundation; DOD ADNI (Departamento de Defensa); Iniciativa sobre medicamentos innovadores de la Unión Europea/EFPIA, proyecto conjunto ADAPTED; Iniciativa sobre medicamentos innovadores de la Unión Europea/EFPIA, proyecto conjunto MOPEAD; Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa"); Ministerio Federal de Educación e Investigación de Alemania (BMBF): Red de Competencia en Demencia (CND); ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion; Lille University Hospital; Centro de Enfermedad de Alzheimer de Mayo Clinic; Medical Research Council; Ministerio de Educacion y Ciencia (Gobierno de Espana); National Alzheimer's Coordinating Center; Instituto Nacional sobre el Envejecimiento (Centro de Enfermedad de Alzheimer de Arizona); NHLBI; NIA; NIA Division of Neuroscience; NINDS; Las PYME como parte de InnoMed (Medicamentos Innovadores en Europa) - Unión Europea del Sexto Programa Marco, prioridad FP6-2004-LIFESCIHEALTH-5; Wellcome Trust
Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
High rate of major drug–drug interactions of lopinavir–ritonavir for COVID-19 treatment
(Nature Publishing Group; Nature Portfolio, 2020-12-01) Macías Sánchez, Juan; Pinilla, Ana; Lao-Dominguez, Francisco A.; Corma, Anaïs; Contreras Macías, Enrique; González-Serna Martín, Manuel Alejandro; Morillo Verdugo, Ramón Alejandro; Real Navarrete, Luis Miguel; Pineda Vergara, Juan Antonio; Medicina; Fisiología; Farmacología; Bioquímica Médica y Biología Molecular e Inmunología
The impact of drug–drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69–85%) patients, and in 33 (26%, 95% CI 19–35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10–731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04–0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.
CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis
(Wiley ; Springer Nature, 2020-06-11) Martin-Leal, A.; Blanco, R.; Casas, J; Saez, Maria Eugenia; Rodríguez-Bovolenta, Elena; Rojas, Itziar de; Real Navarrete, Luis Miguel; Mañes, Santos; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; Gobierno de España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Comunidad Autónoma de Madrid; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); European Community (EC)
CCR5 is not only a coreceptor for HIV-1 infection in CD4+ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T-cell antigen receptor (TCR) nanoclustering in antigen-experienced mouse and human CD4+ T cells. This activity is CCR5-specific and independent of CCR5 co-stimulatory activity. CCR5-deficient mice showed reduced production of high-affinity class-switched anti bodies, but only after antigen rechallenge, which implies an impaired memory CD4+ T-cell response. This study identifies a CCR5 function in the generation of CD4+ T-cell memory responses and establishes an antigen-independent mechanism that regulates TCR nanoclustering by altering specific lipid species.
Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis
(Impact journals LLC, 2021-04-12) Madrid, Laura; Moreno-Grau, Sonia; Ahmad, Shahzad; González-Pérez, Antonio; de Rojas, Itziar; Xia, Rui; Real Navarrete, Luis Miguel; Saez, Maria Eugenia; Bioquímica Médica y Biología Molecular e Inmunología
Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
Fucodendropeptides induce changes in cells of the immune system in food allergic patients via DC-SIGN receptor
(Elsevier, 2022-07) Palomares, Francisca; Gómez, Francisca; Fuente, M. Carmen de la; Pérez-Sánchez, Natalia; Torres, María José; Mayorga, Cristobalina; Rojo, Javier; Ramos-Soriano, Javier; Bioquímica Médica y Biología Molecular e Inmunología; Consejería de Salud de la Junta de Andalucía; ISCIII; Junta de Andalucía; RETICS ARADyAL; Fondo Europeo de Desarrollo Regional (FEDER); CTS1100: Inmunometabolismo e Inflamación
Food allergy induced by lipid transfer proteins (LTPs) of Rosacea fruit family, such as peach, is becoming an important health problem in the Mediterranean area. Current treatments, such as allergen specific immunotherapy (AIT) with allergenic extracts show promising, but in many cases, they need an improvement in homogeneity, availability and induction of tolerant responses. Peptide-based vaccines containing adjuvants, such as carbohydrates for C-type lectin receptors (CLRs) are presented as an alternative approach. In this work, we have prepared fucosylated glycodendropeptides (GDPs) functionalized with Pru p 3 peptides via click chemistry. These GDPs, DnFuc9Prup3, induced changes in moDC maturation and lymphocyte proliferation in food allergic patients, indicating specific recognition via DC-SIGN receptor. From these data, D4Fuc9Prup3 can be considered a promising candidate for specific immunotherapy development.
High sensitivity troponins: A potential biomarkers of cardiovascular risk for primary prevention
(Frontiers Media SA, 2022-11-30) Leite, Luis; Matos, Pedro; León Justel, Antonio; Espírito-Santo, Claudio; Rodríguez-Padial, Luis; Rodrigues, Fernando; Orozco, Domingo; Redon, Josep; Bioquímica Médica y Biología Molecular e Inmunología
There have been several approaches to building charts for CV risk, all of which have both strengths and limitations. Identifying early organ damage provides relevant information and should be included in risk charts, although the direct relationship with risk is imprecise, variability between operators at the time to assess, and low availability in some healthcare systems, limits its use. Biomarkers, like troponin (cTns) isoforms cTnI and cTnT, a cardiac specific myocyte injury marker, have the great advantage of being relatively reproducible, more readily accessible, and applicable to di erent populations. New and improved troponin assays have good analytical performance, can measure very low levels of circulating troponin, and have low intra individual variation, below %. Several studies have analyzed the blood levels in healthy subjects and their predictive value for cardiovascular events in observational, prospective and post-hoc studies. All of them o ered relevant information and shown that high sensitivity hscTnI has a place as an additional clinical marker to add to current charts, and it also reflects sex and agedependent di erences. Although few more questions need to be answered before recommend cTnI for assessing CV risk in primary prevention, seems to be a potential strong marker to complement CV risk charts.
Plasmacytoid and cd141+ myeloid dendritic cells cooperation with cd8+ t cells in lymph nodes is associated with hiv control
(Wiley, 2025-09-12) Vitallé, Joana; Bachiller, Sara; Domínguez-Molina, Beatriz; Moysi, Eirini; Ferrando Martínez, Sara; Camacho Sojo, María Inés; Ostos Marcos, Francisco José; Rafii-El-Idrissi Benhnia, Mohammed; López Cortés, Luis Fernando; Ruiz Mateos Carmona, Ezequiel; Medicina; Bioquímica Médica y Biología Molecular e Inmunología; Química Física; FQM206: Grupo de Cinética del Profesor Rodríguez Velasco
Dendritic cells (DC) are known to modulate antiviral immune responses; however, the knowledge about the role of different DC subsets in antiviral T cell priming in human tissues remains uncompleted. In the context of HIV infection, we determined the phenotype and location of plasmacytoid and CD141+ myeloid DCs (pDCs and mDCs) in lymph nodes of people living with HIV (PLWH). We found an interaction between pDCs and CD141+ mDCs with CD8+ T cells, being associated with participants’ viral levels in blood and tissue. Moreover, we demonstrated a higher and more polyfunctional superantigen- and HIV-specific CD8+ T cell response after the coculture with Toll-like receptor (TLR)-primed pDCs and CD141+ mDCs. Last, we showed the potential of programmed cell death-1 (PD-1) blocking using pembrolizumab to further increase antigen-specific CD8+ T cell response along with TLR agonists. Therefore, these results showed a cooperation between pDCs, CD141+ mDCs and CD8+ T cells in lymph nodes of PLWH, which is associated with higher HIV control, highlighting the importance of DC subsets crosstalk to achieve a more potent anti-HIV response and support the use of DC-based immunotherapies for HIV control.
Structural and Functional Characterization of Anti-A33 Antibodies Reveal a Potent Cross-Species Orthopoxviruses Neutralizer
(Public Library of Science, 2015-09-01) Matho, Michael H.; Schlossman, Andrew; Meng, Xiangzhi; Rafii-El-Idrissi Benhnia, Mohammed; Kaever, Thomas; Zajonc, Dirk M.; Bioquímica Médica y Biología Molecular e Inmunología
Vaccinia virus A33 is an extracellular enveloped virus (EEV)-specific type II membrane glycoprotein that is essential for efficient EEV formation and long-range viral spread within the host. A33 is a target for neutralizing antibody responses against EEV. In this study, we produced seven murine anti-A33 monoclonal antibodies (MAbs) by immunizing mice with live VACV, followed by boosting with the soluble A33 homodimeric ectodomain. Five A33 specific MAbs were capable of neutralizing EEV in the presence of complement. All MAbs bind to conformational epitopes on A33 but not to linear peptides. To identify the epitopes, we have adetermined the crystal structures of three representative neutralizing MAbs in complex with A33. We have further determined the binding kinetics for each of the three antibodies to wild-type A33, as well as to engineered A33 that contained single alanine substitutions within the epitopes of the three crystallized antibodies. While the Fab of both MAbs A2C7 and A20G2 binds to a single A33 subunit, the Fab from MAb A27D7 binds to both A33 subunits simultaneously. A27D7 binding is resistant to single alanine substitutions within the A33 epitope. A27D7 also demonstrated high-affinity binding with recombinant A33 protein that mimics other orthopoxvirus strains in the A27D7 epitope, such as ectromelia, monkeypox, and cowpox virus, suggesting that A27D7 is a potent cross-neutralizer. Finally, we confirmed that A27D7 protects mice against a lethal challenge with ectromelia virus.

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