Artículos (Bioquímica Médica y Biología Molecular e Inmunología)
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Artículo Obesity and overweight in R/R DLBCL patients is associated with a better response to treatment of R2-GDP-GOTEL trial. Potential role of NK CD8+cells and vitamin D(BMC, 2025-03-04) Hontecillas-Prieto, L; García-Domínguez, Daniel J.; Jimenez Cortegana, Carlos; Nogales-Fernández, E.; Palazón-Carrión, N; García-Sancho, AM; Ríos Herranz, Eduardo; Gumà-Padrò, J; Provencio-Pulla, M; Rueda-Domínguez, A; Cruz Merino, Luis de la; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina; Instituto de Biomedicina de Sevilla (IBIS); VII Plan Propio de Investigación y Transferencia de la Universidad de Sevilla; Universidad de Sevilla. CTS151: Bioquímica MedicaDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide and is characterized by its heterogeneity. Although first-line therapy improves survival outcomes for DLBCL patients, approximately one third will relapse, often with a poor prognosis. Among the factors influencing prognosis and response to treatment in cancer patients, including those with lymphoma, overweight and obesity have emerged as significant considerations. However, the role of excess weight in DLBCL remains controversial, with studies reporting both negative and positive effects on cancer outcomes. In this translational substudy of the R2-GDP-GOTEL trial, we have evaluated the impact of excess weight as a predictor of treatment response and survival in patients with relapsed/refractory (R/R) DLBCL, and examining its relationship with immune cell dynamics. Methods Of the 79 patients who received the R2-GDP scheme in the phase II trial, weight and height parameters were obtained in 75 patients before starting treatment. Blood samples were analyzed by flow cytometry. Statistical analyses were performed to determine the prognostic value of overweight and obesity at baseline in R/R DLBCL patients. Results Our results indicate that overweight (including obese) patients exhibit longer survival compared to patients of ideal weight. This group also demonstrated a reduction of regulatory T cells with supposedly protumor activity and an increase of Natural Killer (NK)-like T cells with supposedly antitumor activity. Additionally, we have found that excess weight correlates with better treatment response, associated with elevated levels of vitamin D and CD8 + NK cells. Conclusions Our findings suggest that excess weight does not exacerbate the progression of DLBCL. Instead, it appears to confer a survival advantage and improve treatment response, with the immune system playing a possible pivotal role in mediating these effects.Artículo Melatonin, an Antitumor Necrosis Factor Therapy(Wiley, 2024-12-30) Álvarez López, Ana Isabel; Cruz Chamorro, Iván; Lardone, Patricia Judith; Bejarano Hernando, Ignacio; Aspiazu-Hinostroza, K; Ponce-España, E; Santos Sánchez, Guillermo; Álvarez Sánchez, Nuria; Carrillo Vico, Antonio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Consejería de Economía, Conocimiento, Empresa y Universidad de la Junta de Andalucía; Consejería de Salud de la Junta de Andalucía; Junta de Andalucía; Gobierno de España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla. CTS160: Neuroinmunoendocrinología MolecularTumor necrosis factor (TNF) is a biomarker of inflammation whose levels are elevated in patients with several diseases associated with dysregulation of the immune response. The main limitations of currently used anti-TNF therapies are the induction of immunodepression, which in many cases leads to serious adverse effects such as infection and cancer, and the inability to cross the blood-brain barrier in neuroinflammatory conditions. Melatonin, in addition to being a chronobiotic compound, is widely known for its antioxidant and immunomodulatory capacity to control inflammatory processes in different pathological contexts. The aim of the present review is to address human-based studies that describe the effect of melatonin on TNF production. The review includes all the articles published in PubMed databases until April 15, 2024. After depuration, 45 studies were finally included in the review, 23 related to the in vitro action of melatonin in human cells and 22 in vivo studies in humans. Most of the data reviewed support the idea that melatonin has an immunosuppressive effect on TNF levels, which, together with its low toxicity profile, low cost, and ability to cross the blood-brain barrier, points to melatonin as a potential anti-TNF therapy. Therefore, improving our knowledge of the action of melatonin in regulating TNF through appropriate clinical trials would reveal the true potential of this molecule as a possible anti-TNF therapy.Artículo Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO(Springer, 2025-03-25) Puerta, Raquel; de Rojas, Itziar; García-González, Pablo; Olivé, Clàudia; Sotolongo-Grau, Oscar; García-Sánchez, Ainhoa; Real Navarrete, Luis Miguel; Mir Rivera, Pablo; Ruiz, Agustín; Alzheimer’s Disease Neuroimaging Initiative; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina; Instituto de Biomedicina de Sevilla (IBIS); Gobierno de España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane's anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology.Artículo Decreased number of myeloid-derived suppressor cells in the placental trophoblast of gestational diabetes mellitus. Possible role of leptin(Elsevier, 2025-03-25) Tami, Malika; Hontecillas-Prieto, Lourdes; García-Domínguez, Daniel J.; Flores-Campos, Rocío; Vilariño-García, Teresa; Sanchez Jimenez , Flora; Guadix, Pilar; Dueñas Díez, José Luis; Jimenez Cortegana, Carlos; Cruz Merino, Luis de la; Pérez Pérez, Antonio; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Medicina; Instituto de Biomedicina de Sevilla (IBIS); FEDER Funds; Instituto de Salud Carlos III (ISCIII); Universidad de Sevilla. CTS607: Salud Reproductiva de la Mujer; Universidad de Sevilla. CTS151: Bioquímica MedicaGestational diabetes mellitus (GDM) is the most common complication of pregnancy and significantly increases both maternal and fetal morbidity and mortality. Inflammation is a hallmark of GDM, and placental inflammation may play a key role in the pathophysiology of the disease. Myeloid-derived suppressor cells (MDSCs), which are innate immunosuppressive, are thought to contribute to feto-maternal tolerance. In normal pregnancies, elevated levels of MDSCs have been observed in both peripheral and umbilical cord blood. Our hypothesis postulates that trophoblasts from placentas belonging to women with GDM may have lower levels of MDSCs compared to trophoblasts from placentas originating from healthy pregnancies. Furthermore, since leptin is overexpressed in the placenta of GDM patients, we hypothesized that leptin might contribute to the reduction of MDSCs. To test this, we investigated the in vitro effects of leptin on MDSC levels in isolated peripheral blood leukocytes after 24 h of incubation. Our findings indicate that trophoblasts from placentas from women with GDM contain a lower percentage of MDSCs compared to trophoblasts from healthy pregnancies. In addition, in vitro studies demonstrated that leptin reduces the number of MDSCs in peripheral blood leukocytes. In conclusion, MDSCs are decreased in placentas from pregnancies with GDM, and leptin appears to reduce the number of MDSCs in leukocytes isolated in vitro. Increased leptin expression in trophoblasts from placentas of women with GDM may contribute to the lower levels of MDSCs, potentially playing a role in placental inflammation. However, further investigations are required to fully elucidate this mechanism.Artículo Analysis of lipoprotein (a) determination in a selection of Spanish Clinical Laboratories. Batary study(Elsevier, 2025) Arrobas Velilla, Teresa; Martin Perez, Salomon; Fernández Prendes, Carla; Castro Castro, Maria Jose; Camos Anguila, Silvia; León Justel, Antonio; Proyecto Batary; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e InmunologíaIntroducción La lipoproteína (a) (Lp(a)) es considerada como un factor independiente de la enfermedad cardiovascular arteriosclerótica con alta prevalencia, pero la disponibilidad de datos reales y actualizados en España, así como los protocolos de determinación son limitados. Objetivo principal Analizar el estado actual del proceso preanalítico, analítico y postanalítico de la Lp(a) y valorar por su relación con otras variables. Material y método Estudio retrospectivo, observacional, multicéntrico, anonimizado realizado en el año 2022 por encuesta a laboratorios clínicos. Resultados Se obtuvieron 21.926 determinaciones correspondientes a 49 laboratorios. Los valores obtenidos fueron: Lp(a) > 30 mg/dl = 46,87%, Lp(a) > 50 mg/dl 35,31%, Lp(a) > 70 mg/dl = 26,8%, Lp(a) > 90 mg/dl = 19,3%, con predominio de superioridad en el genero femenino en todos los puntos de corte establecidos. Casi el 30% de los médicos de atencion primaria no tienen acceso a su solicitud. El 56,9% no disponen de criterio de rechazo. El 70,6% no disponen de protocolos para su determinación. Existen 2 técnicas analíticas predominantes, la inmunonefelometria (40%) y la inmunoturbidimetría (60%), El 24% utiliza nmon/l, el 68% mg/dl y un 8% informa ambas. Conclusiones Existe un bajo numero de pacientes que presenta medición de Lp(a), y de ellos el porcentaje de pacientes según puntos de corte de riesgo son más elevados que los descritos. Existe falta de uniformidad en procesos pre-analiticos, analítico y postanalítico en los que hay que trabajar de forma multidisciplinar para evitar futuros eventos cardiovasculares.Artículo IFNL4 genotype influences the rate of HIV-1 seroconversion in men who have sex with men(Taylor & Francis INC; Informa UK Limited, 2022-04-28) Meza, Giovanna; Galian, Fatima; Jaimes-Bernal, Claudia; Márquez Lasso, Fernando J.; Sinangil, Faruk; Scagnolari, Carolina; Real Navarrete, Luis Miguel; Forthal, Donald; Caruz, Antonio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Ministerio de Economia, Industria y Competitividad, Spain; European Regional Development Fund; AUIP (Asociacion Universitaria Iberoamericana de Postgrado)Individuals lacking interferon lambda 4 (IFNL4) protein due to a common null mutation (rs368234815) in the IFNL4 gene display higher resistance against several infections. The influence of IFNL4 on HIV-1 infection is still under discussion and conflicting results have been reported. This study intended to corroborate or refute the association of the null allele of IFNL4 and HIV-1 predisposition in a cohort of men who have sex with men (MSM). IFNL4 null genotype was assessed on 619 HIV-1-seronegative MSM who were followed for 36 months during a trial of a prophylactic vaccine against HIV-1. Of those, 257 individuals seroconverted during this period. A logistic regression model was constructed including demographic and IFNL4 genotype. In addition, a meta-analysis using data from the current study and other European populations was conducted. The null IFNL4 genotypes were correlated with lower HIV-1 seroconversion (Adjusted OR = 0.4 [95%CI: 0.2-0.8], P = 0.008) and longer time to seroconversion (889 vs. 938 days, P= 0.01). These results were validated by a meta-analysis incorporating data from other European populations and the result yielded a significant association of the IFNL4 null genotype under a dominant model with a lower probability of HIV-1 infection (OR=0.4 [95% CI: 0.3-0.6]; P= 1.3 x 10E-5).Artículo A Lupin (Lupinus angustifolius) Protein Hydrolysate Decreases the Severity of Experimental Autoimmune Encephalomyelitis: A Preliminary Study(MDPI, 2024-12-24) Cruz Chamorro, Iván; Alvarez-Lopez, Ana Isabel; Santos Sánchez, Guillermo; Álvarez-Sánchez, Nuria; Pedroche, Justo; Millán Linares, María del Carmen; Lardone, Patricia Judith; Carrillo Vico, Antonio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Consejeria de Economia, Conocimiento, Empresas y Universidad; Consejeria de Salud y Familias, Junta de Andalucia; Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucia; Ministerio de Ciencia e Innovacion, Gobierno de Espana (RETICEF); Ministerio de Economia y Competitividad, Gobierno de España; Ministerio de Educacion, Cultura y Deporte, Gobierno de España; National Net NutriCrop - Ministerio de Ciencia e Innovacion; PAIDI Program Andalusian Government; Universidad de Sevilla. CTS160: Neuroinmunoendocrinología MolecularMultiple sclerosis (MS) is a neurodegenerative disease, with inflammation and oxidative stress in the central nervous system being the main triggers. There are many drugs that reduce the clinical signs of MS, but none of them cure the disease. Food proteins have been shown to contain encrypted peptides that can be released after hydrolysis and exert numerous biological activities. Recently, we have demonstrated the anti-inflammatory and antioxidant activities of a lupin protein hydrolysate (LPH) both in vitro and in vivo. Therefore, the aim of this study was to evaluate whether LPH is capable of reducing the clinical signs of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE was induced in female C57BL/6N mice and they were treated intragastrically with LPH (100 mg/kg) or vehicle (control group) from day 0 (prophylactic approach) or from the onset of the disease (day 12 post-induction; therapeutic approach) and the clinical score of each mouse was recorded daily. Prophylactic treatment with LPH reduced the clinical score of the mice compared to the control group, as well as the maximum and cumulative scores, without changing the day of onset of the symptoms while the therapeutic intervention did not significantly improve the severity of the disease. For the first time, we demonstrated that prophylactic administration of LPH reduces the severity of MS, suggesting a potential nutraceutical or new functional foods in neuroinflammation. However, further studies are needed to confirm this nutritional effect in a clinical context.Artículo Long-Term Mental Health after High-Density Polyethylene-Based Porous Orbital Implant in Enucleated and Eviscerated Patients(Mdpi, 2024-08-27) Garrido Hermosilla, Antonio Manuel; Martínez-Alberquilla, Irene; Díaz-Ruiz, María C; Monge-Carmona, Raquel; Méndez-Muros, Mariola; López Díaz, Álvaro; Sánchez Margalet, Víctor; Gutiérrez Sánchez, Estanislao; Relimpio-López, María Isabel; Rodríguez de la Rúa Franch, Enrique; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Psiquiatría; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. CTS1086: Psiquiatría Traslacional; Universidad de Sevilla. CTS151: Bioquímica MedicaObjectives: To assess the overall mental health of enucleated or eviscerated patients after high-density porous polyethylene OCULFIT implantation and external prosthesis over a 1-year follow-up. Methods: Patients with an indication of enucleation or evisceration with OCULFIT implantation were included in a prospective study. The patients completed four questionnaires regarding mental health at three different visits (baseline, 3–6 months, and 9–12 months post-surgery). The questionnaires used were the following: SF-12 for multidimensional health-related quality of life (scale 0–100); Rosemberg self-esteem scale (scale 0–40); Patients Health Questionnaire-4 (PHQ-4) (scale 0–6); and a Lifetime Major Depression and Anhedonia questionnaire (categorised in groups with/without symptoms). Results: A total of 33 patients (16 enucleations and 17 eviscerations) were included in the study. The physical domain of the SF-12 questionnaire did not change between visits, but the mental domain significantly improved from the baseline to the last visit (41.71 ± 12.72 vs. 46.80 ± 10.68, p = 0.04). The number of patients with high, moderate, and low self-esteem (Rosemberg scale) was similar between the baseline and the last visit. The depression and anxiety scores of the PHQ-4 were not significantly different among visits. The number of patients with no symptoms (depression or anhedonia) improved from the baseline (42.2%) throughout the follow-up (66.7% at the last visit). Conclusions: OCULFIT orbital implant and external prosthesis placement maintained and/or improved the quality of life related to mental health in eviscerated and enucleated eyes. The number of patients with no symptoms improved from the baseline throughout the follow-up. The patients’ self-esteem was already high before implantation and remained stable over the follow-up.Artículo Characterization of Rugulopteryx okamurae algae: A source of bioactive peptides, omega-3 fatty acids, and volatile compounds(Elsevier, 2025-05-01) Rivero Pino, Fernando; González de la Rosa, Teresa; Torrecillas López, María; Barrera Chamorro, Luna; Río-Vázquez, José Luis del; Márquez Parada, Elvira; Fernández Prior, África; Garcáa-Vaquero, Marco; García Gómez, José Carlos; Montserrat de la Paz, Sergio; Claro Cala, Carmen María; Universidad de Sevilla. Departamento de Zoología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaThis study provides a detailed characterization of the invasive algae Rugulopteryx okamurae, highlighting its nutritional composition, mineral content, and potential bioactive compounds. This biomass contains 14.18 % protein, 21.29 % lipids (with a high omega-3 content), fibre (31.32 %), and significant amounts of minerals like calcium, sodium, potassium, sulphur, and iron. Phenolic compounds (0.74 %) and volatile compounds, such as retinol, were also identified. Peptidome analysis revealed 626 unique peptides, with 21 low molecular weight peptides showing potential activity against angiotensin converting enzyme and dipeptidyl peptidase IV when assessed using in silico tools and using molecular docking. Additionally, the antioxidant capacity of the alga was demonstrated with a significant free radical inhibition (EC50: 2.09 mg/mL). Overall, this study provides initial evidence on the nutritional potential of R. okamurae, which may have potential for future applications in food and biotechnology fields.Artículo Genotype–phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants(BioMed Central, 2021-05-21) Hernández Arévalo, Paula; Santotoribio, José D.; Delarosa Rodríguez, Rocío; González-Meneses López, Antonio; García Morillo, Salvador; Jiménez Arriscado, Pilar; Guerrero Montávez, Juan Miguel; Macher, Hada C.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI); European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Background: Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype–phenotype correlation. Methods: A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Results: Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7–64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. Conclusions: This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.Artículo The combination of epigenetic drugs SAHA and HCI-2509 synergistically inhibits EWS-FLI1 and tumor growth in Ewing sarcoma(Impact Journals Llc, 2018-07-31) García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Rodríguez-Núñez, Pablo; Pascual-Pasto, Guillem; Vila-Ubach, Monica; García-Mejías, Rosa; Robles, María José; Tirado, Oscar M.; Mora, Jaume; Carcaboso, Angel M.; Álava Casado, Enrique de; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica; Universidad de Sevilla. CTS1035: Patología Molecular del Cáncer SólidoPurpose: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments. Results: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume. Conclusions: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.Artículo Expression and immunohistochemical localization of leptin in human periapical granulomas(Medicina oral S L, 2015) Martín González, Jenifer; Carmona-Fernández, Antonio; Pérez Pérez, Antonio; Sánchez Jiménez, Flora; Sánchez Margalet, Víctor; Segura Egea, Juan José; Universidad de Sevilla. Departamento de Estomatología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. CTS941: Patología Dentaria, Operatoria Dental y Endodoncia; Universidad de Sevilla. CTS151: Bioquímica Medicaackground: Leptin, initially described as an adipocyte-derived hormone to regulate weight control, is expressed in normal and inflamed human dental pulp, being up-regulated during pulp experimental inflammation. Leptin receptor (LER) has been identified in human periapical granulomas. The aim of this study was to analyze and characterize the expression of leptin in human periapical granulomas. Material and methods: Fifteen periapical inflammatory lesions were obtained from extracted human teeth and teeth which underwent periapical surgery. After their morphological categorization as periapical granulomas and gradation of the inflammatory infiltrate, they were examined by immunohistochemistry using human leptin policlonal antibodies. Leptin mRNA expression was also determined by quantitative real-time PCR (qRT-PCR) and the amount of leptin protein was analyzed by immunoblot. Results: All periapical lesions exhibited the characteristic of chronic granulomatous inflammatory process with inflammatory infiltrate grade III. Leptin+ cells were detected in 13 periapical granulomas (86.6%). The median number of Leptin+ cells in periapical granulomas was 1.70 (0.00-7.4). Amongst the inflammatory cells in the periapical granulomas, only macrophages were reactive to leptin antibodies. Western blot analysis revealed the presence in all samples of a protein with apparent molecular weight of approximately 16 kDa, corresponding to the estimated molecular weights of leptin. The expression of leptin mRNA was confirmed by qRT-PCR analysis and the size of the amplified fragment (296 bp for leptin and 194 bp for cyclophilin) was assessed by agarose gel electrophoresis. Conclusions: For the first time, it has been demonstrated that human periapical granuloma expresses the adipokine leptin.Artículo Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review)(International journal of oncology; Espandidos Publications Ltd, 2024-06-27) Jiménez Cortegana, Carlos; Gutiérrez-García, Cristian; Sánchez Jiménez, Flora; Vilariño-García, Teresa; Flores-Campos, Rocío; Pérez Pérez, Antonio; Garnacho Montero, Carmen; García-Domínguez, Daniel J.; Cruz Merino, Luis de la; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica; Universidad de Sevilla. Departamento de Medicina; Junta de Andalucía; Universidad de Sevilla. CTS151: Bioquímica Medica; Universidad de Sevilla. CTS229: BioPatología CelularAbstract. Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abili ties. Obesity associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipo cytes, plays in MDSC driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity related cancer.Artículo Ketone Bodies Are Potential Prognostic Biomarkers in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results from the R2-GDP-GOTEL Trial(Multidisciplinary Digital Publishing Institute (MDPI), 2025-02-05) Fernández-Castillejo, Sara; Badia, Joan; Cruz Merino, Luis de la; Martín Garcia-Sáncho, Alejandro; Carnicero-González, Fernando; Palazón-Carrión, Natalia; Ríos Herranz, Eduardo; Cruz-Vicente, Fátima de la; Rueda-Domínguez, Antonio; Martínez-Banaclocha, Natividad; Sánchez Margalet, Víctor; Jiménez Cortegana, Carlos; Gumà, Josep; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e InmunologíaBackground: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL. Methods: This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p < 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5–24.1; acetone: HR 9.32, 95% CI 2.75–31.6) and OS (3OHB: HR 9.32, 95% CI 2.75–31.6; acetone: HR 1.92, 95% CI 1.36–2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization. Conclusions: The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status.Artículo Nutritional modulation of leptin expression and leptin action in obesity and obesity-associated complications(Elsevier Science Inc, 2021) Montserrat de la Paz, Sergio; Pérez Pérez, Antonio; Vilariño-García, Teresa; Jiménez Cortegana, Carlos; Muriana, Francisco Javier G.; Millán Linares , Carmen; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; Universidad de Sevilla. CTS151: Bioquímica Medica; Universidad de Sevilla. CTS1074: Inmunonutrición e InmunometabolismoIn obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.Artículo Expression of nutrient transporters in placentas affected by gestational diabetes: role of leptin(Frontiers Media S.A., 2023-07) Guadix, Pilar; Corrales-Gutiérrez, Isabel; Vilariño García, Teresa; Rodríguez Chacón, Carmen; Sánchez Jiménez, Flora; Jiménez Cortegana, Carlos; Dueñas, José L.; Sánchez Margalet, Víctor; Pérez Pérez, Antonio; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. CTS607: Salud Reproductiva de la Mujer; Universidad de Sevilla. CTS151: Bioquímica MedicaGestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased nutrient transport in the placenta. Recent studies by our group have demonstrated that leptin is a key hormone in placental physiology, and its expression is increased in placentas affected by GDM. However, the effect of leptin on placental nutrient transport, such as transport of glucose, amino acids, and lipids, is not fully understood. Thus, we aimed to review literature on the leptin effect involved in placental nutrient transport as well as activated leptin signaling pathways involved in the expression of placental transporters, which may contribute to an increase in placental nutrient transport in human pregnancies complicated by GDM. Leptin appears to be a relevant key hormone that regulates placental transport, and this regulation is altered in pathophysiological conditions such as gestational diabetes. Adaptations in the placental capacity to transport glucose, amino acids, and lipids may underlie both under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered due to changes in maternal nutrition or metabolic disease. Implementing new strategies to modulate placental transport may improve maternal health and prove effective in normalizing fetal growth in cases of intrauterine growth restriction and fetal overgrowth. However, further studies are needed to confirm this hypothesis.Artículo Leptin and Leptin Signaling in Multiple Sclerosis: A Narrative Review(Springer Nature, 2025-02-28) Flores Cordero, Juan Antonio; Aranaz Murillo, Amalia; Vilariño-García, Teresa; Pérez Pérez, Antonio; Izquierdo, Guillermo; Flores-Campos, Rocío; Hontecillas-Prieto, Lourdes; García-Domínguez, Daniel J.; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Junta de AndalucíaObesity, a pandemic health problem, is now considered as a chronic inflammatory state, related to many autoimmune diseases, such as multiple sclerosis. Thus, adipokines, inflammatory mediators secreted by adipose tissue, play an important role modulating the immune response. In this context, obesity, especially during adolescent age, seems to be a key factor for the development of multiple sclerosis. Leptin, the main pro-inflammatory adipokine secreted by the adipose tissue, has been found increased in patients with multiple sclerosis and is able to regulate the immune system promoting a pro-inflammatory response. Leptin signaling in both innate and adaptative immune cells might have immunomodulatory effects in the context of multiple sclerosis. In this way, leptin has been found to produce a Th1 and Th17 response, increasing M1 macrophages and decreasing regulatory T cells and Th2 response. Moreover, circulating inflammatory adipokines, such as leptin, have been found in people with multiple sclerosis. In the present work, we are reviewing literature to update the body of knowledge regarding the role of obesity and leptin in multiple sclerosis.Artículo A comprehensive review on the functionality and biological relevance of pectin and the use in the food industry(Elsevier, 2024-09-26) Barrera Chamorro, Luna; Fernández Prior, África; Rivero Pino, Fernando; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Gobierno de España; Universidad de Sevilla. CTS1074: Inmunonutrición e InmunometabolismoPectin is a natural biopolymer, which can be extracted from food by-products, adding value to raw material, with a structure more complex than that of other polysaccharides. The gelling properties of these molecules, together with the bioactivity that these can exert, make them suitable to be used as ingredients and bioactive agents. In this review, the characterization of pectin (structure, sources, techno-functional, and biological properties), the extraction methods, and their use in the food industry (food packaging, as carriers, and as ingredients) are described. Different by-products can be used as substrates to extract pectin, enhancing a sustainable food system as described by the circular economy principles. Pectin is characterized for their techno-functional and biological properties, such as gelling and thickening properties or modulation of microbiota both in animals and humans. Such properties make these molecules suitable for a wide range of applications within the food chain, serving as packaging or carriers in foodstuff, or for direct use as functional ingredients as fiber. Overall, pectin has been shown to exert as promising components to be introduced in the food system, although further research on scaling-up the production process and feasibility has to be done.Artículo Food-derived vesicles as immunomodulatory drivers: Current knowledge, gaps, and perspectives(Elsevier, 2024-06-20) Rivero Pino, Fernando; Márquez Parada, Elvira; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Gobierno de EspañaExtracellular vesicles (EVs) are lipid-bound membrane vesicles released from cells, containing active compounds, which can be found in different foods. In this review, the role of food-derived vesicles (FDVs) as immunomodulatory drivers is summarized, with a focus on sources, isolation techniques and yields, as well as bioavailability and potential health implications. In addition, gaps and perspectives detected in this research field have been highlighted. FDVs have been efficiently extracted from different sources, and differential ultracentrifugation seems to be the most adequate isolation technique, with yields ranging from 108 to 1014 EV particles/mL. Animal studies show promising results in how these FDVs might regulate different pathways related to inflammation. Further investigation on the production of stable components in a cost-effective way, as well as human studies demonstrating safety and health-promoting properties, since scarce information has been reported until now, in the context of modulating the immune system are needed.Artículo Neuroprotective effect of mealworm protein hydrolysate-derived bioactive peptides in human microglial cells(Brill Academic Publishers, 2024-12-07) González de la Rosa, Teresa; del Valle Alonso, M.A.; Montserrat de la Paz, Sergio; Rivero Pino, Fernando; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e InmunologíaThe larva of Tenebrio molitor, better known as mealworm, is one of the most studied insects today, since it was recently classified as safe for human consumption. Specifically, its high protein content makes it a splendid candidate for the search for bioactive peptides, with properties ranging from anti-inflammatory to neuroprotective. In this study, the effect of a digested hydrolysate on microglia cells (which previously demonstrated high anti-inflammatory activity in intestinal CACO-2 cells) was analysed, specifically on their levels of gene expression of various cytokines, such as IL-6, IL-10, or IL-1β, among others. In addition, four chemically synthesised peptides, selected from this digested hydrolysate based on in silico analysis, including the estimation of the bioactive properties of these peptides, their physicochemical properties and their toxicokinetic, were evaluated in the microglia cells as well. In addition, molecular docking assays of the peptides were performed with two receptors relevant to inflammation. Relevant changes in the expression of IL-6, IL-1β, and BDNF were observed due to the action of the peptides, especially in the case of IYVDAVIN and SLPSLPEPV. These results provide an insight on how specific peptides found in Tenebrio molitor could be used as therapeutics agent in the immunomodulation of brain cells.