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Circulating miR-320a as a Predictive Biomarker for Left Ventricular Remodelling in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention
(2020) Galeano-Otero, Isabel; Toro Estévez, Raquel del; Guisado Rasco, Agustín; Díaz, Ignacio; Mayoral González, Isabel; Guerrero Márquez, Francisco; Ordóñez Fernández, Antonio; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica
Restoration of epicardial coronary blood flow, achieved by early reperfusion with primary percutaneous coronary intervention (PPCI), is the guideline recommended to treat patients with ST-segment-elevation myocardial infarction (STEMI). However, despite successful blood restoration, increasing numbers of patients develop left ventricular adverse remodelling (LVAR) and heart failure. Therefore, reliable prognostic biomarkers for LVAR in STEMI are urgently needed. Our aim was to investigate the role of circulating microRNAs (miRNAs) and their association with LVAR in STEMI patients following the PPCI procedure. We analysed the expression of circulating miRNAs in blood samples of 56 patients collected at admission and after revascularization (at 3, 6, 12 and 24 h). The associations between miRNAs and left ventricular end diastolic volumes at 6 months were estimated to detect LVAR. miRNAs were also analysed in samples isolated from peripheral blood mononuclear cells (PBMCs) and human myocardium of failing hearts. Kinetic analysis of miRNAs showed a fast time-dependent increase in miR-133a, miR-133b, miR-193b, miR-499, and miR-320a in STEMI patients compared to controls. Moreover, the expression of miR-29a, miR-29b, miR-324, miR-208, miR-423, miR-522, and miR-545 was differentially expressed even before PPCI in STEMI. Furthermore, the increase in circulating miR-320a and the decrease in its expression in PBMCs were significantly associated with LVAR and correlated with the expression of miR-320a in human failing myocardium from ischaemic origin. In conclusion, we determined the time course expression of new circulating miRNAs in patients with STEMI treated with PPCI and we showed that miR-320a was positively associated with LVAR.
Hempseed (Cannabis sativa) protein hydrolysates: A valuable source of bioactive peptides with pleiotropic health-promoting effects
(ScienceDirect, 2022) Santos-Sánchez, Guillermo; Álvarez-López, Ana Isabel; Ponce España, Eduardo; Carrillo Vico, Antonio; Bollati, Carlotta; Cruz-Chamorro, Ivan; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología
Background: Recently, the study of hydrolysates from food proteins has been increasingly due to their wide range of biological activities. Hydrolysates contain peptides of 2–20 amino acids that are inactive within the sequence of the parent protein, but, once released after proteolytic processes, they exert numerous beneficial health effects. Hemp, the non-drug variety of Cannabis sativa, is known as an important source of bioactive peptides due to the high quality of hempseeds protein (20–25%) and well-balanced amino acid profile. For this reason, during the last decade, numerous investigations have searched to elucidate the beneficial effects on the health of these hempseed protein hydrolysates. Scope and approach: The aim of this review was to collect all the scientific evidence on the demonstrated beneficial effects of hempseed protein hydrolysates (HHs). Key findings and conclusions: HHs have showed to possess antioxidant, immunomodulatory, hypotensive, hypo- glycemic, and lipid-lowering capacities in vitro systems. All these effects have pointed out HHs as future ingredient for the development of functional foods or dietary supplements useful for the prevention of chronic diseases such as metabolic syndrome, diabetes or hypertension. However, few studies have evaluated the in vivo effects of HHs. For this reason, further studies carried out in animal models or human are necessary to better exploit the use of HHs for the development of new dietary supplements.
Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study
(Elsevier, 2021) Gutiérrez Gutiérrez, Belén; Toro López, María Dolores del; Borobia, Alberto M.; Carcas, Antonio; Jarrín, Inmaculada; Yllescas, María; Pachón Díaz, Jerónimo; Rodríguez-Baño, Jesús; Salamanca Rivera, Celia; Valido-Morales, Agustín S.; Retamar Gentil, Pilar; Cisneros, José Miguel; Nieto Martín, María Dolores; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Medicina Preventiva y Salud Pública; Instituto de Salud Carlos III
Background The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality. Methods In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model. Findings Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)— phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p<0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4–8·1] for phenotype A, 31·3% [28·5–34·2] for phenotype B, and 59·5% [48·8–69·3] for phenotype C; external validation cohort: 3·7% [2·0–6·4] for phenotype A, 23·7% [21·8–25·7] for phenotype B, and 51·4% [41·9–60·7] for phenotype C). Interpretation Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated.
Impact of De-escalation on Prognosis of Patients With Bacteremia due to Enterobacteriaceae: A Post Hoc Analysis From a Multicenter Prospective Cohort
(Oxford University Press, 2019) Palacios-Baena, ZR; Delgado Valverde, Mercedes; Mendez, AV; Almirante, Benito; Gomez-Zorrilla, S; Borrell, N; Corzo Delgado, Juan Enrique; Pascual Hernández, Álvaro; Rodríguez-Baño, Jesús; Cueto López, Marina de; Lepe Jiménez, José Antonio; Cisneros, José Miguel; Lara, R; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Medicina; European Development Regional Fund "A Way to Achieve Europe," Spanish Network for Research in Infectious Diseases
Background More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. The aims of this study were to investigate predictors of de-escalation and its impact on the outcome of patients with bloodstream infection due to Enterobacteriaceae (BSI-E). Methods A post hoc analysis was performed on a prospective, multicenter cohort of patients with BSI-E initially treated with ertapenem or antipseudomonal β-lactams. Logistic regression was used to analyze factors associated with early de-escalation (EDE) and Cox regression for the impact of EDE and late de-escalation (LDE) on 30-day all-cause mortality. A propensity score (PS) for EDE vs no de-escalation (NDE) was calculated. Failure at end of treatment and length of hospital stay were also analyzed. Results Overall, 516 patients were included. EDE was performed in 241 patients (46%), LDE in 95 (18%), and NDE in 180 (35%). Variables independently associated with a lower probability of EDE were multidrug-resistant isolates (odds ratio [OR], 0.50 [95% confidence interval {CI}, .30–.83]) and nosocomial infection empirically treated with imipenem or meropenem (OR, 0.35 [95% CI, .14–.87]). After controlling for confounders, EDE was not associated with increased risk of mortality; hazard ratios (HR) (95% CIs) were as follows: general model, 0.58 (.25–1.31); model with PS, 0.69 (.29–1.65); and PS-based matched pairs, 0.98 (.76–1.26). LDE was not associated with mortality. De-escalation was not associated with clinical failure or length of hospital stay. Conclusions De-escalation in patients with monomicrobial bacteremia due to Enterobacteriaceae was not associated with a detrimental impact on clinical outcome.
In vivo confocal microscopy indicates an inverse relationship between the sub-basal corneal plexus and the conjunctivalisation in patients with limbal stem cell deficiency
(BMJ Journals, 2019) Caro Magdaleno, Manuel; Alfaro-Juarez, Asunción; Montero Iruzubieta, Jesús; Fernández Palacín, Ana; Muñoz Morales, Ana; Castilla Martino, Manuel Alberto; Spínola Muñoz, Consuelo; Rodríguez-de-la-Rúa, Enrique; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Medicina Preventiva y Salud Pública; Universidad de Sevilla. CTS-312: Análisis de la Demanda Sanitaria
Background/aims: Limbal stem cell deficiency (LSCD) is characterised by a marked decrease in limbal stem cells. It is classified primarily using subjective slit-lamp observations. In vivo confocal microscopy (IVCM) can non-invasively provide objective information on the condition of the limbal niche, the corneal epithelial basal cell density and the corneal sub-basal nerve plexus density (SND). We here used IVCM to evaluate changes in SND to improve LSCD classification. Methods: We evaluated and classified 38 patients (76 eyes, 44 with LSC and 32 control eyes) using the Rama, López-García and Deng (clinical and confocal) classifications and evaluated the concordance of the confocal and clinical classifications. We constructed a logistic regression model using multivariate analysis to correlate different degrees of conjunctivalisation with IVCM parameters and used receiver operating characteristic (ROC) curve analysis to establish the SND cut-off value with maximum diagnostic sensitivity and specificity. Results: The classification systems correlated moderately at best (kappa, 0.449). The corneal SND of cases (6469±6295 µm/mm2) was less (p<0.001) than in controls (20911±4142 µm/mm2). The SND, but not basal cell density, played a protective role against conjunctivalisation (OR, 0.069; 95% CI 0.008–0.619; p=0.01). An SND cut-off value of 17 215 µm/mm2 yielded a sensitivity and specificity of 95.5% and 90.6%, respectively, for LSCD diagnosis. Conclusion: The density of the corneal sub-basal nerve plexus was inversely related to conjunctivalisation in LSCD. Further studies are needed to verify this and to elucidate the directionality between these factors.
Lenalidomide plus R-GDP (R2-GDP) in Relapsed/ Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis
(AMER ASSOC CANCER RESEARCH, 2022) Palazón Carrión, Natalia; Martín García-Sancho, Alejandro; Nogales-Fernández, Esteban; Jiménez Cortegana, Carlos; Carnicero-González, Fernando; Ríos Herranz, Eduardo; Sánchez Margalet, Víctor; Rueda Domínguez, Antonio; Cruz Merino, Luis de la; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Purpose: New therapeutic options are needed in relapsed/refrac tory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide based schedules can reverse rituximab refractoriness in lymphoma. Patients and Methods: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1–14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1–3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1–21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Reg ister number: EudraCT 2014-001620-29). Results: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3–4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutro penia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. Conclusions: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.
NK cells and solid tumors therapeutic potential and persisting obstacles
(BMC, 2022-11-01) Tong, Le; Jiménez Cortegana, Carlos; Tay, Apple H.M.; Wickström, Stina; Galluzzi, Lorenzo; Lundqvist, Andreas; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; 2019 Laura Ziskin Prize in Translational Research; Cancer Research Foundations of Radiumhemmet; Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US); donations from Promontory (New York, US); Functional Genomics Initiative (New York, US); Leukemia and Lymphoma Society (LLS); Luke Heller TECPR2 Foundation (Boston, US); Lytix Biopharma (Oslo, Norway); NIH/NCI; Noxopharm (Chatswood, Australia); Onxeo (Paris, France); Ricerchiamo (Brescia, Italy); romontory (New York, US); Sotio a.s. (Prague, Czech Republic); Stand Up to Cancer (SU2C); Swedish Cancer Society; Swedish Childhood Cancer Foundation; US DoD BCRP
Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.
Polyphenolic Maqui Extract as a Potential Nutraceutical to Treat TNBS-Induced Crohn' s Disease by the Regulation of Antioxidant and Anti-Inflammatory Pathways
(MDPI, 2020) Ortiz Cerda, Tamara Andrea; Argüelles Arias, Federico; Illanes Moreno, Matilde; García Montes, Josefa María; Talero Barrientos, Elena Mª; Macías García, Laura; Alcudia Cruz, Ana; Vázquez Román, María Victoria; Motilva Sánchez, Virginia; Miguel Rodríguez, Manuel de; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica; Ministerio de Educación y Ciencia (MEC). España; Junta de Andalucía
Nutraceuticals include a wide variety of bioactive compounds, such as polyphenols, which have been highlighted for their remarkable health benefits. Specially, maqui berries have shown great antioxidant activity and anti-inflammatory effects on some inflammatory diseases. The objectives of the present study were to explore the therapeutic effects of maqui berries on acute-phase inflammation in Crohn’s disease. Balb/c mice were exposed to 2,4,6-trinitrobenzene sulfonic acid (TNBS) via intracolonic administration. Polyphenolic maqui extract (Ach) was administered orally daily for 4 days after TNBS induction (Curative Group), and for 7 days prior to the TNBS induction until sacrifice (Preventive Group). Our results showed that both preventive and curative Ach administration inhibited body weight loss and colon shortening, and attenuated the macroscopic and microscopic damage signs, as well as significantly reducing transmural inflammation and boosting the recovery of the mucosal architecture and its muco-secretory function. Additionally, Ach promotes macrophage polarization to the M2 phenotype and was capable of down-regulating significantly the expression of inflammatory proteins COX-2 and iNOS, and at the same time it regulates the antioxidant Nrf-2/HO-1 pathway. In conclusion, this is the first study in which it is demonstrated that the properties of Ach as could be used as a preventive and curative treatment in Crohn’s disease.
Population pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli
(Elsevier, 2018) Merino Bohórquez, Vicente; Docobo Pérez, Fernando; Sojo Dorado, Jesús; Morales, Isabel; Lupión Mendoza, Carmen; Martín, D.; Pascual Hernández, Álvaro; Rodríguez-Baño, Jesús; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Medicina
Objectives: To describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. Methods: Data of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. Results: Sixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. Conclusions: Fosfomycin concentrations are highly variable-a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non-critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised.
Primary Cilium in the Human Thyrocyte: Changes in Frequency and Length in Relation to the Functional Pathology of the Thyroid Gland
(Mary Ann Liebert, Inc. Publishers, 2019-04) Fernández-Santos, José María; Utrilla Alcolea, José Carmelo; Vázquez Román, María Victoria; Villar Rodríguez, José Luis; Gutiérrez-Avilés, Lorenzo; Martín Lacave, Inés María; ; Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica
Background: Primary cilia (PC) are conserved structures in the adult thyroid gland of different mammals. We have recently described that, in humans, PC are usually present as a single copy per follicular cell emerging from the follicular cell apex into the follicular lumen. Methods: To better understand the role developed by PC in thyroid hormonogenesis, we investigated their changes in different human functional thyroid diseases (diffuse toxic hyperplasia/ Grave’s disease and nodular hyperplasia/nodular goiter), in comparison with normal thyroid tissue, using immunofluorescence, morphometry and electron microscopy analyzes. Results: We found significantly decreased ciliary frequencies in both nodular hyperplasia (51.16±11.69%) and Grave’s disease (44.43±23.70%) vs. normal thyroid glands (76.09±7.31%). Similarly, PC lengths were also significantly decreased in both nodular hyperplasia (2.02±0.35 µm) and Grave’s disease (2.42±0.48 µm) compared to normal glands (3.93±0.90 µm). Moreover, in Grave’s disease patients, hyperactive-follicle foci always showed diminished ciliary frequency and length compared to any other thyroid follicle pattern, independent of their thyroid status. Conclusions: Our results suggest a direct relationship between ciliogenesis and both follicle activity and tissue heterogeneity. Furthermore, the analysis of PC patterns in the “normal-appearance areas” of Grave’s disease thyroid samples could be useful to identify subgroups of patients, who would be expected to have a poorer response to antithyroid drug treatment.
Role of blaTEM and OmpC in the piperacillin-tazobactam resistance evolution by E. coli in patients with complicated intra-abdominal infection
(Elsevier, 2023) Galvez-Benitez, Lydia; Ortiz de la Rosa, Jose Manuel; Rodríguez-Villodres, Angel; Casimiro-Soriguer, Carlos S.; Molina-Panadero, Irene; Alvarez-Marín, Rocío; Bonnin, Remy A; Naas, Thierry; Pachón Díaz, Jerónimo; Cisneros, José Miguel; Lepe Jiménez, José Antonio; Smani, Younes; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Medicina; Economa y Competitividad, Spain; Universidad Pablo de Olavide
Piperacillin-tazobactam resistance (P/T-R) is increasingly reported among Escherichia coli isolates. Although in vitro experiments have suggested that blaTEM gene plays a key role in the P/T-R acquisition, no clinical in vivo study has yet confirmed the role of blaTEM or other genes. Therefore, we aimed to identify the mechanisms underlying P/T-R by following up patients with E. coli complicated intra-abdominal infections (cIAI) who experienced P/T treatment failure. Four pairs of strains, clonally related from four patients, were isolated both before and after treatment with P/T dosed at 4 g/0.5 g intravenously. The P/T MIC was tested using broth microdilution, and β-lactamase activity was determined in these isolates. Whole-genome sequencing (WGS) was performed to decipher the role of blaTEM and other genes associated with P/T-R. Changes in the outer membrane protein (OMP) profile were analyzed using SDS-PAGE, and blaTEM and ompC transcription levels were measured by RT-qPCR. In addition, in vitro competition fitness was performed between each pairs of strains (P/T-susceptible vs. P/T-resistant). We found a higher copy number of blaTEM gene in P/T-R isolates, generated by three different genetic events: (1) IS26-mediated duplication of the blaTEM gene, (2) generation of a small multicopy plasmid (ColE-like) carrying blaTEM, and (3) adaptive evolution via reduction of plasmid size, leading to a higher plasmid copy number. Moreover, two P/T-R strains showed reduced expression of OmpC. This study describes the mechanisms involved in the acquisition of P/T-R by E. coli in patients with cIAI. The understanding of P/T-R evolution is crucial for effectively treating infected patients and preventing the spread of resistant microorganisms.
Serum IFN-γ and RNAemia temporal profiles as biomarkers of severe COVID-19 in solid organ transplant and immunocompetent patients
(Elsevier, 2023) Salto Alejandre, Sonsoles; Carretero-Ledesma, Marta; Camacho-Martínez, Pedro; Berastegui-Cabrera, Judith; Infante, Carmen; Rodríguez-Álvarez, Regino; Pérez Palacios, Patricia; Gómez Bravo, Miguel Ángel; Pascual Hernández, Álvaro; Lepe Jiménez, José Antonio; Rodríguez-Baño, Jesús; Cisneros, José Miguel; Pachón, Jerónimo; Sánchez-Céspedes, Javier; Cordero, Elisa; COVIDSOT working team; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Medicina; CIBERINFEC - Consorcio Centro de Investigacion Biomedica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion, Proyectos de Investigacion sobre el SARS-CoV-2 y la enfermedad COVID-19; Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Ciencia, Innovacion y Universidades, Spanish Network for Research in Infectious Diseases; Plan Nacional de I + D +i 2013-2016; Servicio Andaluz de Salud, Junta de Andalucia, Spain; Union Europea - NextGenerationEU
Serum lipid profile among sporadic and familial forms of Parkinson's disease
(Springer, 2021) Macías-García, D.; Periñán Tocino, María Teresa; Muñoz-Delgado, L.; Jiménez-Jaraba, M. V.; Labrador-Espinosa, Miguel Á.; Jesús, S.; Buiza-Rueda, D.; Mir Rivera, Pablo; Universidad de Sevilla. Departamento de Medicina; Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia; Consejeria de Salud y Bienestar Social de la Junta de Andalucia; Consejeria de Salud y Familias de la Junta de Andalucia; Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER)
Brain cholesterol metabolism has been described as altered in Parkinson’s disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.
Temporal expression patterns of the melatoninergic system in the human thymus of children
(Elsevier BV, 2019) Cruz-Chamorro, Ivan; Álvarez-Sánchez, Nuria; Escalante-Andicoechea, Cristina; Carrillo Vico, Antonio; Rubio, Amalia; Guerrero, Juan Miguel; Molinero, Patrocinio; Lardone, Patricia Judith; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología
Objectives: To obtain greater knowledge of the extra-pineal sources of melatonin during development, the amount of indolamine and the expression levels of the last two enzymes involved in its biosynthesis, Arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin Omethyltransferase (ASMT), were analyzed in the human thymus from children from three different age groups (from days to years). The melatonin membrane and nuclear receptor expression levels also were studied. Methods: Quantitative reverse transcriptase PCR and western blot were performed to investigate the receptor and enzyme expression levels. The results were examined and correlated with the ages of the thymuses. Results: We found high levels of indolamine in the thymuses of newborns (younger than 1 month), which decreased during development; thymuses from the months (from 2 to 11 months) and years (from 1 to 12 years) groups showed lower levels. A similar decline was also observed in the mRNA of the AANAT enzyme and the expression levels of melatonin receptors. However, ASMT expression was exactly the opposite, with low levels in the newborn group and higher levels in the years group. Our results show that the thymic synthesis of melatonin occurs very early in childhood. Additionally, this is the first report that is focused on melatonin receptors expression in the human thymus. Conclusion: Considering the limited melatonin synthesis performed by the newborn pineal gland, we suggest that the high levels of melatonin found in human thymus in this experimental group arise from synthesis in the tissue itself, which could be contributing to the immune efficiency at the thymic level.
Urocortin-2 Prevents Dysregulation of Ca2+ Homeostasis and Improves Early Cardiac Remodeling After Ischemia and Reperfusion
(Frontiers Research Foundation, 2018-07-03) Domínguez Rodríguez, Alejandro; Mayoral-González, Isabel; Ávila Medina, Javier; Sánchez de Rojas de Pedro, Eva; Calderón Sánchez, Eva María; Díaz Carrasco, Ignacio; Hmadcha, Abdelkrim; Castellano Orozco, Antonio Gonzalo; Ordóñez Fernández, Antonio; Smani Hajami, Tarik; Instituto de Biomedicina de Sevilla (IBIS); Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)
Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca2+]i handling. Methods and Results: Cardiac Wistar rat model of I/R was induced by transient ligation of the left coronary artery and experiments were conducted 1 week after surgery in tissue and adult cardiomyocytes isolated from risk and remote zones. We observed that I/R promoted significant alteration in cardiac contractility as well as an increase in hypertrophy and fibrosis in both zones. The study of confocal [Ca2+]i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca2+]i transient and cardiomyocytes contraction in risk and remote zones. Interestingly, intravenous infusion of Ucn-2 before heart’s reperfusion recovered significantly cardiac contractility and prevented fibrosis, but it didn’t affect cardiac hypertrophy. Moreover, Ucn-2 recovered the amplitude of [Ca2+]i transient and modulated the expression of several proteins related to [Ca2+]i homeostasis, such as TRPC5 and Orai1 channels. Using Neonatal Rat Ventricular Myocytes (NRVM) we demonstrated that Ucn-2 blunted I/R-induced Store Operated Ca2+ Entry (SOCE), decreased the expression of TRPC5 and Orai1 as well as their interaction in reperfusion. Conclusion: Our study provides the first evidences demonstrating that Ucn-2 addition at the onset of reperfusion attenuates I/R-induced adverse cardiac remodeling, involving the [Ca2+]i handling and inhibiting the expression and interaction between TRPC5 and Orai1.

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