Publicaciones

Mediterranean Diet Prior to Ischemic Stroke and Potential Circulating Mediators of Favorable Outcomes

María Castañón-Apilánez, Carmen García-Cabo, Cristina Martin-Martin et al. Nutrients. 2024 Sep 23;16(18):3218.doi: 10.3390/nu16183218.. PMID: 39339817

https://pubmed.ncbi.nlm.nih.gov/39339817/

Abstract: Background/Objectives. A Mediterranean diet (MD) has been associated with neuroprotective effects. We aimed to assess the MD’s association with stroke prognosis and the potential mediators involved. Methods. Seventy patients with acute anterior circulation ischemic stroke were included. Dietary patterns were evaluated using the MEDAS scale, a food-frequency questionnaire, and a 24 h recall. Circulating biomarkers including insulin resistance (HOMA index), adipokines (resistin, adiponectin, leptin), choline pathway metabolites (TMAO, betaine, choline), and endothelial progenitor cells (EPCs) were measured. Early neurological improvement (ENI) at 24 h, final infarct volume, and functional outcome at 3 months were assessed. Results. Adherence to MD and olive oil consumption were associated with a lower prevalence of diabetes and atherothrombotic stroke, and with lower levels of fasting glycemia, hemoglobinA1C, insulin resistance, and TMAO levels. Monounsaturated fatty acids and oleic acid consumption correlated with lower resistin levels, while olive oil consumption was significantly associated with EPC mobilization. Multivariate analysis showed that higher MD adherence was independently associated with ENI and good functional prognosis at 3 months. EPC mobilization, lower HOMA levels, and lower resistin levels were associated with ENI, a smaller infarct volume, and good functional outcome. Conclusions. MD was associated with better prognosis after ischemic stroke, potentially mediated by lower insulin resistance, increased EPC mobilization, and lower resistin levels, among other factors.

Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) through RICORS-ICTUS (RD21/0006/0022, PI18/01096, CM19/00235, INT19/00075) by means of NextGenerationEU funds, which support the actions of the Mecanismo de Recuper-ación y Resiliencia (MRR)/PRTR 

 

The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors

Carmen Choya-Foces , Elisa Navarro , Cristóbal de Los Ríos et al. Redox Biol. 2024 Nov:77:103364. doi: 10.1016/j.redox.2024.103364. PMID: 39341036.

https://pubmed.ncbi.nlm.nih.gov/39341036/

Abstract: Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.

Funding: This research has been financed by grants from the Spanish Government (partially funded by the European Union ERDF “A way of making Europe” and Next GenerationEU): RedoxStroke (RTI2018- 094203-B-I00), excellence network RED2018-102576-T, NCLRedoX (PID2021-124688OB-I00), NCLXtroke (PDC2022-133246-I00),
PID2021-125986OB-I00 and PID2022-139936OA-I00 from AEI (MICIU/ AEI/10.13039/501100011033); PI15/00107, PI22/00362 and RICORSICTUS (RD21/0006/0009) from Instituto de Salud Carlos III (ISCIII) and fellowships IJC2020-042679-I (MICIU) and RYC2022-036516-I (MICIU) to P.H.-A. from AEI and FPU18/03475 to C.C.-F. from MICIU, and by a grant from the Fundacion ´ Domingo Martínez.

A dual colorimetric-electrochemical microfluidic paper-based analytical device for point-of-care testing of ischemic strokes

Dortez S, Pacheco M, Gasull T, Crevillen AG, Escarpa A. Lab Chip. 2024 Aug 9. doi: 10.1039/d4lc00398e. Online ahead of print. PMID: 39118539
Abstract: A novel microfluidic paper-based analytical device with dual colorimetric and electrochemical detection (dual μPAD) was developed for the assessment of transferrin saturation (TSAT) in samples from ischemic stroke patients. TSAT was calculated from the ratio between transferrin-bound iron, which was colorimetrically measured, and the total iron-binding capacity, which was electrochemically measured. To this end, a μPAD was smartly designed, which integrated both colorimetric and electrochemical detection reservoirs, communicating via a microchannel acting as a chemical reactor, and with preloading/storing capabilities (reagent-free device). This approach allowed the dual and simultaneous determination of both parameters, providing an improvement in the reliability of the results due to an independent signal principle and processing. The μPADs were validated by analyzing a certified reference material, showing excellent accuracy (Er ≤ 5%) and precision (RSD ≤ 2%). Then they were applied to the analysis of diagnosed serum samples from ischemic stroke patients. The results were compared to those provided by a free-interference method (urea-PAGE). Impressively, both methods exhibited a good correlation (r = 0.96, p < 0.05) and no significant differences were found between them (slope 1.0 ± 0.1 and the intercept 1 ± 4, p < 0.05), demonstrating the excellent accuracy of our approach during the analysis of complex samples from ischemic stroke patients, using just 90 μL of clinical samples and taking less than 90 min in comparison with the 18 hours required by the urea-PAGE approach. The developed fully integrated colorimetric-electrochemical μPAD is a promising ready to use reagent-free device for the point-of-care testing of TSAT, which can be used to assist physicians in the fast diagnosis and prognosis of ischemic strokes, where the decision-time is crucial for the patient’s survival.
Funding: This work has been financially supported by the TRANSNANOAVANSENS program from the Community of Madrid (P2018/NMT-4349) (A. E.), by the grant PID2020-118154GB-I00 funded by MCIN/AEI/10.13039/501100011033 (A. E.), by the NEURO-CHIP-CM program from the Community of Madrid (Y2020/NMT6312) (A. E.), by the RICORS RD21/0006/0024 (NextGeneration EU funding) and 2021SGR00925 (Agencia de gestio d’Ajuts Universitaris i de Recerca de Catalunya) (T. G.), and by the Spanish Ministry of Economy and Competitiveness (CTQ2017-86441-C2-1-R, FPI fellowship (S. D.)).

Influence of Hospital Type on Outcomes of Patients With Acute Spontaneous Intracerebral Hemorrhage: A Population-Based Study.

Marti-Fabregas J, Ramos-Pachón A, Prats-Sanchez L,et al. Neurology. 2024 Jul 23;103(2):e209539. doi: 10.1212/WNL.0000000000209539. Epub 2024 Jun 14.. PMID: 38875516
Abstract:

Background and objectives: Whether the outcome of patients with spontaneous intracerebral hemorrhage (ICH) differs depending on the type of hospital where they are admitted is uncertain. The objective of this study was to determine influence of hospital type at admission (telestroke center [TSC], primary stroke center [PSC], or comprehensive stroke center [CSC]) on outcome for patients with ICH. We hypothesized that outcomes may be better for patients admitted to a CSC.

Methods: This is a multicenter prospective observational and population-based study of a cohort of consecutively recruited patients with ICH (March 2020-March 2022). We included all patients with spontaneous ICH in Catalonia (Spain) who had a pre-ICH modified Rankin scale (mRS) score of 0-3 and who were admitted to the hospital within 24 hours of onset. We compared patients admitted to a TSC/PSC (n = 641) or a CSC (n = 1,320) and also analyzed the subgroup of patients transferred (n = 331) or not transferred (n = 310) from a TSC/PSC to a CSC. The main outcome was the 3-month mRS score obtained by blinded investigators. Outcomes were compared using adjusted ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI for a shift in mRS scores. A propensity score matching (PSM) analysis was performed for the subgroup of transferred patients.

Results: Relevant data were obtained from 1961 of a total of 2,230 patients, with the mean (SD) age of 70 (14.1) years, and 713 (38%) patients were women. After adjusting for confounders (age, NIH Stroke Scale score, intraventricular hemorrhage, hematoma volume, and pre-ICH mRS score), type of hospital of initial admission (CSC vs TSC/PSC) was not associated with outcome (adjusted common OR 1.13, 95% CI 0.93-1.38). A PSM analysis indicated that transfer to a CSC was not associated with more favorable outcomes (OR 0.77, 95% CI 0.55-1.10; p = 0.16).

Discussion: In this population-based study, we found that, after adjusting for confounders, hospital types were not associated with functional outcomes. In addition, for patients who were transferred from a TSC/PSC to a CSC, PSM indicated that outcomes were similar to nontransferred patients. Our findings suggest that patient characteristics are more important than hospital characteristics in determining outcome after ICH.

Trial registration information: ClinicalTrials.gov Identifier: NCT03956485.

Funding: Fundaciô Ictus, RICORS RD21/006/006

DNA methylation and stroke prognosis: an epigenome-wide association study.

Jiménez-Balado J, Fernández-Pérez I, Gallego-Fábrega C et al. Clin Epigenetics. 2024 Jun 6;16(1):75. doi: 10.1186/s13148-024-01690-2.PMID: 38845005
Abstract:
Background and aims Stroke is the leading cause of adult-onset disability. Although clinical factors infuence stroke outcome, there is a signifcant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis.
Methods and results To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N=316] and St. Pau [replication, N=92]). Functional outcome was assessed using the modifed Rankin Scale (mRS) at three months after stroke, being poor outcome defned as mRS>2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the frst 24 h. We searched for diferentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value< 10–5 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify diferentially methylated regions (DMRs). After doing the epigenome-wide association study, we found 29 DMPs at p-value< 10–5 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-valuediscovery=1.54·10–6; p-value replication=9.17·10–4; p-valuemeta-analysis=6.39·10–9). Besides, four DMRs were identifed in patients with poor outcome annotated to zinc fnger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value<1·10–9 in all cases).
Discussion Patients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms.
Funding: This work was supported by grants from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III with the grants “Registro BASICMAR” Funding for Research in Health (PI051737), Fondos de Investigación Sanitaria ISC III (PI12/01238), (PI15/00451), (PI18/00022), (PI21/00593); Sara Borrell program, funded by Instituto de Salud Carlos III (CD22/00001, J.J.-B.); and Fondos FEDER/EDRF Spanish stroke research network INVICTUS+(RD16/0019/0002) and Grant “RICORS-ICTUS” (RD21/0006/0021) funded by Instituto de Salud Carlos III (ISCIII), and by the European Union NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). Additional support provided by the Fundació la Marató TV3 with the grant “GOD’s project. Genestroke Consor‑ tium” (76/C/2011) and Recercaixa’13 (JJ086116). Fundings were received from National Institute of Health, SiGN study, The NINDS Stroke Genetics Network Study (U01NS069208) and CaNVAS (1R01NS114045-01).