Publicaciones

The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery

Casado-Fernández L,Laso-García F, Piniella D et al.  Neurobiol Dis. 2024 Oct 15;201:106665. doi: 10.1016/j.nbd.2024.106665. Epub 2024 Sep 12. PMID: 39277144.

https://pubmed.ncbi.nlm.nih.gov/39277144/

Abstract: Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms. This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months’ follow- up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or >50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0–2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes. Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h. In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.

Funding: This work was supported by Carlos III Health Institute (ISCIII) and co-funded by the European Union (European Regional Development Fund-FEDER) under grant PI17/01922 and PI20/00243, Invictus plus network under grant RD16/0019/0005, RICORS ICTUS network under grant RD21/0006/0012 and the Next Generation EU fundig for actions in the Recovery and Resilience Mechanism, Miguel Servet under grant CPII20/00002 to MG-F; CP20/00024 to LO-O, Ministerio de Universidades, Plan de Recuperaci´ on, Transformaci´ on y Resiliencia y la Universidad Aut´ onoma de Madrid under grant CA1/RSUE/2021-00753 to DP, and the Spanish Ministry of Health- (ISCIII) under grant CM20/ 00047 to EA-L, CM23/00022 to LC-F, FI18/00026 to FL-G and FI17/ 00188 to MG-dF. We also thank the editing assistance of Morote Traducciones.

Dubbing language-therapy CINEma-based in aphasia post-stroke (DULCINEA): A feasibility randomized crossover controlled trial

Fuentes B, Jordi-Perea P, Sempere-Iborra C et al. Digit Health. 2024 Oct 10;10:20552076241288311. doi: 10.1177/20552076241288311. PMID: 39421311.

https://pubmed.ncbi.nlm.nih.gov/39421311/

Abstract: Background: Helping people recover from aphasia is among the top 10 research priorities relating to life after stroke. Objective: We aimed to evaluate the feasibility of dubbing techniques (using newly developed software) for post-stroke aphasia therapy and explore its potential efficacy. Methods: Randomised, crossover, interventional, feasibility trial that included patients with chronic post-stroke non-fluent aphasia. The intervention consisted of an individualised programme (16 sessions; 8 weeks) based on dubbing words and sentences progressively adapted to the severity of the aphasia. Patients were allocated to groups that underwent therapy within the first 3 months, or between 3 and 6 months from inclusion, each group serving as the control during the nontherapy periods. Outcomes were the pre-post differences in the Communicative Activity Log, the Boston Diagnostic Aphasia Examination, the General Health Questionnaire-12, the Stroke Aphasia Quality of Life Scale, and the Western Aphasia Battery Revised, administered by psychologists blinded to the patients’ allocation. Results: Recruitment was limited due to COVID-19 and prematurely stopped because of funding coming to an end. A total of 23 patients were randomised, 20 of whom completed the study (1 withdrew consent, and 2 dropped out). The adherence rate to the allocated group was 95.3%. No statistically significant differences were found in any of the outcomes; however, 17 (85%) patients reported subjective improvements in communication skills. Conclusions: This trial shows the feasibility of dubbing therapy (using dedicated software) for patients with post-stroke nonf luent aphasia. Although it lacks statistical power, certain effects on language and communication cannot be ignored.

Funding: This study was promoted by the Research Foundation of La Paz University Hospital, which hosted a research consortium joined by the Department of Neurology at La Paz University Hospital, the Department of Psychology at Comillas Pontifical University, and the patients’ association, Afasia Activa. This project has received funding from “la Caixa” Banking Foundation under the project code LCF/PR/HR19/52160009. The funder was not involved in any of the following processes: design of the trial, data collection, analysis, or interpretation, or writing the manuscript. BF, EdC-R, RR, GR-A, JR-P, EA and MA-L are members of the Spanish Stroke Research Network RICORS ICTUS (RD21/0006/0012) funded by the Carlos III Institute of Health and the European Union (NextGenerationEU). ‘la Caixa’ Foundation, Instituto de Salud Carlos III, (grant number LCF/PR/ HR19/52160009, RD21/0006/0012).

 

Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach

Muiño E, Carcel-Marquez J, Llucià-Carol L et al. Neurology. 2024 Oct 22;103(8):e209666. doi: 10.1212/WNL.0000000000209666. Epub 2024 Sep 19.PMID: 39298701

https://pubmed.ncbi.nlm.nih.gov/39298701/

Background and Objetives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets.

Methods: Weuse the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAGcombining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component ofexpression or proteinlevels withthe genetic componentofa trait. We use the ICH cohort from UK Biobank as replication.

Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10−12), 10q24.33 (OBFC1, β = −0.12, SE =0.02, p value = 1.67 ×10−8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10−11), and 19q13.32 (APOC1, β =−0.19, SE =0.03, p value = 1.38 × 10−12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10−11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10−8); 2 genes (SH3PXD2A, Zscore = 4.83, p value = 6.67 × 10−7;andAPOC1, Z-score: = 5.11, p value = 1.60 × 10−7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10−12) and protein levels (Z-score = −5.8, p value = 6.7 × 10−9).

Funding: This work was supported by grants from the Institutode SaludCarlosIII (PI11/0176),Generaci´on Project,Maestro Project (PI18/01338), INVICTUS+ network, RICORSICTUS (RD21/0006/0006) together with Next-Generation EU funds that finance the actions of the Recovery and ResilienceMechanism,andtheEpigenesisProject(Marat´ode TV3),FEDERfunds, iBioStrokeproject(AC19/00106).E. Muiño is supportedby aR´ıoHortegaContract (CM18/00198) from the Instituto de Salud Carlos III. E. Muiño is supported by the Juan Rod´es contract (JR23/00045) from Instituto de Salud Carlos III. C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lled´os is supported by a PFIS Contract (Contratos Predoctorales de Formaci´on en Investigaci´on en Salud) from the Instituto de Salud Carlos III (FI19/00309). I. Fern´andez-Cadenas (CP12/03298) is supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III.

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.