Targeting Pro-Oxidant Iron with Exogenously Administered Apotransferrin Provides Benefits Associated with Changes in Crucial Cellular Iron Gate Protein TfR in a Model of Intracerebral Hemorrhagic Stroke in Mice

Alexia García-Serran, Jesús Ordoño, Núria DeGregorio-Rocasolano, Marc Melià-Sorolla, Karla Odendaal, Octavi Martí-Sistac* and Teresa Gasull*. Antioxidants 2023, 12, 1945.

Abstract: We have previously demonstrated that the post-stroke administration of iron-free transferrin (apotransferrin, ATf) is beneficial in different models of ischemic stroke (IS) through the inhibitionof the neuronal uptake of pro-oxidant iron. In the present study, we asked whether ATf is safeand also beneficial when given after the induction of intracerebral hemorrhage (ICH) in mice, and investigated the underlying mechanisms. We first compared the main iron actors in the brain of IS- or collagenase-induced ICH mice and then obtained insight into these iron-related proteins in ICH 72 h after the administration of ATf. The infarct size of the IS mice was double that of hemorrhage in ICH mice, but both groups showed similar body weight loss, edema, and increased ferritin and transferrin levels in the ipsilateral brain hemisphere. Although the administration of human ATf (hATf) to ICH mice did not alter the hemorrhage volume or levels of the classical ferroptosis GPX4/system xcpathways, hATf induced better neurobehavioral performance, decreased 4-hydroxynonenal levels and those of the second-generation ferroptosis marker transferrin receptor (TfR), and restored the mRNA levels of the recently recognized cytosolic iron chaperone poly(RC) binding protein 2. In addition, hATf treatment lowered the ICH-induced increase in both endogenous mouse transferrin mRNA levels and the activation of caspase-2. In conclusion, hATf treatment provides neurobehavioral benefits post-ICH associated with the modulation of iron/oxidative players.

Funding: This study was supported by grants from the Agency for Management of University and Research Grants (AGAUR) Catalan Research Group (SGR) 2021SGR00925 and 2019PROD00120, and by the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III projects PI18/01813 and PI21/01925, RICORS RD21/0006/0024, that were susceptible to be co-financed by FEDER/FSE funds. MMS was supported by a PFIS contract from the ISCIII (FI19/00174), and AGS was supported by contracts associated with 2019PROD00120 and PI18/01813. The IGTP is a Research Center of Catalonia of the CERCA Program/Government of Catalonia. The group has received funding from “la Caixa” CI15-00009 from the European Institute of Innovation and Technology (EIT) PoC-2016- SPAIN-04, which receives support from the European Union’s Horizon 2020 research and innovation program; and from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18.

Paper-Based Analytical Devices for Accurate Assessment of Transferrin Saturation in Diagnosed Clinical Samples from Ischemic Stroke Patients

Silvia Dortez, Nùria DeGregorio-Rocasolano, Mónica Millán, Teresa Gasull, Agustín G Crevillen, Alberto Escarpa. Anal Chem. 2023 Aug 22;95(33): 12391-12397. DOI: 10.1021/acs.analchem.3c01982. PMID: 37486019

Abstract: For the first time, a paper-based analytical device (PAD) was developed for the assessment of transferrin saturation (TSAT), which is defined as the ratio between iron bound to transferrin (Tf) and the total iron-binding capacity (TIBC) of Tf. Both parameters were simultaneously measured on the same PAD using ferrozine as a chromophore and a smartphone as the color reader. To this end, Tf was first isolated from serum using anti-Tf immunomagnetic beads to ensure that only the Tf-bound iron was measured, improving the selectivity and accuracy of TSAT assessment. To demonstrate the practical utility of the device, it was validated by analyzing a certified reference material, showing excellent accuracy (Er < 4%) and good precision (RSD ≤ 6%). Finally, 18 diagnosed serum samples from ischemic stroke patients were analyzed by this approach, and the results were compared with those obtained by urea-PAGE, showing not only an excellent correlation (r = 0.93, p < 0.05) but that the PAD approach has become statistically identical to the free-interference urea-PAGE. In comparison with the slow, tedious, and non-miniaturized-PAGE, this PAD approach exhibited attractive characteristics such as low cost, disposability, and connectivity, showing great potential for future point-of-care testing, especially in developing countries and/or remote areas, where access to medical or clinical facilities is limited.

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 RICORS RD21/0006/0024 and 2021SGR00925 (T.G.), and by the Spanish Ministry of Economy and Competitiveness (CTQ2017-86441-C2-1-R, FPI fellowship (S. D.)).


Establishment of a reproducible and minimally invasive ischemic stroke model in swine

Carlos Castaño Marc Melià-Sorolla Alexia García-Serran et al. JCI Insight 2023. Apr 24;8(8):e163398. doi: 10.1172/jci.insight.163398. PMID: 36853828

Abstract: The need for advances in the management/treatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate, although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a guide catheter and guide wire were introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique, Squid-12 embolization material was deposited to fill, overflow, and occlude the left RM, the left internal carotid artery, and left circle of Willis wing up to the origins of the middle cerebral arteries (MCAs), mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MRI was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 of 8 swine, inducing early damage 90 minutes after occlusion that later evolved to a large cerebral infarction and producing no mortality during the intervention. This minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.

Funding: This academic research was supported by grants from the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III PI18/01813 and PI21/01925 to AD and TG, INVICTUS PLUS RD16/0019/0020 and RICORS RD21/0006/0024 that was susceptible to be cofinanced by FEDER/FSE funds, and grants from Agency for Management of University and Research Grants (AGAUR) Catalan Research Group (SGR) 2017SGR1520, 2021SGR00925, and 2019PROD00120 susceptible to be cofinanced by FEDER funds. MMS was supported by a PFIS contract of the ISCIII (FI19/00174), and AGS was supported by contracts associated to 2019PROD00120 and PI18/01813. The IGTP is a Research Center of Catalonia of the CERCA Program/government of Catalonia. The group has received funding from “la Caixa” CI15-00009; from the European Institute of Innovation and Technology (EIT) PoC-2016-SPAIN-04, which receives support from the European Union’s Horizon 2020 research and innovation program; and from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18.

Periodontitis is associated with subclinical cerebral and carotid atherosclerosis in hypertensive patients: A cross-sectional study

Vázquez-Reza M, López-Dequidt I, Ouro A, Iglesias-Rey R et al. Clin Oral Investig. 2023 Apr 1. doi: 10.1007/s00784-023-04958-8. Online ahead of print. PMID: 37004529

Conclusions:  Periodontitis is associated with subclinical atherosclerosis in both intracranial and carotid arteries in elderly subjects with hypertension.

Funding: Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was partially supported by grants from the Xunta de Galicia (TS: IN607A2018/3 and TS: IN607D 2020/09), Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), Institute of Health Carlos III (PI22/00938), and RICOR-ICTUS Network (RD21/0006/003). Furthermore, this study was also supported by grants from the Interreg Atlantic Area (TS: EAPA_791/2018_ NeuroATLANTIC project), Interreg V-A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E), and the European Regional Development Fund. YL is supported by a Sara Borrell fellowship (CD22/00051), and TS (CPII17/00027) and FC (CPII19/00020) are recipients of Miguel Servet contracts, all of them funded by the Institute of Health Carlos III.

Intelligence-Based Recommendation System for Critical Stroke Management in Intensive Care Units

García Terriza, L.; Risco-Martín, J.; Ayala, J. and Roselló, G. BIOINFORMATICS 2023, ISBN 978-989-758-631-6; ISSN 2184-4305, pages 131-138. DOI: 10.5220/0011621000003414

Abstract: This work presents an integrated recommendation system capable of providing support in healthcare critical environments such as Intensive Care Units or Stroke Care Units using Machine Learning techniques. The system can manage several patients by reading monitoring hemodynamic data in real-time, presenting current death risk probability, and showing recommendations that would reduce such probability and, in some cases, avoid death. This system introduces a novel method to produce recommendations based on genetic models and supervised machine learning. The interface is built upon a web application where clinicians can evaluate recommendations and straightforwardly provide feedback.

Funding: This research has been funded by Instituto de Salud Carlos III (RICORS-RD21/0006/0009) and cofinanced with FEDER Funds and/or from the European funds of the Recovery, Transformation and Resilience Plan and by NextGenerationEU. This work is also supported by Spanish Ministry of Science and Innovation under project PID2019-110866RB-I00.

N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated with Post-Stroke In-Hospital Complications

Ruiz-Franco ML, Guevara-Sánchez E, Amaya-Pascasio L et al. J Pers Med. 2023 Mar 5;13(3):474. doi: 10.3390/jpm13030474. PMID: 36983656

Abstract: Previous studies have shown the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) with stroke mortality and functional outcome after an acute ischemic stroke (AIS). Knowledge of its association with systemic and neurological in-hospital complications is scarce. Our objective is to analyze this. We performed an observational, retrospective study that included consecutive AIS patients during a 1-year period (2020). A multivariate analysis was performed to identify if NT-proBNP levels were independently associated with in-hospital complications. 308 patients were included, of whom 96 (31.1%) developed systemic and 62 (20.12%) neurological in-hospital complications. Patients with any complication (39.3%) showed higher NT-proBNP levels than those without (median (IQR): 864 (2556) vs. 142 (623) pg/dL, p < 0.001). The receiver operating characteristic curve (ROC) pointed to 326 pg/dL of NT-proBNP as the optimal cutoff level for developing in-hospital systemic complications (63.6% sensitivity and 64.7% specificity for any complication; 66.7% and 62.7% for systemic; and 62.9% and 57.7% for neurological complications). Multivariate analyses showed that NT-proBNP > 326 pg/dL was associated with systemic complications (OR 2.336, 95% CI: 1.259–4.335), adjusted for confounders. This did not reach statistical significance for neurological complications. NT-proBNP could be a predictor of in-hospital systemic complications in AIS patients. Further studies are needed.

Funding: This study is part of the Spanish Health Outcomes-Oriented Cooperative Research Networks (RICORTS-ICTUS), Instituto de Salud Carlos III (Carlos III Health Institute), Ministerio de Ciencia e Innovación (Ministry of Science and Innovation), RD21/0006/0010.