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Molecular Mechanisms and Pathophysiology of Acute Stroke

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 39784

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Dr. Teresa Gasull

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Guest Editor

Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
Interests: stroke; iron dyshomeostasis; excitotoxicity; ferroptosis; new-generation therapies; glutamate excitotoxicity; transferrin; free radicals; therapeutic targets; proteomics
Special Issues, Collections and Topics in MDPI journals

Dr. Adria Arboix

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Guest Editor

Unit of Cerebrovascular Diseases, Service of Neurology, Hospital Universitari del Sagrat Cor, Universitat de Barcelona, Barcelona, Catalonia, Spain
Interests: cerebrovascular diseases; lacunar strokes; acute stroke; vascular cognitive impairment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stroke remains a leading cause of death and disability and has a complex pathophysiology. Increasing evidence suggests that the brain is exquisitely sensitive to even short-duration ischemia, and that multiple mechanisms are involved in the tissue damage that results from cerebral ischemia. Ischemic stroke initiates a cascade of events including ATP depletion, ionic dysregulation, increased release of glutamate, excess production of free radicals, as well as edema and inflammation; all these events eventually contribute to cell death. In contrast, in intracerebral hemorrhage, oppression and destruction of brain tissue by hematoma is the primary cause of brain injury, but inflammation, coagulation response, and the toxicity of the released hemoglobin play a pivotal role as well. Cell death after stroke has been attributed in the past mainly to necrosis or apoptosis, but recent reports show the involvement of other newly described forms of cell death.

The goal of this Special Issue is to provide a critical overview of the underlying factors involved in stroke-related brain injury, especially the role of cell signaling in excitotoxicity, inflammation, apoptosis, and the newly described types of cell death such as ferroptosis. Gene and protein expression profiles after stroke and neurogenesis, angiogenesis, and neuroplasticity are other important features in stroke, and should lead to a better understanding of the pathophysiology of acute stroke.

We warmly welcome submissions, including original articles and reviews, on these hot topics.

Dr. Teresa Gasull
Prof. Dr. Adria Arboix
Guest Editors

Manuscript Submission Information

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Keywords

stroke
ischemic
hemorrhagic
neuronal death
molecular mechanisms
inflammation
epigenetics
ischemic tolerance
ferroptosis
free radicals

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

6 pages, 223 KiB

Open AccessEditorial

Molecular Mechanisms and Pathophysiology of Acute Stroke: Emphasis on Biomarkers in the Different Stroke Subtypes

by Teresa Gasull and Adrià Arboix

Int. J. Mol. Sci. 2022, 23(16), 9476; https://doi.org/10.3390/ijms23169476 - 22 Aug 2022

Cited by 7 | Viewed by 1709

Abstract

According to WHO data, strokes are the second leading cause of death in adult males, the first cause of death of adult women worldwide and one of the most important causes of disability and dementia in adults [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

Research

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12 pages, 1208 KiB

Open AccessArticle

Evaluation and Characterization of Post-Stroke Lung Damage in a Murine Model of Cerebral Ischemia

by Júlia Faura, Laura Ramiro, Alba Simats, Feifei Ma, Anna Penalba, Teresa Gasull, Anna Rosell, Joan Montaner and Alejandro Bustamante

Int. J. Mol. Sci. 2022, 23(15), 8093; https://doi.org/10.3390/ijms23158093 - 22 Jul 2022

Cited by 3 | Viewed by 2102

Abstract

After stroke and other brain injuries, there is a high incidence of respiratory complications such as pneumonia or acute lung injury. The molecular mechanisms that drive the brain-lung interaction post-stroke have not yet been elucidated. We performed transient middle cerebral artery occlusion (MCAO) and sham surgery on C57BL/6J mice and collected bronchoalveolar lavage fluid (BALF), serum, brain, and lung homogenate samples 24 h after surgery. A 92 proteins-panel developed by Olink Proteomics^® was used to analyze the content in BALF and lung homogenates. MCAO animals had higher protein concentration levels in BALF than sham-controls, but these levels did not correlate with the infarct volume. No alteration in alveolar-capillary barrier permeability was observed. A total of 12 and 14 proteins were differentially expressed between the groups (FDR < 0.1) in BALF and lung tissue homogenates, respectively. Of those, HGF, TGF-α, and CCL2 were identified as the most relevant to this study. Their protein expression patterns were verified by ELISA. This study confirmed that post-stroke lung damage was not associated with increased lung permeability or cerebral ischemia severity. Furthermore, the dysregulation of HGF, TGF-α, and CCL2 in BALF and lung tissue after ischemia could play an important role in the molecular mechanisms underlying stroke-induced lung damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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12 pages, 2177 KiB

Open AccessArticle

ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

by Natalia Cullell, Cristina Gallego-Fábrega, Jara Cárcel-Márquez, Elena Muiño, Laia Llucià-Carol, Miquel Lledós, Jesús M. Martín-Campos, Jessica Molina, Laura Casas, Marta Almeria, Israel Fernández-Cadenas and Jerzy Krupinski

Int. J. Mol. Sci. 2022, 23(6), 3161; https://doi.org/10.3390/ijms23063161 - 15 Mar 2022

Cited by 11 | Viewed by 3051

Abstract

Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (q-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and p-value = 9.6 × 10⁻⁶) and non-lobar ICH (z-score = −4.8 and p-value = 1.58 × 10⁻⁶) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (p-value = 3.66 × 10⁻⁵) and non-lobar ICH (p-value = 1.81 × 10⁻⁵). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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Review

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25 pages, 844 KiB

Open AccessReview

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

by Cristina Gallego-Fabrega, Elena Muiño, Jara Cárcel-Márquez, Laia Llucià-Carol, Miquel Lledós, Jesús M. Martín-Campos, Natalia Cullell and Israel Fernández-Cadenas

Int. J. Mol. Sci. 2022, 23(12), 6840; https://doi.org/10.3390/ijms23126840 - 20 Jun 2022

Cited by 4 | Viewed by 3495

Abstract

Ischaemic stroke is a complex disease with some degree of heritability. This means that heritability factors, such as genetics, could be risk factors for ischaemic stroke. The era of genome-wide studies has revealed some of these heritable risk factors, although the data generated by these studies may also be useful in other disciplines. Analysis of these data can be used to understand the biological mechanisms associated with stroke risk and stroke outcome, to determine the causality between stroke and other diseases without the need for expensive clinical trials, or to find potential drug targets with higher success rates than other strategies. In this review we will discuss several of the most relevant studies regarding the genetics of ischaemic stroke and the potential use of the data generated. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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12 pages, 1441 KiB

Open AccessReview

Genetics and Epigenetics of Spontaneous Intracerebral Hemorrhage

by Eva Giralt-Steinhauer, Joan Jiménez-Balado, Isabel Fernández-Pérez, Lucía Rey Álvarez, Ana Rodríguez-Campello, Ángel Ois, Elisa Cuadrado-Godia, Jordi Jiménez-Conde and Jaume Roquer

Int. J. Mol. Sci. 2022, 23(12), 6479; https://doi.org/10.3390/ijms23126479 - 09 Jun 2022

Cited by 13 | Viewed by 2443

Abstract

Intracerebral hemorrhage (ICH) is a complex and heterogeneous disease, and there is no effective treatment. Spontaneous ICH represents the final manifestation of different types of cerebral small vessel disease, usually categorized as: lobar (mostly related to cerebral amyloid angiopathy) and nonlobar (hypertension-related vasculopathy) ICH. Accurate phenotyping aims to reflect these biological differences in the underlying mechanisms and has been demonstrated to be crucial to the success of genetic studies in this field. This review summarizes how current knowledge on genetics and epigenetics of this devastating stroke subtype are contributing to improve the understanding of ICH pathophysiology and their potential role in developing therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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22 pages, 1402 KiB

Open AccessReview

Clinical Parameters and Epigenetic Biomarkers of Plaque Vulnerability in Patients with Carotid Stenosis

by Laia Carballo-Perich, Dolors Puigoriol-Illamola, Saima Bashir, Mikel Terceño, Yolanda Silva, Carme Gubern-Mérida and Joaquín Serena

Int. J. Mol. Sci. 2022, 23(9), 5149; https://doi.org/10.3390/ijms23095149 - 05 May 2022

Cited by 10 | Viewed by 2903

Abstract

Atheromatous disease is the first cause of death and dependency in developed countries and carotid artery atherosclerosis is one of the main causes of severe ischaemic strokes. Current management strategies are mainly based on the degree of stenosis and patient selection has limited accuracy. This information could be complemented by the identification of biomarkers of plaque vulnerability, which would permit patients at greater and lesser risk of stroke to be distinguished, thus enabling a better selection of patients for surgical or intensive medical treatment. Although several circulating protein-based biomarkers with significance for both the diagnosis of carotid artery disease and its prognosis have been identified, at present, none have been clinically implemented. This review focuses especially on the most relevant clinical parameters to take into account in routine clinical practice and summarises the most up-to-date data on epigenetic biomarkers of carotid atherosclerosis and plaque vulnerability. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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10 pages, 1280 KiB

Open AccessReview

Stress Granules and Acute Ischemic Stroke: Beyond mRNA Translation

by Marta Aramburu-Núñez, Antía Custodia, María Pérez-Mato, Ramón Iglesias-Rey, Francisco Campos, José Castillo, Alberto Ouro, Daniel Romaus-Sanjurjo and Tomás Sobrino

Int. J. Mol. Sci. 2022, 23(7), 3747; https://doi.org/10.3390/ijms23073747 - 29 Mar 2022

Cited by 12 | Viewed by 2777

Abstract

Ischemic stroke is a leading cause of death and disability worldwide. Following an ischemic insult, cells undergo endoplasmic reticulum (ER) stress, which increases the ER’s protein-folding and degradative capacities and blocks the global synthesis of proteins by phosphorylating the eukaryotic translation initiation factor 2-alpha (eIF2α). Phosphorylation of eIF2α is directly related to the dynamics of stress granules (SGs), which are membraneless organelles composed of RNA-binding proteins and mRNA. SGs play a critical role in mRNA metabolism and translational control. Other translation factors are also linked to cellular pathways, including SG dynamics following a stroke. Because the formation of SGs is closely connected to mRNA translation, it is interesting to study the relationship between SG dynamics and cellular outcome in cases of ischemic damage. Therefore, in this review, we focus on the role of SG dynamics during cerebral ischemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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26 pages, 12621 KiB

Open AccessReview

The Potential Impact of Neuroimaging and Translational Research on the Clinical Management of Lacunar Stroke

by Salvatore Rudilosso, Alejandro Rodríguez-Vázquez, Xabier Urra and Adrià Arboix

Int. J. Mol. Sci. 2022, 23(3), 1497; https://doi.org/10.3390/ijms23031497 - 28 Jan 2022

Cited by 73 | Viewed by 8269

Abstract

Lacunar infarcts represent one of the most frequent subtypes of ischemic strokes and may represent the first recognizable manifestation of a progressive disease of the small perforating arteries, capillaries, and venules of the brain, defined as cerebral small vessel disease. The pathophysiological mechanisms leading to a perforating artery occlusion are multiple and still not completely defined, due to spatial resolution issues in neuroimaging, sparsity of pathological studies, and lack of valid experimental models. Recent advances in the endovascular treatment of large vessel occlusion may have diverted attention from the management of patients with small vessel occlusions, often excluded from clinical trials of acute therapy and secondary prevention. However, patients with a lacunar stroke benefit from early diagnosis, reperfusion therapy, and secondary prevention measures. In addition, there are new developments in the knowledge of this entity that suggest potential benefits of thrombolysis in an extended time window in selected patients, as well as novel therapeutic approaches targeting different pathophysiological mechanisms involved in small vessel disease. This review offers a comprehensive update in lacunar stroke pathophysiology and clinical perspective for managing lacunar strokes, in light of the latest insights from imaging and translational studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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16 pages, 2129 KiB

Open AccessReview

Potential Biomarkers for Post-Stroke Cognitive Impairment: A Systematic Review and Meta-Analysis

by Ka Young Kim, Ki Young Shin and Keun-A Chang

Int. J. Mol. Sci. 2022, 23(2), 602; https://doi.org/10.3390/ijms23020602 - 06 Jan 2022

Cited by 30 | Viewed by 5321

Abstract

Stroke is a primary debilitating disease in adults, occurring in 15 million individuals each year and causing high mortality and disability rates. The latest estimate revealed that stroke is currently the second leading cause of death worldwide. Post-stroke cognitive impairment (PSCI), one of the major complications after stroke, is frequently underdiagnosed. However, stroke has been reported to increase the risk of cognitive impairment by at least five to eight times. In recent decades, peripheral blood molecular biomarkers for stroke have emerged as diagnostic, prognostic, and therapeutic targets. In this study, we aimed to evaluate some blood-derived proteins for stroke, especially related to brain damage and cognitive impairments, by conducting a systematic review and meta-analysis and discussing the possibility of these proteins as biomarkers for PSCI. Articles published before 26 July 2021 were searched in PubMed, Embase, the Web of Science, and the Cochrane Library to identify all relevant studies reporting blood biomarkers in patients with stroke. Among 1820 articles, 40 were finally identified for this study. We meta-analyzed eight peripheral biomarker candidates: homocysteine (Hcy), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), uric acid, and glycated hemoglobin (HbA1c). The Hcy, CRP, TC, and LDL-C levels were significantly higher in patients with PSCI than in the non-PSCI group; however, the HDL-C, TG, uric acid, and HbA1c levels were not different between the two groups. Based on our findings, we suggest the Hcy, CRP, TC, and LDL-C as possible biomarkers in patients with post-stroke cognitive impairment. Thus, certain blood proteins could be suggested as effective biomarkers for PSCI. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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17 pages, 872 KiB

Open AccessReview

MicroRNAs as Biomarkers for Predicting Complications following Aneurysmal Subarachnoid Hemorrhage

by Wang-Xia Wang, Joe E. Springer and Kevin W. Hatton

Int. J. Mol. Sci. 2021, 22(17), 9492; https://doi.org/10.3390/ijms22179492 - 31 Aug 2021

Cited by 11 | Viewed by 2954

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is a high mortality hemorrhagic stroke that affects nearly 30,000 patients annually in the United States. Approximately 30% of aSAH patients die during initial hospitalization and those who survive often carry poor prognosis with one in five having permanent physical and/or cognitive disabilities. The poor outcome of aSAH can be the result of the initial catastrophic event or due to the many acute or delayed neurological complications, such as cerebral ischemia, hydrocephalus, and re-bleeding. Unfortunately, no effective biomarker exists to predict or diagnose these complications at a clinically relevant time point when neurologic injury can be effectively treated and managed. Recently, a number of studies have demonstrated that microRNAs (miRNAs) in extracellular biofluids are highly associated with aSAH and complications. Here we provide an overview of the current research on relevant human studies examining the correlation between miRNAs and aSAH complications and discuss the potential application of using miRNAs as biomarkers in aSAH management. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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27 pages, 1267 KiB

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The Role of Biomarkers in Atherothrombotic Stroke—A Systematic Review

by Sebastian Andone, Zoltan Bajko, Anca Motataianu, Oana Mosora and Rodica Balasa

Int. J. Mol. Sci. 2021, 22(16), 9032; https://doi.org/10.3390/ijms22169032 - 21 Aug 2021

Cited by 11 | Viewed by 3099

Abstract

Stroke represents the primary debilitating disease in adults and is the second-highest cause of death worldwide. Atherosclerosis, the most prevalent etiology for vascular conditions, is a continuous process that gradually creates and develops endothelial lesions known as atherosclerotic plaques. These lesions lead to the appearance of atherothrombotic stroke. In the last decades, the role of biological biomarkers has emerged as either diagnostic, prognostic, or therapeutic targets. This article aims to create a list of potential biomarkers related to atherothrombotic stroke by reviewing the currently available literature. We identified 23 biomarkers and assessed their roles as risk factors, detection markers, prognostic predictors, and therapeutic targets. The central aspect of these biomarkers is related to risk stratification, especially for patients who have not yet suffered a stroke. Other valuable data are focused on the predictive capabilities for stroke patients regarding short-term and long-term prognosis, including their influence over the acute phase treatment, such as rt-PA thrombolysis. Although the role of biomarkers is anticipated to be of extreme value in the future, they cannot yet compete with traditional stroke neuroimaging markers but could be used as additional tools for etiological diagnosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Acute Stroke)

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