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Advances in Molecular Mechanisms of 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 (30 November 2022) | Viewed by 14960

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Prof. Dr. Saema Ansar

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Guest Editor

Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden
Interests: stroke; cerebral arteries; subarachnoid hemorrhage; cerebrovascular circulation medicine

Special Issue Information

Dear Colleagues,

Stroke is a global health problem and is the second most common cause of death and a leading cause of adult disability worldwide, making this an important active field of research. With the recent development of molecular biology and genetic engineering techniques, the focus of research on the pathogenesis of ischemia has rapidly shifted to the cellular, intracellular organelle, and molecular levels, and many research results have been accumulated. Despite a large amount of fundamental research focused on ischemic and hemorrhagic stroke, much remains to be elucidated pertaining to molecular mechanisms central to stroke.

This Special Issue of IJMS will focus on the molecular mechanisms of stroke with the aim of attaining a greater level of knowledge about stroke and the discovery of new treatments. Original manuscripts and reviews dealing with the mechanisms associated with stroke are especially welcome.

Prof. Dr. Saema Ansar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

stroke
blood–brain barrier
neurogenesis
angiogenesis

Published Papers (6 papers)

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Research

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18 pages, 14811 KiB

Open AccessArticle

E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury

by Yu Gao, Xinyu Xiao, Jing Luo, Jianwei Wang, Qiling Peng, Jing Zhao, Ning Jiang and Yong Zhao

Int. J. Mol. Sci. 2022, 23(21), 13648; https://doi.org/10.3390/ijms232113648 - 07 Nov 2022

Cited by 6 | Viewed by 2294

Abstract

Ischemic stroke, one of the most universal causes of human mortality and morbidity, is pathologically characterized by inflammatory cascade, especially during the progression of ischemia/reperfusion (I/R) injury. F-Box Protein 3 (FBXO3), a substrate-recognition subunit of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, has recently been proven to be severed as an underlying pro-inflammatory factor in pathological processes of diverse diseases. Given these considerations, the current study aims at investigating whether FBXO3 exerts impacts on inflammation in cerebral I/R injury. In this study, first, it was verified that FBXO3 protein expression increased after a middle cerebral artery occlusion/reperfusion (MCAO/R) model in Sprague–Dawley (SD) rats and was specifically expressed in neurons other than microglia or astrocytes. Meanwhile, in mouse hippocampal neuronal cell line HT22 cells, the elevation of FBXO3 protein was observed after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment. It was also found that interference of FBXO3 with siRNA significantly alleviated neuronal damage via inhibiting the inflammatory response in I/R injury both in vivo and in vitro. The FBXO3 inhibitor BC-1215 was used to confirm the pro-inflammatory effect of FBXO3 in the OGD/R model as well. Furthermore, by administration of FBXO3 siRNA and BC-1215, FBXO3 was verified to reduce the protein level of Homeodomain-Interacting Protein Kinase 2 (HIPK2), likely through the ubiquitin–proteasome system (UPS), to aggravate cerebral I/R injury. Collectively, our results underline the detrimental effect FBXO3 has on cerebral I/R injury by accelerating inflammatory response, possibly through ubiquitylating and degrading HIPK2. Despite the specific interaction between FBXO3 and HIPK2 requiring further study, we believe that our data suggest the therapeutic relevance of FBXO3 to ischemic stroke and provide a new perspective on the mechanism of I/R injury. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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14 pages, 3702 KiB

Open AccessArticle

Increased Expression of Interferon-Induced Transmembrane 3 (IFITM3) in Stroke and Other Inflammatory Conditions in the Brain

by Elisabeth Harmon, Andrea Doan, Jesus Bautista-Garrido, Joo Eun Jung, Sean P. Marrelli and Gab Seok Kim

Int. J. Mol. Sci. 2022, 23(16), 8885; https://doi.org/10.3390/ijms23168885 - 10 Aug 2022

Cited by 9 | Viewed by 2088

Abstract

Microglia, the resident innate immune cells of the brain, become more highly reactive with aging and diseased conditions. In collaboration with other cell types in brains, microglia can contribute both to worsened outcome following stroke or other neurodegenerative diseases and to the recovery process by changing their phenotype toward reparative microglia. Recently, IFITM3 (a member of the “interferon-inducible transmembrane” family) has been revealed as a molecular mediator between amyloid pathology and neuroinflammation. Expression of IFITM3 in glial cells, especially microglia following stroke, is not well described. Here, we present evidence that ischemic stroke causes an increase in IFITM3 expression along with increased microglial activation marker genes in aged brains. To further validate the induction of IFITM3 in post-stroke brains, primary microglia and microglial-like cells were exposed to a variety of inflammatory conditions, which significantly induced IFITM3 as well as other inflammatory markers. These findings suggest the critical role of IFITM3 in inducing inflammation. Our findings on the expression of IFITM3 in microglia and in aged brains following stroke could establish the basic foundations for the role of IFITM3 in a variety of neurodegenerative diseases, particularly those that are prevalent or enhanced in the aged brain. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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Review

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27 pages, 908 KiB

Open AccessReview

Matrix Metalloproteinases in Cardioembolic Stroke: From Background to Complications

by Anna Wysocka, Jacek Szczygielski, Marta Kopańska, Joachim M. Oertel and Andrzej Głowniak

Int. J. Mol. Sci. 2023, 24(4), 3628; https://doi.org/10.3390/ijms24043628 - 11 Feb 2023

Cited by 5 | Viewed by 1645

Abstract

Matrix metalloproteinases (MMPs) are endopeptidases participating in physiological processes of the brain, maintaining the blood–brain barrier integrity and playing a critical role in cerebral ischemia. In the acute phase of stroke activity, the expression of MMPs increase and is associated with adverse effects, but in the post-stroke phase, MMPs contribute to the process of healing by remodeling tissue lesions. The imbalance between MMPs and their inhibitors results in excessive fibrosis associated with the enhanced risk of atrial fibrillation (AF), which is the main cause of cardioembolic strokes. MMPs activity disturbances were observed in the development of hypertension, diabetes, heart failure and vascular disease enclosed in CHA₂DS₂VASc score, the scale commonly used to evaluate the risk of thromboembolic complications risk in AF patients. MMPs involved in hemorrhagic complications of stroke and activated by reperfusion therapy may also worsen the stroke outcome. In the present review, we briefly summarize the role of MMPs in the ischemic stroke with particular consideration of the cardioembolic stroke and its complications. Moreover, we discuss the genetic background, regulation pathways, clinical risk factors and impact of MMPs on the clinical outcome. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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15 pages, 1647 KiB

Open AccessReview

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

by Gianluca Costamagna, Sara Bonato, Stefania Corti and Megi Meneri

Int. J. Mol. Sci. 2023, 24(4), 3419; https://doi.org/10.3390/ijms24043419 - 08 Feb 2023

Cited by 1 | Viewed by 2154

Abstract

Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients’ thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches—such as proteomics, metabolomics, transcriptomics, or a combination of these—to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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16 pages, 1338 KiB

Open AccessReview

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets

by Qingyun Guo, Ichiro Kawahata, An Cheng, Wenbin Jia, Haoyang Wang and Kohji Fukunaga

Int. J. Mol. Sci. 2022, 23(17), 9648; https://doi.org/10.3390/ijms23179648 - 25 Aug 2022

Cited by 6 | Viewed by 2712

Abstract

Stroke is among the leading causes of death and disability worldwide. However, despite long-term research yielding numerous candidate neuroprotective drugs, there remains a lack of effective neuroprotective therapies for ischemic stroke patients. Among the factors contributing to this deficiency could be that single-target therapy is insufficient in addressing the complex and extensive mechanistic basis of ischemic brain injury. In this context, lipids serve as an essential component of multiple biological processes and play important roles in the pathogenesis of numerous common neurological diseases. Moreover, in recent years, fatty acid-binding proteins (FABPs), a family of lipid chaperone proteins, have been discovered to be involved in the onset or development of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. However, comparatively little attention has focused on the roles played by FABPs in ischemic stroke. We have recently demonstrated that neural tissue-associated FABPs are involved in the pathological mechanism of ischemic brain injury in mice. Here, we review the literature published in the past decade that has reported on the associations between FABPs and ischemia and summarize the relevant regulatory mechanisms of FABPs implicated in ischemic injury. We also propose candidate FABPs that could serve as potential therapeutic targets for ischemic stroke. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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23 pages, 1999 KiB

Open AccessReview

Promising Strategies for the Development of Advanced In Vitro Models with High Predictive Power in Ischaemic Stroke Research

by Elise Van Breedam and Peter Ponsaerts

Int. J. Mol. Sci. 2022, 23(13), 7140; https://doi.org/10.3390/ijms23137140 - 27 Jun 2022

Cited by 4 | Viewed by 3271

Abstract

Although stroke is one of the world’s leading causes of death and disability, and more than a thousand candidate neuroprotective drugs have been proposed based on extensive in vitro and animal-based research, an effective neuroprotective/restorative therapy for ischaemic stroke patients is still missing. In particular, the high attrition rate of neuroprotective compounds in clinical studies should make us question the ability of in vitro models currently used for ischaemic stroke research to recapitulate human ischaemic responses with sufficient fidelity. The ischaemic stroke field would greatly benefit from the implementation of more complex in vitro models with improved physiological relevance, next to traditional in vitro and in vivo models in preclinical studies, to more accurately predict clinical outcomes. In this review, we discuss current in vitro models used in ischaemic stroke research and describe the main factors determining the predictive value of in vitro models for modelling human ischaemic stroke. In light of this, human-based 3D models consisting of multiple cell types, either with or without the use of microfluidics technology, may better recapitulate human ischaemic responses and possess the potential to bridge the translational gap between animal-based in vitro and in vivo models, and human patients in clinical trials. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)

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