Search Results (13)

Hypoxia leads to endothelial dysfunction and increased blood–brain barrier (BBB) permeability, promoting the incidence of diseases such as stroke and acute high-altitude illness. Brain microvascular endothelial cells (BMECs) are important structural and functional components of the BBB; however, the molecular changes that occur in BMECs during hypoxia remain unknown. We reported the molecular and functional changes in BMECs under hypoxia through whole-transcriptome sequencing, small RNA microarray, TMT quantitative proteomic, and untargeted metabolomic analyses. We found that hypoxia affected pathways such as ncRNA processing, the HIF-1 signaling pathway, the cell cycle, DNA replication, glucose metabolism, protein synthesis, and inflammation pathways. ncRNA processing was significantly downregulated. However, the levels of some miRNAs, tRNAs, tsRNAs, snoRNAs, lncRNAs, and circRNAs were significantly upregulated under hypoxia. These results suggest that ncRNAs may play an important role in oxidative stress and cellular adaptation to hypoxia, helping us understand the pathological process of BBB injury and providing potential targets for the treatment of BBB-related cerebrovascular diseases. Full article

Stroke is an often underrecognized albeit significant complication in patients with brain cancer, arising from the intricate interplay between cancer biology and cerebrovascular health. This review delves into the multifactorial pathophysiological framework linking brain cancer to elevated stroke risk, with particular emphasis on the crucial role of the neurotoxic microenvironment (NTME). The NTME, characterized by oxidative stress, neuroinflammation, and blood–brain barrier (BBB) disruption, creates a milieu that promotes and sustains vascular and neuronal injury. Key pathogenic factors driving brain cancer-related stroke include cancer-related hypercoagulability, inflammatory and immunological mechanisms, and other tumor-associated processes, including direct tumor compression, infection-related sequelae, and treatment-related complications. Recent advances in genomic and proteomic profiling present promising opportunities for personalized medicine, enabling the identification of biomarkers—such as oncogenes and tumor suppressor genes—that predict stroke susceptibility and inform individualized therapeutic strategies. Targeting the NTME through antioxidants to alleviate oxidative stress, anti-inflammatory agents to mitigate neuroinflammation, and therapies aimed at reinforcing the BBB could pave the way for more effective stroke prevention and management strategies. This integrative approach holds the potential to reduce both the incidence and severity of stroke, ultimately improving clinical outcomes and quality of life for brain cancer patients. Further research and well-designed clinical trials are essential to validate these strategies and integrate them into routine clinical practice, thereby redefining the management of stroke risk in brain cancer patients. Full article

Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications of the GLA gene may cause the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriasylsphingosine (lyso-Gb3), in lysosomes of several types of cells of the heart, kidneys, skin, eyes, peripheral and central nervous system (not clearly and fully demonstrated), and gut with different and pleiotropic clinical symptoms. Among the main symptoms are acroparesthesias and pain crisis (involving the peripheral nervous system), hypohidrosis, abdominal pain, gut motility abnormalities (involving the autonomic system), and finally, cerebrovascular ischemic events due to macrovascular involvement (TIA and stroke) and lacunar strokes and white matter abnormalities due to a small vessel disease (SVS). Gb3 lysosomal accumulation causes cytoplasmatic disruption and subsequent cell death. Additional consequences of Gb3 deposits are inflammatory processes, abnormalities of leukocyte function, and impaired trafficking of some types of immune cells, including lymphocytes, monocytes, CD8+ cells, B cells, and dendritic cells. The involvement of inflammation in AFD pathogenesis conflicts with the reported poor correlation between CRP levels as an inflammation marker and clinical scores such as the Mainz Severity Score Index (MSSI). Also, some authors have suggested an autoimmune reaction is involved in the disease’s pathogenetic mechanism after the α-galactosidase A deficiency. Some studies have reported a high degree of neuronal apoptosis inhibiting protein as a critical anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Notably, this apoptotic upregulation did not change after treatment with enzymatic replacement therapy (ERT), with a further upregulation of the apoptosis-inducing factor after ERT started. Gb3-accumulation has been reported to increase the degree of oxidative stress indexes and the production of reactive oxygen species (ROS). Lipids and proteins have been reported as oxidized and not functioning. Thus, neurological complications are linked to different pathogenetic molecular mechanisms. Progressive accumulation of Gb3 represents a possible pathogenetic event of peripheral nerve involvement. In contrast, central nervous system participation in the clinical setting of cerebrovascular ischemic events seems to be due to the epitheliopathy of Anderson–Fabry disease with lacunar lesions and white matter hyperintensities (WMHs). In this review manuscript, we revised molecular mechanisms of peripheral and central neurological complications of Anderson–Fabry Disease. The management of Fabry disease may be improved by the identification of biomarkers that reflect the clinical course, severity, and progression of the disease. Intensive research on biomarkers has been conducted over the years to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. Recent proteomic or metabolomic studies are in progress, investigating plasma proteome profiles in Fabry patients: these assessments may be useful to characterize the molecular pathology of the disease, improve the diagnostic process, and monitor the response to treatment. Full article

Cerebrovascular pathology that involves altered protein levels (or signaling) of the transforming growth factor beta (TGFβ) family has been associated with various forms of age-related dementias, including Alzheimer disease (AD) and vascular cognitive impairment and dementia (VCID). Transgenic mice overexpressing TGFβ1 in the brain (TGF mice) recapitulate VCID-associated cerebrovascular pathology and develop cognitive deficits in old age or when submitted to comorbid cardiovascular risk factors for dementia. We characterized the cerebrovascular proteome of TGF mice using mass spectrometry (MS)-based quantitative proteomics. Cerebral arteries were surgically removed from 6-month-old-TGF and wild-type mice, and proteins were extracted and analyzed by gel-free nanoLC-MS/MS. We identified 3602 proteins in brain vessels, with 20 demonstrating significantly altered levels in TGF mice. For total and/or differentially expressed proteins (p ≤ 0.01, ≥ 2-fold change), using multiple databases, we (a) performed protein characterization, (b) demonstrated the presence of their RNA transcripts in both mouse and human cerebrovascular cells, and (c) demonstrated that several of these proteins were present in human extracellular vesicles (EVs) circulating in blood. Finally, using human plasma, we demonstrated the presence of several of these proteins in plasma and plasma EVs. Dysregulated proteins point to perturbed brain vessel vasomotricity, remodeling, and inflammation. Given that blood-isolated EVs are novel, attractive, and a minimally invasive biomarker discovery platform for age-related dementias, several proteins identified in this study can potentially serve as VCID markers in humans. Full article

Stroke is a serious disease caused by the rupture or blockage of the cerebrovascular system. Its pathogenesis is complex and involves multiple mechanisms. Iristectorin B is a natural isoflavone that has certain anti stroke effects. In this study, an in vitro stroke injury model of glyoxylate deprivation was established using PC12 cells, which was used to evaluate the anti-stroke activity of Iristectorin B in ejecta stem. The results showed that Iristectorin B, a natural isoflavone derived from Dried Shoot, significantly reduced the damage to PC12 cells caused by oxygen glucose deprivation/reoxygenation, decreased apoptosis, enhanced cell survival and reduced Ca²⁺, LDH and ROS levels. The results showed that Iristectorin B had a significant protective effect on Na₂S₂O₄-injured PC12 cells, and the mechanism may be related to the protective effect of neurons in the brain. After protein extraction and various analyses were performed, a series of cutting-edge technologies were organically combined to study the quantitative proteome of each group. Differential proteins were then analyzed. According to the protein screening principle, ferroptosis-related proteins were most closely associated with stroke. The differential proteins associated with ferroptosis screened were SLC3A2, TFR1 and HMOX1, with HMOX1 being the most significantly elevated and reduced via dosing. Iristectorin B may act as a protective agent against stroke by regulating ferroptosis, and SLC3A2, TFR1 and HMOX1 may serve as potential diagnostic biomarkers for stroke, providing additional evidence to support the importance of ferroptosis in stroke. Full article

Moyamoya angiopathy (MMA) is an uncommon cerebrovascular disease characterized by a progressive steno-occlusive lesion of the internal carotid artery and the compensatory development of an unstable network of collateral vessels. These vascular hallmarks are responsible for recurrent ischemic/hemorrhagic strokes. Surgical treatment represents the preferred procedure for MMA patients, and indirect revascularization may induce a spontaneous angiogenesis between the brain surface and dura mater (DM), whose function remains rather unknown. A better understanding of MMA pathogenesis is expected from the molecular characterization of DM. We performed a comprehensive, label-free, quantitative mass spectrometry-based proteomic characterization of DM. The 30 most abundant identified proteins were located in the extracellular region or exosomes and were involved in extracellular matrix organization. Gene ontology analysis revealed that most proteins were involved in binding functions and hydrolase activity. Among the 30 most abundant proteins, Filamin A is particularly relevant because considering its well-known biochemical functions and molecular features, it could be a possible second hit gene with a potential role in MMA pathogenesis. The current explorative study could pave the way for further analyses aimed at better understanding such uncommon and disabling intracranial vasculopathy. Full article

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

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis. Full article

The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated. In this study, we used molecular and proteomic approaches to identify and investigate major cellular targets of APP down-regulation in endothelial cells. We found that APP is necessary for endothelial cells proliferation, migration and adhesion. The loss of APP alters focal adhesion stability and cell–cell junctions’ expression. Moreover, APP is necessary to mediate endothelial response to the VEGF-A growth factor. Finally, we document that APP propagates exogenous stimuli and mediates cellular response in endothelial cells by modulating the Scr/FAK signaling pathway. Thus, the intact expression and processing of APP is required for normal endothelial function. The identification of molecular mechanisms responsible for vasoprotective properties of endothelial APP may have an impact on clinical efforts to preserve and protect healthy vasculature in patients at risk of the development of cerebrovascular disease and dementia including AD and CAA. Full article

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by occlusion of bilateral internal carotid and intracerebral arteries with the compensatory growth of fragile small vessels. MMD patients develop recurrent infarctions in the basal ganglia and subcortical regions. Symptoms include transient ischemic attack or stroke, seizures, and headaches, which may occur suddenly or in a stepwise progression. Mutations in Ring Finger Protein 213 (RNF213), a Zinc ring finger protein, have been identified in some MMD patients but the etiology of MMD is still largely unknown. To gain insight into the pathophysiology of MMD, we characterized the impact of the RNF213 mutations on plasma protein and RNA profiles. Isobaric tags for relative and absolute quantitation and proximity extension assay were used to characterize the plasma proteome. Next generation sequencing-based small RNAseq was used to analyze the cell-free small RNAs in whole plasma and RNA encapsulated in extracellular vesicles. The changes of miRNAs and proteins identified are associated with signaling processes including angiogenesis and immune activities which may reflect the pathology and progression of MMD. Full article

Loss-of-function mutations in the KRIT1 gene are associated with the pathogenesis of cerebral cavernous malformations (CCMs), a major cerebrovascular disease still awaiting therapies. Accumulating evidence demonstrates that KRIT1 plays an important role in major redox-sensitive mechanisms, including transcriptional pathways and autophagy, which play major roles in cellular homeostasis and defense against oxidative stress, raising the possibility that KRIT1 loss has pleiotropic effects on multiple redox-sensitive systems. Using previously established cellular models, we found that KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in total GSH levels and increase in oxidized glutathione disulfide (GSSG), with a consequent deficit in the GSH/GSSG redox ratio and GSH-mediated antioxidant capacity. Redox proteomic analyses showed that these effects are associated with increased S-glutathionylation of distinct proteins involved in adaptive responses to oxidative stress, including redox-sensitive chaperonins, metabolic enzymes, and cytoskeletal proteins, suggesting a novel molecular signature of KRIT1 loss-of-function. Besides providing further insights into the emerging pleiotropic functions of KRIT1, these findings point definitively to KRIT1 as a major player in redox biology, shedding new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell sensitivity to oxidative stress, which may eventually lead to cellular dysfunctions and CCM disease pathogenesis. Full article

The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases. Full article

Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder, caused by deficiency or absence of the alpha-galactosidase A activity, with a consequent glycosphingolipid accumulation. Biomarkers and imaging findings may be useful for diagnosis, identification of an organ involvement, therapy monitoring and prognosis. The aim of this article is to review the current available literature on biomarkers and imaging findings of AFD patients. An extensive bibliographic review from PubMed, Medline and Clinical Key databases was performed by a group of experts from nephrology, neurology, genetics, cardiology and internal medicine, aiming for consensus. Lyso-GB3 is a valuable biomarker to establish the diagnosis. Proteinuria and creatinine are the most valuable to detect renal damage. Troponin I and high-sensitivity assays for cardiac troponin T can identify patients with cardiac lesions, but new techniques of cardiac imaging are essential to detect incipient damage. Specific cerebrovascular imaging findings are present in AFD patients. Techniques as metabolomics and proteomics have been developed in order to find an AFD fingerprint. Lyso-GB3 is important for evaluating the pathogenic mutations and monitoring the response to treatment. Many biomarkers can detect renal, cardiac and cerebrovascular involvement, but none of these have proved to be important to monitoring the response to treatment. Imaging features are preferred in order to find cardiac and cerebrovascular compromise in AFD patients. Full article