|
1
|
Lemche E, Hortobágyi T, Kiecker C, Turkheimer F. Neuropathological links between T2DM and LOAD: systematic review and meta-analysis. Physiol Rev 2025; 105:1429-1486. [PMID: 40062731 DOI: 10.1152/physrev.00040.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/01/2025] [Accepted: 02/22/2025] [Indexed: 04/16/2025] Open
Abstract
Recent decades have described parallel neuropathological mechanisms increasing the risk for developing late-onset Alzheimer's dementia (LOAD) in type 2 diabetes mellitus (T2DM); however, still little is known of the role of diabetic encephalopathy and brain atrophy in LOAD. The aim of this systematic review is to provide a comprehensive view on diabetic encephalopathy/cerebral atrophy, taking into account neuroimaging data, neuropathology, metabolic and endocrine mechanisms, amyloid formation, brain perfusion impairments, neuroimmunology, and inflammasome activation. Key switches were identified, to further meta-analyze genomic candidate loci and epigenetic modifications. For the qualitative meta-analysis of genomic bases extracted, human linkage studies were examined; for epigenetic mechanisms, data from both human and animal studies are described. For the systematic review of pathophysiological mechanisms, 1,259 publications were evaluated and 93 gene loci extracted for candidate risk linkages. Sixty-six publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight the insulin signaling system, vascular markers, inflammation and inflammasome pathways, amylin interactions, and glycosylation mechanisms. The protocol was registered with PROSPERO (ID: CRD42023440535).
Collapse
Affiliation(s)
- Erwin Lemche
- Section of Cognitive Neuropsychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Tibor Hortobágyi
- Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
- Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Clemens Kiecker
- Department for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Federico Turkheimer
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| |
Collapse
|
|
2
|
Divecha YA, Rampes S, Tromp S, Boyanova ST, Fleckney A, Fidanboylu M, Thomas SA. The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player. Pharmacol Rev 2025; 77:100052. [PMID: 40215558 PMCID: PMC12163501 DOI: 10.1016/j.pharmr.2025.100052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 02/28/2025] [Indexed: 05/27/2025] Open
Abstract
High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.
Collapse
Affiliation(s)
- Yasmin Amy Divecha
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Sanketh Rampes
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Sabine Tromp
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Sevda T Boyanova
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Alice Fleckney
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Mehmet Fidanboylu
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom
| | - Sarah Ann Thomas
- King's College London, Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, Waterloo, London, United Kingdom.
| |
Collapse
|
|
3
|
Li J, Du M, Dong G, Hu D, Zhang H, Yu Z, Lu Y, Yang Y. Early intervention with pericyte Fli-1 post-TBI attenuates hippocampal BBB disruption and subsequent neuroinflammation with neurological deficits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167671. [PMID: 39826850 DOI: 10.1016/j.bbadis.2025.167671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/29/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
The ETS transcription factor Fli-1, known for regulating the vitality of pericyte in mice, has not been thoroughly investigated in traumatic brain injury (TBI). In this study, we used a mouse TBI model to demonstrate that Fli-1 expression in pericyte within the ipsilateral hippocampus is significantly increased following TBI and is associated with pericyte loss. Interfering with Fli-1 expression in pericyte disrupted their interactions with microglia, which in turn inhibited the transformation of microglia to a pro-inflammatory phenotype. Administration of Fli-1 siRNA via lateral ventricle injection reduced pericyte loss, microglial activation, and neuroinflammation induced by TBI. Additionally, Fli-1 siRNA treatment reduced neurological damage in the hippocampus and improved memory and cognitive function. Overall, our findings suggest that Fli-1 expression in pericyte is closely linked to pericyte apoptosis and pericyte-microglia interactions. Inhibiting Fli-1 could mitigate pericyte loss, neuroinflammation, blood-brain barrier disruption, and cognitive decline, indicating that targeting Fli-1 may be a viable clinical strategy for TBI intervention.
Collapse
Affiliation(s)
- Jiani Li
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an 710003, China
| | - Minghao Du
- Department of Neurosurgery, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an 710003, China
| | - Gongming Dong
- Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Di Hu
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710000, China
| | - Haitao Zhang
- Xi'an People's Hospital, Northwest University, Xi'an, Shaanxi 710000, China
| | - Zhen Yu
- Xi'an People's Hospital, Northwest University, Xi'an, Shaanxi 710000, China
| | - Yichen Lu
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China.
| | - Yajie Yang
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710000, China.
| |
Collapse
|
|
4
|
Garcia-Martínez T, Gornatti DG, Ortiz M, Cañellas G, Heine-Suñer D, Vives-Bauzà C. The Triad of Blood-Brain Barrier Integrity: Endothelial Cells, Astrocytes, and Pericytes in Perinatal Stroke Pathophysiology. Int J Mol Sci 2025; 26:1886. [PMID: 40076511 PMCID: PMC11900453 DOI: 10.3390/ijms26051886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Pediatric stroke, a significant cause of long-term neurological deficits in children, often arises from disruptions within neurovascular unit (NVU) components. The NVU, a dynamic ensemble of astrocytes, endothelial cells, pericytes, and microglia, is vital for maintaining cerebral homeostasis and regulating vascular brain development. Its structural integrity, particularly at the blood-brain barrier (BBB), depends on intercellular junctions and the basement membrane, which together restrict paracellular transport and shield the brain from systemic insults. Dysfunction in this intricate system is increasingly linked to pediatric stroke and related cerebrovascular conditions. Mutations disrupting endothelial cell adhesion or pericyte-endothelial interactions can compromise BBB stability, leading to pathological outcomes such as intraventricular hemorrhage in the germinal matrix, a hallmark of vascular brain immaturity. Additionally, inflammation, ferroptosis, necroptosis, and autophagy are key cellular processes influencing brain damage and repair. Excessive activation of these mechanisms can exacerbate NVU injury, whereas targeted therapeutic modulation offers potential pathways to mitigate damage and support recovery. This review explores the cellular and molecular mechanisms underlying NVU dysfunction, BBB disruption, and subsequent brain injury in pediatric stroke. Understanding the interplay between genetic mutations, environmental stressors, and NVU dynamics provides new insights into stroke pathogenesis. The susceptibility of the germinal matrix to vascular rupture further emphasizes the critical role of NVU integrity in early brain development. Targeting inflammatory pathways and cell death mechanisms presents promising strategies to preserve NVU function and improve outcomes for affected neonates.
Collapse
Affiliation(s)
- Tania Garcia-Martínez
- Neurobiology, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; (T.G.-M.); (D.G.G.); (M.O.); (G.C.)
| | - Denise G. Gornatti
- Neurobiology, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; (T.G.-M.); (D.G.G.); (M.O.); (G.C.)
| | - Marina Ortiz
- Neurobiology, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; (T.G.-M.); (D.G.G.); (M.O.); (G.C.)
| | - Guillem Cañellas
- Neurobiology, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; (T.G.-M.); (D.G.G.); (M.O.); (G.C.)
- Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), 07122 Palma, Spain
| | - Damià Heine-Suñer
- Genomics of Health Research, Unit of Molecular Diagnostics and Clinical Genetics, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07013 Palma, Spain;
| | - Cristòfol Vives-Bauzà
- Neurobiology, Research Unit, Hospital Universitari Son Espases, Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; (T.G.-M.); (D.G.G.); (M.O.); (G.C.)
- Department of Biology, University of Balearic Islands (UIB), Institut Universitari d’Investigacions en Ciències de la Salut (IUNICS), 07122 Palma, Spain
| |
Collapse
|
|
5
|
Morton L, Garza AP, Debska‐Vielhaber G, Villafuerte LE, Henneicke S, Arndt P, Meuth SG, Schreiber S, Dunay IR. Pericytes and Extracellular Vesicle Interactions in Neurovascular Adaptation to Chronic Arterial Hypertension. J Am Heart Assoc 2025; 14:e038457. [PMID: 39719419 PMCID: PMC12054408 DOI: 10.1161/jaha.124.038457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 11/19/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small-vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. METHODS AND RESULTS In this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat model, focusing on their phenotypic and metabolic transformation. Flow cytometry was used to characterize pericytes by their expression of platelet-derived growth factor receptor β, neuroglial antigen 2, cluster of differentiation 13-alanyl aminopeptidase, and antigen Kiel 67. Microvessels were isolated for gene expression profiling and in vitro pericyte expansion. Immunofluorescence validated the cell culture model. Plasma-derived extracellular vesicles from hypertensive rodents were applied as a treatment to assess their effects on pericyte function and detailed metabolic assessments on enriched pericytes measured oxidative phosphorylation and glycolysis. Our results reveal a shift in platelet-derived growth factor receptor β+ pericytes toward increased neuroglial antigen 2 and cluster of differentiation 13-alanyl aminopeptidase coexpression, indicative of their critical role in vascular stabilization and inflammatory responses within the hypertensive milieu. Significant alterations were found within key pathways including angiogenesis, blood-brain barrier integrity, hypoxia, and inflammation. Circulating extracellular vesicles from hypertensive rodents distinctly influenced pericyte mitochondrial function, evidencing their dual role as carriers of disease pathology and potential therapeutic agents. Furthermore, a shift toward glycolytic metabolism in hypertensive pericytes was confirmed, coupled with ATP production dysregulation. CONCLUSIONS Our findings demonstrate that cerebral pericytes undergo phenotypic and metabolic reprogramming in response to hypertension, with hypertensive-derived plasma-derived extracellular vesicles impairing their mitochondrial function. Importantly, plasma-derived extracellular vesicles from normotensive controls restore this function, suggesting their potential as both therapeutic agents and precision biomarkers for hypertensive vascular complications. Further investigation into plasma-derived extracellular vesicle cargo is essential to further explore their therapeutic potential in vascular health.
Collapse
Affiliation(s)
- Lorena Morton
- Medical Faculty, Institute of Inflammation and NeurodegenerationOtto‐von‐Guericke University MagdeburgMagdeburgGermany
| | - Alejandra P. Garza
- Medical Faculty, Institute of Inflammation and NeurodegenerationOtto‐von‐Guericke University MagdeburgMagdeburgGermany
| | | | - Luis E. Villafuerte
- Medical Faculty, Institute of Inflammation and NeurodegenerationOtto‐von‐Guericke University MagdeburgMagdeburgGermany
| | - Solveig Henneicke
- Department of NeurologyOtto von Guericke University MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, MagdeburgMagdeburgGermany
| | - Philipp Arndt
- Department of NeurologyOtto von Guericke University MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, MagdeburgMagdeburgGermany
| | - Sven G. Meuth
- Department of NeurologyHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Stefanie Schreiber
- Department of NeurologyOtto von Guericke University MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, MagdeburgMagdeburgGermany
- Center for Behavioral Brain Sciences (CBBS)MagdeburgGermany
- German Center for Mental Health (DZPG)Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C‐I‐R‐C)Halle‐Jena‐MagdeburgGermany
| | - Ildiko R. Dunay
- Medical Faculty, Institute of Inflammation and NeurodegenerationOtto‐von‐Guericke University MagdeburgMagdeburgGermany
- Center for Behavioral Brain Sciences (CBBS)MagdeburgGermany
- German Center for Mental Health (DZPG)Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C‐I‐R‐C)Halle‐Jena‐MagdeburgGermany
| |
Collapse
|
|
6
|
Ismail FS, Faustmann PM, Corvace F, Faustmann TJ. Neuroglia in autoimmune encephalitis. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:147-157. [PMID: 40148042 DOI: 10.1016/b978-0-443-19102-2.00002-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Neuroglial cells play a crucial role in central nervous system (CNS) health and disease. Antibody-associated autoimmune encephalitis (AE) represents a group of inflammatory brain diseases with antibodies (Abs) against neuronal cell surface (e.g., anti-N-methyl-d-aspartate receptor (NMDAR), anti-leucine-rich glioma-inactivated 1 (LGI1), γ-aminobutyric acid (GABA) type A or B receptor (GABAA/BR)) or intracellular neuronal proteins. AE with Abs against glial antigens, e.g., myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP) are also described. Besides the known pathomechanisms with direct pathogenic effects of primary neuronal Abs and activation of innate (dendritic cells) and adaptive (B and T cells) immune systems, research findings suggest the involvement of glial cells including astrocytes, microglia, oligodendrocytes in the pathogenesis of Ab-associated AE, but only a limited number of studies is available. Neuropathologic findings showed reactive astrogliosis and microgliosis with microglial activation/proliferation, e.g., in anti-NMDAR and anti-LGI1 encephalitis. Direct effects of the GABAAR and NMDAR Abs on astrocytic receptors are discussed. Because of the primary involvement of B and T cells in the pathogenesis of Ab-associated AE it can be assumed that astrocytic and microglial activation is largely a response to the primary changes, but additional direct effects of Abs on astrocytic receptors are possible. Further research in this field is required to explore the exact role of glial cells in Ab-associated AE.
Collapse
Affiliation(s)
- Fatme Seval Ismail
- Department of Neurology, Klinikum Vest, Academic Teaching Hospital of the Ruhr University Bochum, Recklinghausen, Germany
| | - Pedro M Faustmann
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany.
| | - Franco Corvace
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
| | - Timo Jendrik Faustmann
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| |
Collapse
|
|
7
|
Deshmukh V, Pathan NS, Haldar N, Nalawade S, Narwade M, Gajbhiye KR, Gajbhiye V. Exploring intranasal drug delivery via nanocarriers: A promising glioblastoma therapy. Colloids Surf B Biointerfaces 2025; 245:114285. [PMID: 39366109 DOI: 10.1016/j.colsurfb.2024.114285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/23/2024] [Accepted: 09/29/2024] [Indexed: 10/06/2024]
Abstract
Glioblastoma is one of the most recurring types of glioma, having the highest mortality rate among all other gliomas. Traditionally, the standard course of treatment for glioblastoma involved maximum surgical resection, followed by chemotherapy and radiation therapy. Nanocarriers have recently focused on enhancing the chemotherapeutic administration to the brain to satisfy unmet therapeutic requirements for treating brain-related disorders. Due to the significant drawbacks and high recurrence rates of gliomas, intranasal administration of nanocarrier systems presents several advantages. These include low toxicity, non-invasiveness, and the ability to cross the blood-brain barrier. By customizing their size, encasing them with mucoadhesive agents, or undergoing surface modification that encourages movement over the nose's mucosa, we can exceptionally engineer nanocarriers for intranasal administration. Olfactory and trigeminal nerves absorb drugs administered nasally and transport them to the brain, serving as the primary delivery mechanism for nose-to-brain administration. This review sums up the latest developments in chemotherapeutic nanocarriers, such as metallic nanoparticles, polymeric nanoparticles, nanogels, nano vesicular carriers, genetic material-based nanocarriers, and polymeric micelles. These nanocarriers have demonstrated efficient drug delivery from the nose to the brain, effectively overcoming mucociliary clearance. However, challenges persist, such as limitations in targeted chemotherapy and restricted drug loading capacity for intranasal administration. Additionally, the review addresses regulatory considerations and prospects for these innovative drug delivery systems.
Collapse
Affiliation(s)
- Vishawambhar Deshmukh
- Poona College of Pharmacy, Bharati Vidyapeeth Deemed to be University, Erandwane, Pune 411038, India
| | - Nida Sayed Pathan
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India
| | - Niladri Haldar
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India
| | - Shubhangi Nalawade
- Poona College of Pharmacy, Bharati Vidyapeeth Deemed to be University, Erandwane, Pune 411038, India
| | - Mahavir Narwade
- Poona College of Pharmacy, Bharati Vidyapeeth Deemed to be University, Erandwane, Pune 411038, India
| | - Kavita R Gajbhiye
- Poona College of Pharmacy, Bharati Vidyapeeth Deemed to be University, Erandwane, Pune 411038, India.
| | - Virendra Gajbhiye
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India.
| |
Collapse
|
|
8
|
Zimina TM, Sitkov NO, Gareev KG, Mikhailova NV, Combs SE, Shevtsov MA. Hybrid-integrated devices for mimicking malignant brain tumors ("tumor-on-a-chip") for in vitro development of targeted drug delivery and personalized therapy approaches. Front Med (Lausanne) 2024; 11:1452298. [PMID: 39629230 PMCID: PMC11611596 DOI: 10.3389/fmed.2024.1452298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/14/2024] [Indexed: 12/07/2024] Open
Abstract
Acute and requiring attention problem of oncotheranostics is a necessity for the urgent development of operative and precise diagnostics methods, followed by efficient therapy, to significantly reduce disability and mortality of citizens. A perspective way to achieve efficient personalized treatment is to use methods for operative evaluation of the individual drug load, properties of specific tumors and the effectiveness of selected therapy, and other actual features of pathology. Among the vast diversity of tumor types-brain tumors are the most invasive and malignant in humans with poor survival after diagnosis. Among brain tumors glioblastoma shows exceptionally high mortality. More studies are urgently needed to understand the risk factors and improve therapy approaches. One of the actively developing approaches is the tumor-on-a-chip (ToC) concept. This review examines the achievements of recent years in the field of ToC system developments. The basics of microfluidic chips technologies are considered in the context of their applications in solving oncological problems. Then the basic principles of tumors cultivation are considered to evaluate the main challengers in implementation of microfluidic devices, for growing cell cultures and possibilities of their treatment and observation. The main achievements in the culture types diversity approaches and their advantages are being analyzed. The modeling of angiogenesis and blood-brain barrier (BBB) on a chip, being a principally important elements of the life system, were considered in detail. The most interesting examples and achievements in the field of tumor-on-a-chip developments have been presented.
Collapse
Affiliation(s)
- Tatiana M. Zimina
- Department of Micro and Nanoelectronics, St. Petersburg Electrotechnical University “LETI” (ETU), Saint Petersburg, Russia
| | - Nikita O. Sitkov
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Kamil G. Gareev
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Natalia V. Mikhailova
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Stephanie E. Combs
- Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Maxim A. Shevtsov
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
- Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| |
Collapse
|
|
9
|
Shen Z, Lu Y, Ren Y, Wang Z, Deng J, Nan D, Jia J, Yu W, Jin Y, Sun W, Huang Y, Qu X, Jin H. The relationship between ischemic penumbra progression and the oxygen content of cortex microcirculation in acute ischemic stroke. Neurotherapeutics 2024; 21:e00387. [PMID: 38918128 PMCID: PMC11579870 DOI: 10.1016/j.neurot.2024.e00387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/21/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA3-Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
Collapse
Affiliation(s)
- Zhiyuan Shen
- Department of Neurology, Peking University First Hospital, Beijing 100034, China; Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050030, China
| | - Yuxuan Lu
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Yingying Ren
- Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhaoxia Wang
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Jianwen Deng
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Ding Nan
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Jingjing Jia
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Weiwei Yu
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Yunyi Jin
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Wei Sun
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Yining Huang
- Department of Neurology, Peking University First Hospital, Beijing 100034, China
| | - Xiaozhong Qu
- Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Haiqiang Jin
- Department of Neurology, Peking University First Hospital, Beijing 100034, China.
| |
Collapse
|
|
10
|
Seyedaghamiri F, Geranmayeh MH, Ghadiri T, Ebrahimi-Kalan A, Hosseini L. A new insight into the role of pericytes in ischemic stroke. Acta Neurol Belg 2024; 124:767-774. [PMID: 37805645 DOI: 10.1007/s13760-023-02391-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 09/19/2023] [Indexed: 10/09/2023]
Abstract
The functional structure of the blood-brain barrier (BBB) deteriorates after stroke by developing diffuse microvascular and neurovascular dysfunction and loss of white matter integrity. This causes nervous tissue injury and causes sensory and motor disabilities in stroke patients. Improving the integrity of the BBB and neurovascular remodeling after stroke can promote post-stroke injury conditions. Pericytes are contractile cells abundant in the BBB and sandwiched between astrocytes and endothelial cells of the microvessels. Stroke could lead to the degeneration of pericytes in the BBB. However, recent evidence shows that promoting pericytes enhances BBB integrity and neurovascular remodeling. Furthermore, pericytes achieve multipotent properties under hypoxic conditions, allowing them to transdifferentiate into the brain resident cells such as microglia. Microglia regulate immunity and inflammatory response after stroke. The current review studies recent findings in the intervening mechanisms underlying the regulatory effect of pericytes in BBB recovery after stroke.
Collapse
Affiliation(s)
- Fatemehsadat Seyedaghamiri
- Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Tahereh Ghadiri
- Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Hosseini
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
11
|
Roghani AK, Garcia RI, Roghani A, Reddy A, Khemka S, Reddy RP, Pattoor V, Jacob M, Reddy PH, Sehar U. Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems. Ageing Res Rev 2024; 97:102291. [PMID: 38614367 DOI: 10.1016/j.arr.2024.102291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/18/2024] [Accepted: 04/01/2024] [Indexed: 04/15/2024]
Abstract
The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.
Collapse
Affiliation(s)
- Aryan Kia Roghani
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Frenship High School, Lubbock, TX 79382, USA.
| | - Ricardo Isaiah Garcia
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ali Roghani
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Aananya Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA.
| | - Sachi Khemka
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ruhananhad P Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA.
| | - Vasanthkumar Pattoor
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; University of South Florida, Tampa, FL 33620, USA.
| | - Michael Jacob
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Services, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ujala Sehar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| |
Collapse
|
|
12
|
Bhargava A, Jajoo B, Telkhade T, Patel A, Bhawani J. Rare Encounter: Giant Hemangiopericytoma of Thigh in a Young Male. Cureus 2024; 16:e59514. [PMID: 38826872 PMCID: PMC11143947 DOI: 10.7759/cureus.59514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/02/2024] [Indexed: 06/04/2024] Open
Abstract
A rare tumor called hemangiopericytoma develops from the pericytes, the cells that surround blood vessels. They frequently grow slowly and might be asymptomatic initially. Although they can develop anywhere in the body, these tumors are most frequently found in the head, pelvis, and legs. This uncommon tumor originates in soft tissues like fat, muscles, tendons, nerves, blood vessels, and other fibrous tissues. The tumor in adolescence can be benign or malignant; it frequently develops in the bones but has the potential to metastasize to the lungs. Imaging tests, such as MRIs or CT scans, are commonly used in diagnosis to determine the location and size of the tumor. We present a case of a 23-year-old male who complained of swelling in his left thigh that had persisted for two years. He underwent multiple biopsies which were inconclusive until wide local excision of the swelling was done. On histopathology, the excised tumor was suggestive of hemangiopericytoma. The patient was advised of radiotherapy for completion of the treatment.
Collapse
Affiliation(s)
- Abhilasha Bhargava
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Bhushan Jajoo
- Surgical Oncology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Tejshri Telkhade
- Radiation Oncology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Aditya Patel
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Jayashree Bhawani
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
13
|
Hamani C, Davidson B, Lipsman N, Abrahao A, Nestor SM, Rabin JS, Giacobbe P, Pagano RL, Campos ACP. Insertional effect following electrode implantation: an underreported but important phenomenon. Brain Commun 2024; 6:fcae093. [PMID: 38707711 PMCID: PMC11069120 DOI: 10.1093/braincomms/fcae093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/08/2023] [Accepted: 03/26/2024] [Indexed: 05/07/2024] Open
Abstract
Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as 'insertional effect', can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation as an active part of the deep brain stimulation therapy.
Collapse
Affiliation(s)
- Clement Hamani
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Benjamin Davidson
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Nir Lipsman
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Agessandro Abrahao
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Sean M Nestor
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Jennifer S Rabin
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto M5G 1V7, Canada
| | - Peter Giacobbe
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Rosana L Pagano
- Laboratory of Neuroscience, Hospital Sírio-Libanês, São Paulo, SP CEP 01308-060, Brazil
| | - Ana Carolina P Campos
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
- Laboratory of Neuroscience, Hospital Sírio-Libanês, São Paulo, SP CEP 01308-060, Brazil
| |
Collapse
|
|
14
|
Ali HT, Sula I, AbuHamdia A, Elejla SA, Elrefaey A, Hamdar H, Elfil M. Nervous System Response to Neurotrauma: A Narrative Review of Cerebrovascular and Cellular Changes After Neurotrauma. J Mol Neurosci 2024; 74:22. [PMID: 38367075 PMCID: PMC10874332 DOI: 10.1007/s12031-024-02193-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/22/2024] [Indexed: 02/19/2024]
Abstract
Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood-brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.
Collapse
Affiliation(s)
| | - Idris Sula
- College of Medicine, Sulaiman Al Rajhi University, Al Bukayriyah, Al Qassim, Saudi Arabia
| | - Abrar AbuHamdia
- Department of Medical Laboratory Science, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | | | | | - Hiba Hamdar
- Medical Learning Skills Academy, Beirut, Lebanon
- Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Mohamed Elfil
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
15
|
Nippert AR, Chiang PP, Newman EA. Whisker-evoked neurovascular coupling is preserved during hypoglycemia in mouse cortical arterioles and capillaries. J Cereb Blood Flow Metab 2024; 44:155-168. [PMID: 37728791 PMCID: PMC10993878 DOI: 10.1177/0271678x231201241] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/12/2023] [Accepted: 08/15/2023] [Indexed: 09/21/2023]
Abstract
Hypoglycemia is a serious complication of insulin treatment of diabetes that can lead to coma and death. Neurovascular coupling, which mediates increased local blood flow in response to neuronal activity, increases glucose availability to active neurons. This mechanism could be essential for neuronal health during hypoglycemia, when total glucose supplies are low. Previous studies suggest, however, that neurovascular coupling (a transient blood flow increase in response to an increase in neuronal activity) may be reduced during hypoglycemia. Such a reduction in blood flow increase would exacerbate the effects of hypoglycemia, depriving active neurons of glucose. We have reexamined the effects of hypoglycemia on neurovascular coupling by simultaneously monitoring neuronal and vascular responses to whisker stimulation in the awake mouse somatosensory cortex. We find that neurovascular coupling at both penetrating arterioles and at 2nd order capillaries did not change significantly during insulin-induced hypoglycemia compared to euglycemia. In addition, we show that the basal diameter of both arterioles and capillaries increases during hypoglycemia (10.3 and 9.7% increases, respectively). Our results demonstrate that both neurovascular coupling and basal increases in vessel diameter are active mechanisms which help to maintain an adequate supply of glucose to the brain during hypoglycemia.
Collapse
Affiliation(s)
| | | | - Eric A Newman
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
16
|
Shu H, Wen Z, Li N, Zhang Z, Ceesay BM, Peng Y, Zhou N, Wang DW. COVID-19 and Cardiovascular Diseases: From Cellular Mechanisms to Clinical Manifestations. Aging Dis 2023; 14:2071-2088. [PMID: 37199573 PMCID: PMC10676802 DOI: 10.14336/ad.2023.0314] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/14/2023] [Indexed: 05/19/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quickly spread worldwide and led to over 581 million confirmed cases and over 6 million deaths as 1 August 2022. The binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor is the primary mechanism of SARS-CoV-2 infection. Not only highly expressed in the lung, ACE2 is also widely distributed in the heart, mainly in cardiomyocytes and pericytes. The strong association between COVID-19 and cardiovascular disease (CVD) has been demonstrated by increased clinical evidence. Preexisting CVD risk factors, including obesity, hypertension, and diabetes etc., increase susceptibility to COVID-19. In turn, COVID-19 exacerbates the progression of CVD, including myocardial damage, arrhythmia, acute myocarditis, heart failure, and thromboembolism. Moreover, cardiovascular risks post recovery and the vaccination-associated cardiovascular problems have become increasingly evident. To demonstrate the association between COVID-19 and CVD, this review detailly illustrated the impact of COVID-19 on different cells (cardiomyocytes, pericytes, endothelial cells, and fibroblasts) in myocardial tissue and provides an overview of the clinical manifestations of cardiovascular involvements in the pandemic. Finally, the issues related to myocardial injury post recovery, as well as vaccination-induced CVD, has also been emphasized.
Collapse
Affiliation(s)
- Hongyang Shu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Zheng Wen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Na Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Zixuan Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Bala Musa Ceesay
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Yizhong Peng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ning Zhou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430000, China.
| |
Collapse
|
|
17
|
Berends E, van Oostenbrugge RJ, Foulquier S, Schalkwijk CG. Methylglyoxal, a highly reactive dicarbonyl compound, as a threat for blood brain barrier integrity. Fluids Barriers CNS 2023; 20:75. [PMID: 37875994 PMCID: PMC10594715 DOI: 10.1186/s12987-023-00477-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/10/2023] [Indexed: 10/26/2023] Open
Abstract
The brain is a highly metabolically active organ requiring a large amount of glucose. Methylglyoxal (MGO), a by-product of glucose metabolism, is known to be involved in microvascular dysfunction and is associated with reduced cognitive function. Maintenance of the blood-brain barrier (BBB) is essential to maintain optimal brain function and a large amount of evidence indicates negative effects of MGO on BBB integrity. In this review, we summarized the current literature on the effect of MGO on the different cell types forming the BBB. BBB damage by MGO most likely occurs in brain endothelial cells and mural cells, while astrocytes are most resistant to MGO. Microglia on the other hand appear to be not directly influenced by MGO but rather produce MGO upon activation. Although there is clear evidence that MGO affects components of the BBB, the impact of MGO on the BBB as a multicellular system warrants further investigation. Diminishing MGO stress can potentially form the basis for new treatment strategies for maintaining optimal brain function.
Collapse
Affiliation(s)
- Eline Berends
- Department of Internal Medicine, Maastricht University, Universiteitssingel, Maastricht, 50 6229ER, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht, 6229ER, The Netherlands
| | - Robert J van Oostenbrugge
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht, 6229ER, The Netherlands
- School for Mental Health and Neuroscience (MHeNs), Maastricht University, Universiteitssingel 40, Maastricht, 6229ER, The Netherlands
- Department of Neurology, Maastricht University Medical Centre (MUMC+), P. Debyelaan 25 6202AZ, Maastricht, The Netherlands
| | - Sébastien Foulquier
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht, 6229ER, The Netherlands.
- Department of Neurology, Maastricht University Medical Centre (MUMC+), P. Debyelaan 25 6202AZ, Maastricht, The Netherlands.
- Department of Pharmacology and Toxicology, Maastricht University, Universiteitssingel 50 6229ER, Maastricht, The Netherlands.
| | - Casper G Schalkwijk
- Department of Internal Medicine, Maastricht University, Universiteitssingel, Maastricht, 50 6229ER, The Netherlands.
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht, 6229ER, The Netherlands.
| |
Collapse
|
|
18
|
Li C, Chen S, Siedhoff HR, Grant D, Liu P, Balderrama A, Jackson M, Zuckerman A, Greenlief CM, Kobeissy F, Wang KW, DePalma RG, Cernak I, Cui J, Gu Z. Low-intensity open-field blast exposure effects on neurovascular unit ultrastructure in mice. Acta Neuropathol Commun 2023; 11:144. [PMID: 37674234 PMCID: PMC10481586 DOI: 10.1186/s40478-023-01636-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 08/14/2023] [Indexed: 09/08/2023] Open
Abstract
Mild traumatic brain injury (mTBI) induced by low-intensity blast (LIB) is a serious health problem affecting military service members and veterans. Our previous reports using a single open-field LIB mouse model showed the absence of gross microscopic damage or necrosis in the brain, while transmission electron microscopy (TEM) identified ultrastructural abnormalities of myelin sheaths, mitochondria, and synapses. The neurovascular unit (NVU), an anatomical and functional system with multiple components, is vital for the regulation of cerebral blood flow and cellular interactions. In this study, we delineated ultrastructural abnormalities affecting the NVU in mice with LIB exposure quantitatively and qualitatively. Luminal constrictive irregularities were identified at 7 days post-injury (DPI) followed by dilation at 30 DPI along with degeneration of pericytes. Quantitative proteomic analysis identified significantly altered vasomotor-related proteins at 24 h post-injury. Endothelial cell, basement membrane and astrocyte end-foot swellings, as well as vacuole formations, occurred in LIB-exposed mice, indicating cellular edema. Structural abnormalities of tight junctions and astrocyte end-foot detachment from basement membranes were also noted. These ultrastructural findings demonstrate that LIB induces multiple-component NVU damage. Prevention of NVU damage may aid in identifying therapeutic targets to mitigate the effects of primary brain blast injury.
Collapse
Affiliation(s)
- Chao Li
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510630, China
| | - Shanyan Chen
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA
| | - Heather R Siedhoff
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA
| | - DeAna Grant
- Electron Microscopy Core Facility, University of Missouri, Columbia, MO, 65211, USA
| | - Pei Liu
- Charles W. Gehrke Proteomic Center, University of Missouri, Columbia, MO, 65211, USA
| | - Ashley Balderrama
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA
| | - Marcus Jackson
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
| | - Amitai Zuckerman
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA
| | - C Michael Greenlief
- Charles W. Gehrke Proteomic Center, University of Missouri, Columbia, MO, 65211, USA
| | - Firas Kobeissy
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, 30310-1458, USA
- Atlanta VA Medical and Rehab Center, Decatur, GA, 30033, USA
| | - Kevin W Wang
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, 30310-1458, USA
- Atlanta VA Medical and Rehab Center, Decatur, GA, 30033, USA
| | - Ralph G DePalma
- Office of Research and Development, Department of Veterans Affairs, Washington, DC, 20420, USA
- Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA
| | - Ibolja Cernak
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, 31207, USA
| | - Jiankun Cui
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA
| | - Zezong Gu
- Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, One Hospital Drive, Medical Science Building, M741, Columbia, MO, 65212, USA.
- Truman VA Hospital Research Service, Columbia, MO, 65201, USA.
| |
Collapse
|
|
19
|
Wu DD, Salah YA, Ngowi EE, Zhang YX, Khattak S, Khan NH, Wang Y, Li T, Guo ZH, Wang YM, Ji XY. Nanotechnology prospects in brain therapeutics concerning gene-targeting and nose-to-brain administration. iScience 2023; 26:107321. [PMID: 37554468 PMCID: PMC10405259 DOI: 10.1016/j.isci.2023.107321] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
Neurological diseases are one of the most pressing issues in modern times worldwide. It thus possesses explicit attention from researchers and medical health providers to guard public health against such an expanding threat. Various treatment modalities have been developed in a remarkably short time but, unfortunately, have yet to lead to the wished-for efficacy or the sought-after clinical improvement. The main hurdle in delivering therapeutics to the brain has always been the blood-brain barrier which still represents an elusive area with lots of mysteries yet to be solved. Meanwhile, nanotechnology has emerged as an optimistic platform that is potentially holding the answer to many of our questions on how to deliver drugs and treat CNS disorders using novel technologies rather than the unsatisfying conventional old methods. Nanocarriers can be engineered in a way that is capable of delivering a certain therapeutic cargo to a specific target tissue. Adding to this mind-blowing nanotechnology, the revolutionizing gene-altering biologics can have the best of both worlds, and pave the way for the long-awaited cure to many diseases, among those diseases thus far are Alzheimer's disease (AD), brain tumors (glioma and glioblastoma), Down syndrome, stroke, and even cases with HIV. The review herein collects the studies that tested the mixture of both sciences, nanotechnology, and epigenetics, in the context of brain therapeutics using three main categories of gene-altering molecules (siRNA, miRNA, and CRISPR) with a special focus on the advancements regarding the new favorite, intranasal route of administration.
Collapse
Affiliation(s)
- Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Yasmine Ahmed Salah
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo 11517, Egypt
| | - Ebenezeri Erasto Ngowi
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- Department of Biological Sciences, Dar es Salaam University College of Education, Dar es Salaam 2329, Tanzania
| | - Yan-Xia Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Tao Li
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| | - Zi-Hua Guo
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- Department of Neurology, Kaifeng Hospital of Traditional Chinese Medicine, Henan University, Kaifeng, Henan 475000, China
| | - Yan-Mei Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- School of Nursing and Health, Henan University, Kaifeng, Henan 475004, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
- Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
| |
Collapse
|
|
20
|
Tice C, Zhao H, Langford D. Single nucleotide polymorphisms in aquaporin-4 associate with cognitive impairment status in people with HIV. J Neurovirol 2023; 29:258-271. [PMID: 37191905 PMCID: PMC11450701 DOI: 10.1007/s13365-023-01126-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/20/2023] [Accepted: 03/13/2023] [Indexed: 05/17/2023]
Abstract
Neurocognitive impairments are more frequent in people with HIV (PWH) compared to their uninfected counterparts. HIV-associated neurocognitive disorder (HAND) is a spectrum disorder and up to 50% of PWH are reported to suffer from HAND. Altered waste clearance from the brain, chronic neuroinflammation and impaired metabolic processes may contribute to abnormal aging in PWH and are more common among those who suffer from HAND. Thus, it is important to identify earlier predictors for development of HAND. A key contributor to cognitive impairment in HIV and in Alzheimer's disease (AD) is formation and accumulation of aberrant proteins including hyperphosphorylated Tau (pTau). Previous data from AD and traumatic brain injury studies report that impaired waste clearance from the brain contributes in part to cognitive impairments. Evidence suggests that the aquaporin 4 (aqp4) gene may have an important role in waste clearance from the brain as single nucleotide polymorphisms (SNPs) in aqp4 have been reported to associate with changes in cognitive decline in AD patients. Given some similarities between HAND and AD, we assessed potential associations of several aqp4 SNPS with cognitive impairment in PWH. Our data show that homozygous carriers of the minor allele in SNPs rs3875089 and rs3763040 had significantly lower neuropsychological test Z-scores in multiple domains compared to the other genotypes. Interestingly, this decrease in Z-scores was only observed in PWH and not in HIV-control participants. Conversely, homozygosity of the minor allele of rs335929 associated with better executive function in PWH. Based on these data, tracking large cohorts of PWH to determine if the presence of these SNPs associate with cognitive changes during disease progression is of interest. Furthermore, screening PWH for SNPs that may be associated with cognitive impairment risk after diagnosis could be considered in alignment with traditional treatment plans to potentially work on skills in areas shown to have cognitive decline with these SNPs present.
Collapse
Affiliation(s)
- Caitlin Tice
- Lewis Katz School of Medicine, Temple University, 3500 N Broad St, Philadelphia, PA, 19140, USA
| | - Huaqing Zhao
- Lewis Katz School of Medicine, Temple University, 3500 N Broad St, Philadelphia, PA, 19140, USA
| | - Dianne Langford
- Lewis Katz School of Medicine, Temple University, 3500 N Broad St, Philadelphia, PA, 19140, USA.
| |
Collapse
|
|
21
|
Maraqah HH, Abu-Asab MS, Lee HS, Aboud O. Astrocytoma and glioblastoma IDH1-wildtype cells colonize tumor vessels and deploy vascular mimicry. Ultrastruct Pathol 2023:1-8. [PMID: 37144386 DOI: 10.1080/01913123.2023.2205927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 isocitrate dehydrogenase-wildtype (IDH1-wt) glioblastomas and 12 isocitrate dehydrogenase-mutant (IDH1-mt) High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells' invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels' lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.
Collapse
Affiliation(s)
- Haitham H Maraqah
- Medicine & Health Science Faculty, School of Medicine, An-Najah National University, Nablus, PS, Palestine
| | - Mones S Abu-Asab
- EM Lab, Biological Imaging Core, National Eye Institute/National Institutes of Health, Bethesda, MD, USA
| | - Han Sung Lee
- Department of Pathology and Laboratory Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA
| | - Orwa Aboud
- Department of Neurology and Neurosurgery, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA
| |
Collapse
|
|
22
|
Cai Z, Li Z, Wei Q, Yang F, Li T, Ke C, He Y, Wang J, Ni B, Lin M, Li L. MiR-24-3p regulates the differentiation of adipose-derived stem cells toward pericytes and promotes fat grafting vascularization. FASEB J 2023; 37:e22935. [PMID: 37086094 DOI: 10.1096/fj.202202037rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 04/23/2023]
Abstract
Adipose-derived stem cells (ADSCs) enhance fat graft survival by promoting neovascularization. The mechanism that promotes ADSCs differentiation toward pericytes was not known. We treated ADSCs with conditional medium (CM) from endothelial cells (ECs) or human recombinant transforming growth factor β (TGF-β) to induce differentiation into pericytes. Pericytes markers, including platelet-derived growth factor receptor β (PDGFRβ), alpha-smooth muscle actin (α-SMA), and desmin, were examined. Pericytes differentiation markers, migration, and their association with ECs were examined in ADSCs transfected with miR-24-3p mimics and inhibitors. Bioinformatics target prediction platforms and luciferase assays were used to investigate whether PDGFRβ was directly targeted by miR-24-3p. In vivo, fat mixed with ADSCs transfected with miR-24-3p mimics or inhibitors was implanted subcutaneously on the lower back region of nude mice. Fat grafts were harvested and analyzed at 2, 4, 6, and 8 weeks. Results showed that endogenous TGF-β derived from CM from EC or human recombinant TGF-β promoted migration, association with ECs, and induced expression of pericyte markers (PDGFRβ, α-SMA, Desmin) in ADSCs. MiR-24-3p directly targeted PDGFRβ in ADSCs by lucifer reporter assays. Inhibition of miR-24-3p promoted pericytes differentiation, migration, and association with ECs in ADSCs. Inhibition of miR-24-3p in ADSCs promoted survival, integrity, adipocyte viability, vascularization, pericytes association with ECs, and reduced fibrosis, whereas overexpression of miR-24-3p in ADSCs yielded the opposite results. Collectively, TGF-β released by ECs induced ADSCs differentiation toward pericytes through miR-24-3p. Downregulation of miR-24-3p in ADSCs induced survival, integrity, adipocyte viability, vascularization, pericytes association with ECs, and reduced fibrosis after fat grafting.
Collapse
Affiliation(s)
- Zhongming Cai
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zihao Li
- Department of First Clinical Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Qing Wei
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Fangfang Yang
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Tian Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chen Ke
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yucang He
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Jingping Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Binting Ni
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Ming Lin
- Department of Obstetrics and Gynecology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Liqun Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| |
Collapse
|
|
23
|
Lee HH, Carmichael DJ, Ríbeiro V, Parisi DN, Munzen ME, Charles-Niño CL, Hamed MF, Kaur E, Mishra A, Patel J, Rooklin RB, Sher A, Carrillo-Sepulveda MA, Eugenin EA, Dores MR, Martinez LR. Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents. PLoS Pathog 2023; 19:e1010941. [PMID: 37115795 PMCID: PMC10171644 DOI: 10.1371/journal.ppat.1010941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 05/10/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a "Trojan horse" mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.
Collapse
Affiliation(s)
- Hiu Ham Lee
- Department of Biomedical Sciences, NYIT College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, United States of America
| | - Dylan J Carmichael
- Department of Biomedical Sciences, NYIT College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, United States of America
| | - Victoria Ríbeiro
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Dana N Parisi
- Department of Biomedical Sciences, NYIT College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, United States of America
- Department of Biomedical Sciences, Long Island University-Post, Brookville, New York, United States of America
| | - Melissa E Munzen
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
| | - Claudia L Charles-Niño
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
| | - Mohamed F Hamed
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
- Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Ettiman Kaur
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Ayush Mishra
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Jiya Patel
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Rikki B Rooklin
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Amina Sher
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Maria A Carrillo-Sepulveda
- Department of Biomedical Sciences, NYIT College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, United States of America
| | - Eliseo A Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Michael R Dores
- Department of Biology, Hofstra University, Hempstead, New York, United States of America
| | - Luis R Martinez
- Department of Biomedical Sciences, NYIT College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, United States of America
- Department of Biomedical Sciences, Long Island University-Post, Brookville, New York, United States of America
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America
- Center for Immunology and Transplantation, University of Florida, Gainesville, Florida, United States of America
- Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, United States of America
| |
Collapse
|
|
24
|
Senescence in brain pericytes attenuates blood-brain barrier function in vitro: A comparison of serially passaged and isolated pericytes from aged rat brains. Biochem Biophys Res Commun 2023; 645:154-163. [PMID: 36689812 DOI: 10.1016/j.bbrc.2023.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 01/13/2023] [Indexed: 01/15/2023]
Abstract
Aging is associated with the dysfunction of the blood-brain barrier (BBB), which comprises brain microvessel endothelial cells (BMECs), astrocytes, and pericytes. Pericytes are present at intervals along the walls of the brain capillaries and play a key role in maintaining BBB integrity. Accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) in the brain facilitate the development of age-related neurodegenerative diseases with BBB dysfunction. However, the ability of pericytes to support BBB integrity and their correlation with cellular senescence or aging remain unknown. Here, we investigated cellular senescence in pericytes focusing on its impact on BBB function using BBB models comprising intact BMECs co-cultured with senescent pericytes, which were obtained through a serial passage or isolated from 18-month-old rats. To assess BBB function, transendothelial electrical resistance (TEER) and permeability of sodium fluorescein (Na-F) were studied. Both serially passaged pericytes (in passage 4, 7, and 10) and aged pericytes isolated from 18-month-old rats showed decreased TEER and enhanced permeability of BMECs to Na-F compared to that of normal pericytes (passage 2 or young). Furthermore, serially passaged and aged pericytes showed characteristic features of cellular senescence, including increased β-galactosidase activity, cell cycle arrest, enhanced expression of mRNA, and SASP factors. However, the senescence-induced mRNA expression profile of pericyte markers varied between serially passaged and aged pericytes. Hence, in vitro serial passages and isolation from naturally aged rodents differently influenced genetic and biochemical features of senescent brain pericytes. We conclude that senescent brain pericytes can induce BBB dysfunction and those isolated from aged rodents retain the senescence-specific properties. Our findings provide an alternative tool to investigate the senescence in brain pericytes in vitro.
Collapse
|
|
25
|
Maraqah HH, Abu-Asab MS, Lee HS, Aboud O. Astrocytoma and IDH1-Wildtype Glioblastoma (GBM) Cells Colonize Tumor Vessels and Deploy Vascular Mimicry. RESEARCH SQUARE 2023:rs.3.rs-2456733. [PMID: 36712042 PMCID: PMC9882681 DOI: 10.21203/rs.3.rs-2456733/v1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 IDH1 -wildtype glioblastomas (GBM) and 12 IDH1 -mutant High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells' invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels' lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.
Collapse
|
|
26
|
Wu S, Yin Y, Du L. Blood-Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder. Cell Mol Neurobiol 2022; 42:2571-2591. [PMID: 34637015 PMCID: PMC11421634 DOI: 10.1007/s10571-021-01153-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/01/2021] [Indexed: 12/11/2022]
Abstract
Major depression represents a complex and prevalent psychological disease that is characterized by persistent depressed mood, impaired cognitive function and complicated pathophysiological and neuroendocrine alterations. Despite the multifactorial etiology of depression, one of the most recent factors to be identified as playing a critical role in the development of depression is blood-brain barrier (BBB) disruption. The occurrence of BBB integrity disruption contributes to the disturbance of brain homeostasis and leads to complications of neurological diseases, such as stroke, chronic neurodegenerative disorders, neuroinflammatory disorders. Recently, BBB associated tight junction disruption has been shown to implicate in the pathophysiology of depression and contribute to increased susceptibility to depression. However, the underlying mechanisms and importance of BBB damage in depression remains largely unknown. This review highlights how BBB disruption regulates the depression process and the possible molecular mechanisms involved in development of depression-induced BBB dysfunction. Moreover, insight on promising therapeutic targets for treatment of depression with associated BBB dysfunctions are also discussed.
Collapse
Affiliation(s)
- Shusheng Wu
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yuye Yin
- Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Longfei Du
- Department of Laboratory Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China.
| |
Collapse
|
|
27
|
Mitusova K, Peltek OO, Karpov TE, Muslimov AR, Zyuzin MV, Timin AS. Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches. J Nanobiotechnology 2022; 20:412. [PMID: 36109754 PMCID: PMC9479308 DOI: 10.1186/s12951-022-01610-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/18/2022] [Indexed: 01/06/2023] Open
Abstract
Besides the broad development of nanotechnological approaches for cancer diagnosis and therapy, currently, there is no significant progress in the treatment of different types of brain tumors. Therapeutic molecules crossing the blood-brain barrier (BBB) and reaching an appropriate targeting ability remain the key challenges. Many invasive and non-invasive methods, and various types of nanocarriers and their hybrids have been widely explored for brain tumor treatment. However, unfortunately, no crucial clinical translations were observed to date. In particular, chemotherapy and surgery remain the main methods for the therapy of brain tumors. Exploring the mechanisms of the BBB penetration in detail and investigating advanced drug delivery platforms are the key factors that could bring us closer to understanding the development of effective therapy against brain tumors. In this review, we discuss the most relevant aspects of the BBB penetration mechanisms, observing both invasive and non-invasive methods of drug delivery. We also review the recent progress in the development of functional drug delivery platforms, from viruses to cell-based vehicles, for brain tumor therapy. The destructive potential of chemotherapeutic drugs delivered to the brain tumor is also considered. This review then summarizes the existing challenges and future prospects in the use of drug delivery platforms for the treatment of brain tumors.
Collapse
Affiliation(s)
- Ksenia Mitusova
- Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation
| | - Oleksii O Peltek
- School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation
| | - Timofey E Karpov
- Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation
| | - Albert R Muslimov
- Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation
- Sirius University of Science and Technology, Olympic Ave 1, Sirius, 354340, Russian Federation
| | - Mikhail V Zyuzin
- School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation
| | - Alexander S Timin
- Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation.
- School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation.
| |
Collapse
|
|
28
|
Yu W, Li Y, Hu J, Wu J, Huang Y. A Study on the Pathogenesis of Vascular Cognitive Impairment and Dementia: The Chronic Cerebral Hypoperfusion Hypothesis. J Clin Med 2022; 11:jcm11164742. [PMID: 36012981 PMCID: PMC9409771 DOI: 10.3390/jcm11164742] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/27/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022] Open
Abstract
The pathogenic mechanisms underlying vascular cognitive impairment and dementia (VCID) remain controversial due to the heterogeneity of vascular causes and complexity of disease neuropathology. However, one common feature shared among all these vascular causes is cerebral blood flow (CBF) dysregulation, and chronic cerebral hypoperfusion (CCH) is the universal consequence of CBF dysregulation, which subsequently results in an insufficient blood supply to the brain, ultimately contributing to VCID. The purpose of this comprehensive review is to emphasize the important contributions of CCH to VCID and illustrate the current findings about the mechanisms involved in CCH-induced VCID pathological changes. Specifically, evidence is mainly provided to support the molecular mechanisms, including Aβ accumulation, inflammation, oxidative stress, blood-brain barrier (BBB) disruption, trophic uncoupling and white matter lesions (WMLs). Notably, there are close interactions among these multiple mechanisms, and further research is necessary to elucidate the hitherto unsolved questions regarding these interactions. An enhanced understanding of the pathological features in preclinical models could provide a theoretical basis, ultimately achieving the shift from treatment to prevention.
Collapse
Affiliation(s)
- Weiwei Yu
- Department of Neurology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Futian District, Shenzhen 518036, China
| | - Yao Li
- Department of Neurology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Futian District, Shenzhen 518036, China
| | - Jun Hu
- Department of Neurology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Futian District, Shenzhen 518036, China
| | - Jun Wu
- Department of Neurology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Futian District, Shenzhen 518036, China
- Correspondence: (J.W.); (Y.H.); Tel.: +86-0755-8392-2833 (J.W.); +86-010-83572857 (Y.H.)
| | - Yining Huang
- Department of Neurology, Peking University First Hospital, 8 Xishiku Street Xicheng District, Beijing 100034, China
- Correspondence: (J.W.); (Y.H.); Tel.: +86-0755-8392-2833 (J.W.); +86-010-83572857 (Y.H.)
| |
Collapse
|
|
29
|
Smith-Cohn MA, Burley NB, Grossman SA. Transient Opening of the Blood-Brain Barrier by Vasoactive Peptides to Increase CNS Drug Delivery: Reality Versus Wishful Thinking? Curr Neuropharmacol 2022; 20:1383-1399. [PMID: 35100958 PMCID: PMC9881081 DOI: 10.2174/1570159x20999220131163504] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/02/2021] [Accepted: 01/26/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The blood-brain barrier inhibits the central nervous system penetration of 98% of small molecule drugs and virtually all biologic agents, which has limited progress in treating neurologic disease. Vasoactive peptides have been shown in animal studies to transiently disrupt the blood-brain barrier and regadenoson is currently being studied in humans to determine if it can improve drug delivery to the brain. However, many other vasoactive peptides could potentially be used for this purpose. METHODS We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the blood-brain barrier, we devised a four-tier classification system to organize the available evidence. RESULTS We identified 32 vasoactive peptides with potential blood-brain barrier permeabilityaltering properties. To date, none of these are shown to open the blood-brain barrier in humans. Twelve vasoactive peptides increased blood-brain barrier permeability in rodents. The remaining 20 had favorable physiologic effects on blood vessels but lacked specific information on permeability changes to the blood-brain barrier. CONCLUSION Vasoactive peptides remain an understudied class of drugs with the potential to increase drug delivery and improve treatment in patients with brain tumors and other neurologic diseases. Dozens of vasoactive peptides have yet to be formally evaluated for this important clinical effect. This narrative review summarizes the available data on vasoactive peptides, highlighting agents that deserve further in vitro and in vivo investigations.
Collapse
Affiliation(s)
- Matthew A. Smith-Cohn
- Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA; ,Address correspondence to these authors at the The Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Swedish Health Services, 500 17th Ave, James Tower, Suite 540, Seattle, WA 98122, USA; Tel: 206-320-2300; Fax: 206-320-8149; E-mail: , Sidney Kimmel Cancer Center, Skip Viragh Building, 201 North Broadway, 9th Floor (Mailbox #3), Baltimore, MD 21287, USA; E-mail:
| | - Nicholas B. Burley
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, USA;
| | - Stuart A. Grossman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA,Address correspondence to these authors at the The Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Swedish Health Services, 500 17th Ave, James Tower, Suite 540, Seattle, WA 98122, USA; Tel: 206-320-2300; Fax: 206-320-8149; E-mail: , Sidney Kimmel Cancer Center, Skip Viragh Building, 201 North Broadway, 9th Floor (Mailbox #3), Baltimore, MD 21287, USA; E-mail:
| |
Collapse
|
|
30
|
Current Strategies to Enhance Delivery of Drugs across the Blood–Brain Barrier. Pharmaceutics 2022; 14:pharmaceutics14050987. [PMID: 35631573 PMCID: PMC9145636 DOI: 10.3390/pharmaceutics14050987] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/18/2022] [Accepted: 04/29/2022] [Indexed: 12/13/2022] Open
Abstract
The blood–brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across the BBB. The BBB is disturbed in specific pathological illnesses such as stroke, diabetes, seizures, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The goal of this study is to offer a general overview of current brain medication delivery techniques and associated topics from the last five years. It is anticipated that this review will stimulate readers to look into new ways to deliver medications to the brain. Following an introduction of the construction and function of the BBB in both healthy and pathological conditions, this review revisits certain contested questions, such as whether nanoparticles may cross the BBB on their own and if medications are selectively delivered to the brain by deliberately targeted nanoparticles. Current non-nanoparticle options are also discussed, including drug delivery via the permeable BBB under pathological circumstances and the use of non-invasive approaches to improve brain medication absorption.
Collapse
|
|
31
|
Mou Y, Du Y, Zhou L, Yue J, Hu X, Liu Y, Chen S, Lin X, Zhang G, Xiao H, Dong B. Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging. Front Immunol 2022; 13:796288. [PMID: 35464431 PMCID: PMC9021448 DOI: 10.3389/fimmu.2022.796288] [Citation(s) in RCA: 190] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 02/22/2022] [Indexed: 02/05/2023] Open
Abstract
It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes the brain pathophysiology of neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation. If not all, gut microbiota-induced systemic chronic inflammation (GM-SCI) mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging. To illustrate the immune roles of the BBB in pathophysiology affected by inflammatory or "leaky" IB resulting from GM and their metabolites, we reviewed the selected publications, including the role of the BBB as the immune barrier, systemic chronic inflammation and inflammation influences on BBB permeability, NF&ND, and brain aging. To add depth to the bridging role of systemic chronic inflammation, a plausible mechanism indispensable for BBB corruption was highlighted; namely, BBB maintenance cues are affected by inflammatory cytokines, which may help to understand how GM and its metabolites play a major role in NF&ND and aging.
Collapse
Affiliation(s)
- Yi Mou
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Yu Du
- Department of Emergency and Critical Care Medicine, The Fourth West China Hospital, Sichuan University, Chengdu, China
| | - Lixing Zhou
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jirong Yue
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xianliang Hu
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Yixin Liu
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Sao Chen
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Xiufang Lin
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Gongchang Zhang
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Birong Dong
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
32
|
Zhou SY, Guo ZN, Zhang DH, Qu Y, Jin H. The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets. Front Mol Neurosci 2022; 15:866700. [PMID: 35493333 PMCID: PMC9043812 DOI: 10.3389/fnmol.2022.866700] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/18/2022] [Indexed: 12/25/2022] Open
Abstract
Ischemic stroke (IS) is a cerebrovascular disease causing high rates of disability and fatality. In recent years, the concept of the neurovascular unit (NVU) has been accepted by an increasing number of researchers and is expected to become a new paradigm for exploring the pathogenesis and treatment of IS. NVUs are composed of neurons, endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix. As an important part of the NVU, pericytes provide support for other cellular components and perform a variety of functions, including participating in the maintenance of the normal physiological function of the blood–brain barrier, regulating blood flow, and playing a role in inflammation, angiogenesis, and neurogenesis. Therefore, treatment strategies targeting pericyte functions, regulating pericyte epigenetics, and transplanting pericytes warrant exploration. In this review, we describe the reactions of pericytes after IS, summarize the potential therapeutic targets and strategies targeting pericytes for IS, and provide new treatment ideas for ischemic stroke.
Collapse
Affiliation(s)
- Sheng-Yu Zhou
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Zhen-Ni Guo
- Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Dian-Hui Zhang
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Yang Qu
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Hang Jin
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Hang Jin,
| |
Collapse
|
|
33
|
Zhu S, Chen M, Ying Y, Wu Q, Huang Z, Ni W, Wang X, Xu H, Bennett S, Xiao J, Xu J. Versatile subtypes of pericytes and their roles in spinal cord injury repair, bone development and repair. Bone Res 2022; 10:30. [PMID: 35296645 PMCID: PMC8927336 DOI: 10.1038/s41413-022-00203-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/16/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
Vascular regeneration is a challenging topic in tissue repair. As one of the important components of the neurovascular unit (NVU), pericytes play an essential role in the maintenance of the vascular network of the spinal cord. To date, subtypes of pericytes have been identified by various markers, namely the PDGFR-β, Desmin, CD146, and NG2, each of which is involved with spinal cord injury (SCI) repair. In addition, pericytes may act as a stem cell source that is important for bone development and regeneration, whilst specific subtypes of pericyte could facilitate bone fracture and defect repair. One of the major challenges of pericyte biology is to determine the specific markers that would clearly distinguish the different subtypes of pericytes, and to develop efficient approaches to isolate and propagate pericytes. In this review, we discuss the biology and roles of pericytes, their markers for identification, and cell differentiation capacity with a focus on the potential application in the treatment of SCI and bone diseases in orthopedics.
Collapse
Affiliation(s)
- Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,Molecular Pharmacology Research Centre, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia
| | - Min Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yibo Ying
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Qiuji Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Zhiyang Huang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Wenfei Ni
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Huazi Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Samuel Bennett
- Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia
| | - Jian Xiao
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,Molecular Pharmacology Research Centre, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Jiake Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
| |
Collapse
|
|
34
|
Del Franco AP, Chiang PP, Newman EA. Dilation of cortical capillaries is not related to astrocyte calcium signaling. Glia 2022; 70:508-521. [PMID: 34767261 PMCID: PMC8732319 DOI: 10.1002/glia.24119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/12/2021] [Accepted: 10/31/2021] [Indexed: 12/30/2022]
Abstract
The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca2+ signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca2+ signaling, but previous work suggests that Ca2+ increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca2+ signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca2+ signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca2+ signaling is substantially reduced. Compared to WT mice at rest, Ca2+ signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca2+ signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca2+ signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca2+ events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca2+ increases in the cerebral cortex.
Collapse
Affiliation(s)
- Armani P Del Franco
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
| | - Pei-Pei Chiang
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
| | - Eric A Newman
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
35
|
Tobal R, Potjewijd J, van Empel VPM, Ysermans R, Schurgers LJ, Reutelingsperger CP, Damoiseaux JGMC, van Paassen P. Vascular Remodeling in Pulmonary Arterial Hypertension: The Potential Involvement of Innate and Adaptive Immunity. Front Med (Lausanne) 2022; 8:806899. [PMID: 35004784 PMCID: PMC8727487 DOI: 10.3389/fmed.2021.806899] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/02/2021] [Indexed: 11/30/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.
Collapse
Affiliation(s)
- Rachid Tobal
- Division of Nephrology and Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Judith Potjewijd
- Division of Nephrology and Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Vanessa P M van Empel
- Department of Cardiology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Renee Ysermans
- Division of Nephrology and Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Leon J Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands
| | - Chris P Reutelingsperger
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands
| | - Jan G M C Damoiseaux
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands
| | - Pieter van Paassen
- Division of Nephrology and Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| |
Collapse
|
|
36
|
Effect of Pericytes on Cerebral Microvasculature at Different Time Points of Stroke. BIOMED RESEARCH INTERNATIONAL 2022; 2021:5281182. [PMID: 34977241 PMCID: PMC8716223 DOI: 10.1155/2021/5281182] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 11/30/2021] [Indexed: 02/04/2023]
Abstract
Pericyte, as an important component of the blood-brain barrier, has received increasing attention in the study of cerebrovascular diseases. However, the mechanism of pericytes after the occurrence of cerebral ischemia is controversial. On the one hand, the expression of pericytes increases after cerebral ischemia, constricting the blood vessels to restrict blood supply and aggravating the damage caused by ischemia; on the other hand, pericytes participate in capillary angiogenesis in the ischemic area, which facilitates the repair of the ischemic injury area. The multifunctionality of pericytes is an important reason for this phenomenon, but the different time points of observation for the outcome indicators in each study are also an important factor that leads to the controversy of pericytes. Based on the review of a large database of original studies, the authors' team summarized the effects of pericytes on cerebral microvasculature at different time points after stroke, searched the possible markers, and explored possible therapeutic.
Collapse
|
|
37
|
Samocha-Bonet D, Wu B, Ryugo DK. Diabetes mellitus and hearing loss: A review. Ageing Res Rev 2021; 71:101423. [PMID: 34384902 DOI: 10.1016/j.arr.2021.101423] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/26/2021] [Accepted: 08/05/2021] [Indexed: 12/17/2022]
Abstract
Diabetes (type 2) and sensorineural hearing loss are common health problems manifested with ageing. While both type 1 and type 2 diabetes have been associated with hearing loss, a causal link has been difficult to establish. Individuals with diabetes have twice the incidence of hearing loss compared to those without diabetes and those with prediabetes have a 30% higher rate of hearing loss. Whether hearing loss is associated with diabetes independent of glycemic control remains to be determined. Hearing loss has its own set of risk factors and shares others with diabetes. This review will summarize the complex relationship between diabetes and sensorineural hearing loss.
Collapse
Affiliation(s)
- Dorit Samocha-Bonet
- Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, 2010, Australia.
| | - Buffy Wu
- Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; School of Medical Sciences, UNSW Sydney, Kensington, NSW, 2052, Australia
| | - David K Ryugo
- Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; School of Medical Sciences, UNSW Sydney, Kensington, NSW, 2052, Australia; Department of Otolaryngology Head and Neck and Skull Base Surgery, St. Vincent's Hospital, Darlinghurst, NSW, 2010, Australia
| |
Collapse
|
|
38
|
Sommonte F, Arduino I, Racaniello GF, Lopalco A, Lopedota AA, Denora N. The Complexity of the Blood-Brain Barrier and the Concept of Age-Related Brain Targeting: Challenges and Potential of Novel Solid Lipid-Based Formulations. J Pharm Sci 2021; 111:577-592. [PMID: 34469749 DOI: 10.1016/j.xphs.2021.08.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 11/17/2022]
Abstract
Diseases that affect the Central Nervous System (CNS) are one of the most exciting challenges of recent years, as they are ubiquitous and affect all ages. Although these disorders show different etiologies, all treatments share the same difficulty represented by the Blood-Brain Barrier (BBB). This barrier acts as a protective system of the delicate cerebral microenvironment, isolating it and making extremely arduous delivering drugs to the brain. To overtake the obstacles provided by the BBB it is essential to explore the changes that affect it, to understand how to exploit these findings in the study and design of innovative brain targeted formulations. Interestingly, the concept of age-related targeting could prove to be a winning choice, as it allows to consider the type of treatment according to the different needs and peculiarities depending on the disease and the age of onset. In this review was considered the prospective contribution of lipid-based formulations, namely Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), which have been highlighted as able to overcome some limitations of other innovative approaches, thus representing a promising strategy for the non-invasive specific treatment of CNS-related diseases.
Collapse
Affiliation(s)
- Federica Sommonte
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Ilaria Arduino
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | | | - Antonio Lopalco
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Angela Assunta Lopedota
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Nunzio Denora
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy.
| |
Collapse
|
|
39
|
Heidarzadeh M, Gürsoy-Özdemir Y, Kaya M, Eslami Abriz A, Zarebkohan A, Rahbarghazi R, Sokullu E. Exosomal delivery of therapeutic modulators through the blood-brain barrier; promise and pitfalls. Cell Biosci 2021; 11:142. [PMID: 34294165 PMCID: PMC8296716 DOI: 10.1186/s13578-021-00650-0] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
Nowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50-100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.
Collapse
Affiliation(s)
- Morteza Heidarzadeh
- Koç University Research Center for Translational Medicine (KUTTAM), Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey
| | - Yasemin Gürsoy-Özdemir
- Koç University Research Center for Translational Medicine (KUTTAM), Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey.,Neurology Department, Koç University School of Medicine, Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey
| | - Mehmet Kaya
- Koç University Research Center for Translational Medicine (KUTTAM), Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey.,Physiology Department, Koç University School of Medicine, Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey
| | - Aysan Eslami Abriz
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Emel Sokullu
- Koç University Research Center for Translational Medicine (KUTTAM), Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey. .,Biophysics Department, Koç University School of Medicine, Rumeli Feneri, 34450, Sariyer, Istanbul, Turkey.
| |
Collapse
|
|
40
|
Stackhouse TL, Mishra A. Neurovascular Coupling in Development and Disease: Focus on Astrocytes. Front Cell Dev Biol 2021; 9:702832. [PMID: 34327206 PMCID: PMC8313501 DOI: 10.3389/fcell.2021.702832] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer’s disease.
Collapse
Affiliation(s)
- Teresa L Stackhouse
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, United States
| | - Anusha Mishra
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, United States.,Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, OR, United States
| |
Collapse
|
|
41
|
Kim KJ, Diaz JR, Presa JL, Muller PR, Brands MW, Khan MB, Hess DC, Althammer F, Stern JE, Filosa JA. Decreased parenchymal arteriolar tone uncouples vessel-to-neuronal communication in a mouse model of vascular cognitive impairment. GeroScience 2021; 43:1405-1422. [PMID: 33410092 PMCID: PMC8190257 DOI: 10.1007/s11357-020-00305-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/22/2020] [Indexed: 01/18/2023] Open
Abstract
Chronic hypoperfusion is a key contributor to cognitive decline and neurodegenerative conditions, but the cellular mechanisms remain ill-defined. Using a multidisciplinary approach, we sought to elucidate chronic hypoperfusion-evoked functional changes at the neurovascular unit. We used bilateral common carotid artery stenosis (BCAS), a well-established model of vascular cognitive impairment, combined with an ex vivo preparation that allows pressurization of parenchymal arterioles in a brain slice. Our results demonstrate that mild (~ 30%), chronic hypoperfusion significantly altered the functional integrity of the cortical neurovascular unit. Although pial cerebral perfusion recovered over time, parenchymal arterioles progressively lost tone, exhibiting significant reductions by day 28 post-surgery. We provide supportive evidence for reduced adenosine 1 receptor-mediated vasoconstriction as a potential mechanism in the adaptive response underlying the reduced baseline tone in parenchymal arterioles. In addition, we show that in response to the neuromodulator adenosine, the action potential frequency of cortical pyramidal neurons was significantly reduced in all groups. However, a significant decrease in adenosine-induced hyperpolarization was observed in BCAS 14 days. At the microvascular level, constriction-induced inhibition of pyramidal neurons was significantly compromised in BCAS mice. Collectively, these results suggest that BCAS uncouples vessel-to-neuron communication-vasculo-neuronal coupling-a potential early event in cognitive decline.
Collapse
Affiliation(s)
- Ki Jung Kim
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA
| | - Juan Ramiro Diaz
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA
| | - Jessica L Presa
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA
| | - P Robinson Muller
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA
| | - Michael W Brands
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA
| | - Mohammad B Khan
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - David C Hess
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | | | - Javier E Stern
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA
| | - Jessica A Filosa
- Department of Physiology, Augusta University, Augusta, GA, 30912, USA.
| |
Collapse
|
|
42
|
Charcot-Bouchard aneurysms revisited: clinicopathologic correlations. Mod Pathol 2021; 34:2109-2121. [PMID: 34326486 PMCID: PMC8592842 DOI: 10.1038/s41379-021-00847-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/20/2021] [Accepted: 05/20/2021] [Indexed: 12/02/2022]
Abstract
Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide. Hypertension and cerebral amyloid angiopathy (CAA) are the most common causes of primary ICH, but the mechanism of hemorrhage in both conditions is unclear. Although fibrinoid necrosis and Charcot-Bouchard aneurysms (CBAs) have been postulated to underlie vessel rupture in ICH, the role and significance of CBAs in ICH has been controversial. First described as the source of bleeding in hypertensive hemorrhage, they are also one of the CAA-associated microangiopathies along with fibrinoid necrosis, fibrosis and "lumen within a lumen appearance." We describe clinicopathologic findings of CBAs found in 12 patients out of over 2700 routine autopsies at a tertiary academic medical center. CBAs were rare and predominantly seen in elderly individuals, many of whom had multiple systemic and cerebrovascular comorbidities including hypertension, myocardial and cerebral infarcts, and CAA. Only one of the 12 subjects with CBAs had a large ICH, and the etiology underlying the hemorrhage was likely multifactorial. Two CBAs in the basal ganglia demonstrated associated microhemorrhages, while three demonstrated infarcts in the vicinity. CBAs may not be a significant cause of ICH but are a manifestation of severe cerebral small vessel disease including both hypertensive arteriopathy and CAA.
Collapse
|
|
43
|
Mesnil M, Defamie N, Naus C, Sarrouilhe D. Brain Disorders and Chemical Pollutants: A Gap Junction Link? Biomolecules 2020; 11:51. [PMID: 33396565 PMCID: PMC7824109 DOI: 10.3390/biom11010051] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson's disease, Alzheimer's disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants. In this article, this hypothesis is addressed through three complementary aspects: (1) the gap-junctional organization and connexin expression in brain parenchyma and their function; (2) the effect of major pollutants (pesticides, bisphenol A, phthalates, heavy metals, airborne particles, etc.) on gap-junctional and connexin functions; (3) a description of the major brain disorders categorized as neurodevelopmental (autism spectrum disorders, attention deficit hyperactivity disorders, epilepsy), neurobehavioral (migraines, major depressive disorders), neurodegenerative (Parkinson's and Alzheimer's diseases) and cancers (glioma), in which both connexin dysfunction and pollutant involvement have been described. Based on these different aspects, the possible involvement of pollutant-inhibited gap junctions in brain disorders is discussed for prenatal and postnatal exposures.
Collapse
Affiliation(s)
- Marc Mesnil
- Laboratoire STIM, ERL7003 CNRS-Université de Poitiers, 1 rue G. Bonnet–TSA 51 106, 86073 Poitiers, France; (M.M.); (N.D.)
| | - Norah Defamie
- Laboratoire STIM, ERL7003 CNRS-Université de Poitiers, 1 rue G. Bonnet–TSA 51 106, 86073 Poitiers, France; (M.M.); (N.D.)
| | - Christian Naus
- Faculty of Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T1Z3, Canada;
| | - Denis Sarrouilhe
- Laboratoire de Physiologie Humaine, Faculté de Médecine et Pharmacie, 6 rue de La Milétrie, bât D1, TSA 51115, 86073 Poitiers, France
| |
Collapse
|
|
44
|
Ojo J, Eisenbaum M, Shackleton B, Lynch C, Joshi U, Saltiel N, Pearson A, Ringland C, Paris D, Mouzon B, Mullan M, Crawford F, Bachmeier C. Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma. Neurobiol Dis 2020; 150:105237. [PMID: 33383188 PMCID: PMC8170787 DOI: 10.1016/j.nbd.2020.105237] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/07/2020] [Accepted: 12/26/2020] [Indexed: 12/29/2022] Open
Abstract
A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders.
Collapse
Affiliation(s)
- Joseph Ojo
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Max Eisenbaum
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Ben Shackleton
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Cillian Lynch
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Utsav Joshi
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | | | - Andrew Pearson
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Charis Ringland
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Daniel Paris
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Benoit Mouzon
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Michael Mullan
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK
| | - Fiona Crawford
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK; James A. Haley Veterans' Hospital, Tampa, FL, USA
| | - Corbin Bachmeier
- The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK; Bay Pines VA Healthcare System, Bay Pines, FL, USA.
| |
Collapse
|
|
45
|
Nian K, Harding IC, Herman IM, Ebong EE. Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction. Front Physiol 2020; 11:605398. [PMID: 33424628 PMCID: PMC7793645 DOI: 10.3389/fphys.2020.605398] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 11/27/2020] [Indexed: 12/21/2022] Open
Abstract
Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.
Collapse
Affiliation(s)
- Keqing Nian
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Ian C Harding
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Ira M Herman
- Department of Development, Molecular, and Chemical Biology, Tufts Sackler School of Graduate Biomedical Sciences, Boston, MA, United States.,Center for Innovations in Wound Healing Research, Tufts University School of Medicine, Boston, MA, United States
| | - Eno E Ebong
- Department of Bioengineering, Northeastern University, Boston, MA, United States.,Department of Chemical Engineering, Northeastern University, Boston, MA, United States.,Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, United States
| |
Collapse
|
|
46
|
Bernardo-Castro S, Sousa JA, Brás A, Cecília C, Rodrigues B, Almendra L, Machado C, Santo G, Silva F, Ferreira L, Santana I, Sargento-Freitas J. Pathophysiology of Blood-Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery. Front Neurol 2020; 11:594672. [PMID: 33362697 PMCID: PMC7756029 DOI: 10.3389/fneur.2020.594672] [Citation(s) in RCA: 233] [Impact Index Per Article: 46.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/09/2020] [Indexed: 12/25/2022] Open
Abstract
The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.
Collapse
Affiliation(s)
| | - João André Sousa
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Ana Brás
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Carla Cecília
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Bruno Rodrigues
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Luciano Almendra
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Cristina Machado
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Gustavo Santo
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Fernando Silva
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Lino Ferreira
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - Isabel Santana
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - João Sargento-Freitas
- Stroke Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| |
Collapse
|
|
47
|
Blood-brain barrier integrity in the pathogenesis of Alzheimer's disease. Front Neuroendocrinol 2020; 59:100857. [PMID: 32781194 DOI: 10.1016/j.yfrne.2020.100857] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
The blood-brain barrier (BBB) tightly controls the molecular exchange between the brain parenchyma and blood. Accumulated evidence from transgenic animal Alzheimer's disease (AD) models and human AD patients have demonstrated that BBB dysfunction is a major player in AD pathology. In this review, we discuss the role of the BBB in maintaining brain integrity and how this is mediated by crosstalk between BBB-associated cells within the neurovascular unit (NVU). We then discuss the role of the NVU, in particular its endothelial cell, pericyte, and glial cell constituents, in AD pathogenesis. The effect of substances released by the neuroendocrine system in modulating BBB function and AD pathogenesis is also discussed. We perform a systematic review of currently available AD treatments specifically targeting pericytes and BBB glial cells. In summary, this review provides a comprehensive overview of BBB dysfunction in AD and a new perspective on the development of therapeutics for AD.
Collapse
|
|
48
|
Tice C, McDevitt J, Langford D. Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management? Front Cell Infect Microbiol 2020; 10:523379. [PMID: 33134185 PMCID: PMC7550659 DOI: 10.3389/fcimb.2020.523379] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 08/19/2020] [Indexed: 12/17/2022] Open
Abstract
The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.
Collapse
Affiliation(s)
- Caitlin Tice
- Department of Neuroscience, Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jane McDevitt
- Department of Kinesiology, College of Public Health at Temple University, Philadelphia, PA, United States
| | - Dianne Langford
- Department of Neuroscience, Lewis Katz School of Medicine, Philadelphia, PA, United States
| |
Collapse
|
|
49
|
Francisco DMF, Marchetti L, Rodríguez-Lorenzo S, Frías-Anaya E, Figueiredo RM, Winter P, Romero IA, de Vries HE, Engelhardt B, Bruggmann R. Advancing brain barriers RNA sequencing: guidelines from experimental design to publication. Fluids Barriers CNS 2020; 17:51. [PMID: 32811511 PMCID: PMC7433166 DOI: 10.1186/s12987-020-00207-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/06/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND RNA sequencing (RNA-Seq) in its varied forms has become an indispensable tool for analyzing differential gene expression and thus characterization of specific tissues. Aiming to understand the brain barriers genetic signature, RNA seq has also been introduced in brain barriers research. This has led to availability of both, bulk and single-cell RNA-Seq datasets over the last few years. If appropriately performed, the RNA-Seq studies provide powerful datasets that allow for significant deepening of knowledge on the molecular mechanisms that establish the brain barriers. However, RNA-Seq studies comprise complex workflows that require to consider many options and variables before, during and after the proper sequencing process. MAIN BODY In the current manuscript, we build on the interdisciplinary experience of the European PhD Training Network BtRAIN ( https://www.btrain-2020.eu/ ) where bioinformaticians and brain barriers researchers collaborated to analyze and establish RNA-Seq datasets on vertebrate brain barriers. The obstacles BtRAIN has identified in this process have been integrated into the present manuscript. It provides guidelines along the entire workflow of brain barriers RNA-Seq studies starting from the overall experimental design to interpretation of results. Focusing on the vertebrate endothelial blood-brain barrier (BBB) and epithelial blood-cerebrospinal-fluid barrier (BCSFB) of the choroid plexus, we provide a step-by-step description of the workflow, highlighting the decisions to be made at each step of the workflow and explaining the strengths and weaknesses of individual choices made. Finally, we propose recommendations for accurate data interpretation and on the information to be included into a publication to ensure appropriate accessibility of the data and reproducibility of the observations by the scientific community. CONCLUSION Next generation transcriptomic profiling of the brain barriers provides a novel resource for understanding the development, function and pathology of these barrier cells, which is essential for understanding CNS homeostasis and disease. Continuous advancement and sophistication of RNA-Seq will require interdisciplinary approaches between brain barrier researchers and bioinformaticians as successfully performed in BtRAIN. The present guidelines are built on the BtRAIN interdisciplinary experience and aim to facilitate collaboration of brain barriers researchers with bioinformaticians to advance RNA-Seq study design in the brain barriers community.
Collapse
Affiliation(s)
- David M F Francisco
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Luca Marchetti
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Sabela Rodríguez-Lorenzo
- MS Center Amsterdam, Amsterdam Neuroscience, Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Eduardo Frías-Anaya
- School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, UK
| | - Ricardo M Figueiredo
- GenXPro GmbH, Frankfurt/Main, Germany
- Johann Wolfgang Goethe University, Frankfurt/Main, Germany
| | | | - Ignacio Andres Romero
- School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, UK
| | - Helga E de Vries
- MS Center Amsterdam, Amsterdam Neuroscience, Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - Rémy Bruggmann
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
| |
Collapse
|
|
50
|
Zhou J, Zhang Z, Zhou H, Qian G. Diabetic Cognitive Dysfunction: From Bench to Clinic. Curr Med Chem 2020; 27:3151-3167. [PMID: 30727866 DOI: 10.2174/1871530319666190206225635] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 12/30/2018] [Accepted: 01/30/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes increases the risk of developing cognitive dysfunction in the elderly in the form of short-term memory and executive function impairment. Genetic and diet-induced models of type 2 diabetes further support this link, displaying deficits in working memory, learning, and memory performance. The risk factors for diabetic cognitive dysfunction include vascular disease, hypoglycaemia, hyperlipidaemia, adiposity, insulin resistance, lifestyle factors, and genetic factors. Using neuronal imaging technologies, diabetic patients with cognitive dysfunction show atrophy of the whole brain, particularly the grey matter, hippocampus and amygdala; increased volume of the ventricular and white matter; brain infarcts; impaired network integrity; abnormal microstructure; and reduced cerebral blood flow and amplitude of low-frequency fluctuations. The pathogenesis of type 2 diabetes with cognitive dysfunction involves hyperglycaemia, macrovascular and microvascular diseases, insulin resistance, inflammation, apoptosis, and disorders of neurotransmitters. Large clinical trials may offer further proof of biomarkers and risk factors for diabetic cognitive dysfunction. Advanced neuronal imaging technologies and novel disease animal models will assist in elucidating the precise pathogenesis and to provide better therapeutic interventions and treatment.
Collapse
Affiliation(s)
- Jiyin Zhou
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| | - Zuo Zhang
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| | - Hongli Zhou
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| | - Guisheng Qian
- Institute of Respiratory Diseases, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| |
Collapse
|