Ιmmunity, Vascular Aging, and Stroke

Current Medicinal Chemistry ◽

10.2174/0929867329666220103101700 ◽

2022 ◽

Vol 29 ◽

Author(s):

Anna-Maria Louka ◽

Dimitrios Sagris ◽

George Ntaios

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Brain Barrier ◽

Low Grade ◽

Vascular Aging ◽

Barrier Dysfunction ◽

Blood Brain

Abstract: Stroke is one of the most devastating manifestations of cardiovascular disease. Growing age, arterial hypertension, and atherosclerosis are identified as independent risk factors for stroke, primarily due to structural and functional alterations in the cerebrovascular tree. Recent data from in vitro and clinical studies have suggested that the immune system influences atherosclerosis, promoting vascular stiffness and vascular aging and contributing to ischemic stroke, intracranial haemorrhage and microbleeds, white matter disease, and cognitive decline. Furthermore, aging is related to a chronic low-grade inflammatory state, in which macrophage, neutrophils, natural killer (NK cells), and B and T lymphocytes act as major effectors of the immune-mediated cell responses. Moreover, oxidative stress and vascular inflammation are correlated with endothelial dysfunction, vascular aging, blood-brain barrier disruption, lacunar lesions, and neurodegenerative disorders. This review discusses the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including the complex interplay between them and innate immunity, as well as vascular dysfunction, arterial stiffness, atherosclerosis, atherothrombosis, systemic inflammation, and blood-brain barrier dysfunction.

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Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood–brain barrier dysfunction in vitro

Neuroscience ◽

10.1016/j.neuroscience.2017.03.026 ◽

2017 ◽

Vol 350 ◽

pp. 146-157 ◽

Cited By ~ 28

Author(s):

Takashi Machida ◽

Shinya Dohgu ◽

Fuyuko Takata ◽

Junichi Matsumoto ◽

Ikuya Kimura ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Brain Pericytes

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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In vitro analysis of drugs that improve hyperglycemia-induced blood-brain barrier dysfunction

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2018.07.131 ◽

2018 ◽

Vol 503 (3) ◽

pp. 1885-1890 ◽

Cited By ~ 1

Author(s):

Ryoma Kayano ◽

Yoichi Morofuji ◽

Shinsuke Nakagawa ◽

Shuji Fukuda ◽

Daisuke Watanabe ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Vitro Analysis ◽

In Vitro Analysis

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Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

Science Signaling ◽

10.1126/scisignal.aay5686 ◽

2020 ◽

Vol 13 (626) ◽

pp. eaay5686 ◽

Cited By ~ 4

Author(s):

Feifei Ma ◽

Ping Sun ◽

Xuejing Zhang ◽

Milton H. Hamblin ◽

Ke-Jie Yin

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Neuronal Loss ◽

Glucose Deprivation ◽

Brain Barrier ◽

Protein Abundance ◽

Barrier Dysfunction ◽

Small Noncoding Rnas ◽

Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21093344 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3344 ◽

Cited By ~ 2

Author(s):

Alison Cash ◽

Michelle H. Theus

Keyword(s):

Blood Brain Barrier ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Brain Injuries ◽

The United States ◽

Brain Barrier ◽

Detection Methods ◽

Secondary Injury ◽

Barrier Dysfunction ◽

Blood Brain

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

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Blood–Brain Barrier Dysfunction in a 3D In Vitro Model of Alzheimer's Disease

Advanced Science ◽

10.1002/advs.201900962 ◽

2019 ◽

Vol 6 (20) ◽

pp. 1900962 ◽

Cited By ~ 23

Author(s):

Yoojin Shin ◽

Se Hoon Choi ◽

Eunhee Kim ◽

Enjana Bylykbashi ◽

Jeong Ah Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Blood Brain Barrier ◽

In Vitro Model ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Model Of Alzheimer’S Disease ◽

3D In Vitro Model ◽

Vitro Model

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Blood-Brain Barrier Dysfunction after Primary Blast Injury in vitro

Journal of Neurotrauma ◽

10.1089/neu.2012.2773 ◽

2013 ◽

Vol 30 (19) ◽

pp. 1652-1663 ◽

Cited By ~ 42

Author(s):

Christopher D. Hue ◽

Siqi Cao ◽

Syed F. Haider ◽

Kiet V. Vo ◽

Gwen B. Effgen ◽

...

Keyword(s):

Blood Brain Barrier ◽

Blast Injury ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Primary Blast ◽

Blood Brain

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Comparative analysis of neuroinvasion by Japanese encephalitis virulent and vaccine viral strains in an in vitro model of human blood-brain barrier

PLoS ONE ◽

10.1371/journal.pone.0252595 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252595

Author(s):

Cécile Khou ◽

Marco Aurelio Díaz-Salinas ◽

Anaelle da Costa ◽

Christophe Préhaud ◽

Patricia Jeannin ◽

...

Keyword(s):

Blood Brain Barrier ◽

Japanese Encephalitis ◽

In Vitro Model ◽

Molecular Mechanisms ◽

Brain Barrier ◽

Blood Brain ◽

The Central Nervous System ◽

Vitro Model ◽

Viral Determinants

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that, as a consequence of the inflammatory process during JEV infection, there is disruption of the blood-brain barrier (BBB) tight junctions that in turn allows the virus access to the central nervous system (CNS). However, what happens at early times of JEV contact with the BBB is poorly understood. In the present work, we evaluated the ability of both a virulent and a vaccine strain of JEV (JEV RP9 and SA14-14-2, respectively) to cross an in vitro human BBB model. Using this system, we demonstrated that both JEV RP9 and SA14-14-2 are able to cross the BBB without disrupting it at early times post viral addition. Furthermore, we find that almost 10 times more RP9 infectious particles than SA14-14 cross the model BBB, indicating this BBB model discriminates between the virulent RP9 and the vaccine SA14-14-2 strains of JEV. Beyond contributing to the understanding of early events in JEV neuroinvasion, we demonstrate this in vitro BBB model can be used as a system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB during early times of neuroinvasion.

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