scholarly journals Rac1/Wave2/Arp3 Pathway Mediates Rat Blood-Brain Barrier Dysfunction under Simulated Microgravity Based on Proteomics Strategy

2021 ◽  
Vol 22 (10) ◽  
pp. 5165
Author(s):  
Ranran Yan ◽  
Huayan Liu ◽  
Fang Lv ◽  
Yulin Deng ◽  
Yujuan Li
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Proinflammatory Cytokine ◽  
Brain Barrier ◽  
Cell Junction ◽  
Cycle Phase ◽  
Blood Brain ◽  
Proteomic Approach ◽  
Cytokine Levels ◽  
Stress Levels

The blood-brain barrier (BBB) is critical to maintaining central nervous system (CNS) homeostasis. However, the effects of microgravity (MG) on the BBB remain unclear. This study aimed to investigate the influence of simulated MG (SMG) on the BBB and explore its potential mechanism using a proteomic approach. Rats were tail-suspended to simulate MG for 21 days. SMG could disrupt the BBB, including increased oxidative stress levels, proinflammatory cytokine levels, and permeability, damaged BBB ultrastructure, and downregulated tight junctions (TJs) and adherens junctions (AJs) protein expression in the rat brain. A total of 554 differentially expressed proteins (DEPs) induced by SMG were determined based on the label-free quantitative proteomic strategy. The bioinformatics analysis suggested that DEPs were mainly enriched in regulating the cell–cell junction and cell–extracellular matrix biological pathways. The inhibited Ras-related C3 botulinum toxin substrate 1 (Rac1)/Wiskott–Aldrich syndrome protein family verprolin-homologous protein 2 (Wave2)/actin-related protein 3 (Arp3) pathway and the decreased ratio of filamentous actin (F-actin) to globular actin contributed to BBB dysfunction induced by SMG. In the human brain microvascular endothelial cell (HBMECs), SMG increased the oxidative stress levels and proinflammatory cytokine levels, promoted apoptosis, and arrested the cell cycle phase. Expression of TJs and AJs proteins were downregulated and the distribution of F-actin was altered in SMG-treated HBMECs. The key role of the Rac1/Wave2/Arp3 pathway in BBB dysfunction was confirmed in HBMECs with a specific Rac1 agonist. This study demonstrated that SMG induced BBB dysfunction and revealed that Rac1/Wave2/Arp3 could be a potential signaling pathway responsible for BBB disruption under SMG. These results might shed a novel light on maintaining astronaut CNS homeostasis during space travel.

scholarly journals Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bailey Hiles-Murison ◽  
Andrew P. Lavender ◽  
Mark J. Hackett ◽  
Joshua J. Armstrong ◽  
Michael Nesbit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Hippocampal Formation ◽  
Brain Barrier ◽  
Lateral Ventricles ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

AbstractRepeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

scholarly journals Impairing Proliferation of Glioblastoma Multiforme with CD44+ Selective Conjugated Polymer Nanoparticles

2021 ◽  
Author(s):  
Dorota Lubanska ◽  
Sami Alrashed ◽  
Gage T. Mason ◽  
Fatima Nadeem ◽  
Mitchell DiPasquale ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Conjugated Polymer ◽  
Average Diameter ◽  
Polymer Nanoparticles ◽  
Brain Barrier ◽  
Cycle Phase ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Conjugated Polymer Nanoparticles

Glioblastoma is one of the most aggressive types of cancer with median survival of only 15 months. Successful therapy is hampered by the existence of treatment resistant populations of stem-like tumour initiating cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole (DPP)-based conjugated polymer nanoparticles (CPNs) with an average diameter of 109 nm. The CPN were designed to include fluorescein-conjugated hyaluronic acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone decreases stemness, invasive properties and proliferation of the CD44-TIC population in zebrafish PDX models in vivo. This study is the first to show surface moiety-driven selectivity of conjugated polymer nanoparticles in targeting TIC populations in brain cancer.

scholarly journals Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3842
Author(s):  
Harvey R. Fernandez ◽  
Ashima Varma ◽  
Sarah A. Flowers ◽  
George William Rebeck
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Cancer Chemotherapy ◽  
Apoe Genotype ◽  
Brain Barrier ◽  
Blood Brain

Cancer related cognitive impairment (CRCI) is a serious impairment to maintaining quality of life in cancer survivors. Cancer chemotherapy contributes to this condition through several potential mechanisms, including damage to the blood brain barrier, increases in oxidative stress and inflammation in the brain, and impaired neurogenesis, each of which lead to neuronal dysfunction. A genetic predisposition to CRCI is the E4 allele of the Apolipoprotein E gene (APOE), which is also the strongest genetic risk factor for Alzheimer’s disease. In normal brains, APOE performs essential lipid transport functions. The APOE4 isoform has been linked to altered lipid binding, increased oxidative stress and inflammation, reduced turnover of neural progenitor cells, and impairment of the blood brain barrier. As chemotherapy also affects these processes, the influence of APOE4 on CRCI takes on great significance. This review outlines the main areas where APOE genotype could play a role in CRCI. Potential therapeutics based on APOE biology could mitigate these detrimental cognitive effects for those receiving chemotherapy, emphasizing that the APOE genotype could help in developing personalized cancer treatment regimens.

scholarly journals Lipid Reshaping and Lipophagy Are Induced in a Modeled Ischemia-Reperfusion Injury of Blood Brain Barrier

2019 ◽  
Vol 20 (15) ◽  
pp. 3752 ◽  
Author(s):  
Elena Lonati ◽  
Paola Antonia Corsetto ◽  
Gigliola Montorfano ◽  
Stefania Zava ◽  
Tatiana Carrozzini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Ischemia Reperfusion Injury ◽  
Neutral Lipids ◽  
Ischemia Reperfusion ◽  
Neurovascular Unit ◽  
Standard Condition ◽  
Brain Barrier ◽  
Inflammatory Status ◽  
Blood Brain

Ischemic-reperfusion (I/R) injury induced a remodeling of protein and lipid homeostasis, under oxidative stress and inflammatory status. Starvation occurring during I/R is a condition leading to autophagy activation, which allows abnormal material clearance or amino acid, or both, and fatty acid (FA) recycling essential for survival. This study investigated the lipid reshaping, peroxidation, and related-signaling pathways, in rat brain endothelial cells (RBE4) subjected to 3 h of oxygen and glucose deprivation (OGD) and restoration of standard condition (I/R in vitro model). Lipids and proteins were analyzed after 1 or 24 h of oxygen and nutrient restoration. Together with the oxidative stress and inflammatory status, I/R injury induced a reshaping of neutral lipids and biogenesis of lipid droplets (LD) with excessive lipid storage. The increase of LC3-II/LC3-I ratio, an autophagy marker, and LC3 co-localization with LD suggest the activation of lipophagy machinery to counteract the cell engulfment. Lipophagy leads to cholesterol ester (CE) hydrolysis, increasing free cholesterol (FC) secretion, which occurred by specific transporters or unconventional exocytosis pathways, or both. Here, we propose that an unconventional spreading of FC and other lipid metabolites may influence the neurovascular unit (NVU) cells, contributing to Blood brain barrier (BBB) alteration or adaptation, or both, to the cumulative effects of several transient ischemia.

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