scholarly journals Pinocytosis as the Biological Mechanism That Protects Pgp Function in Multidrug Resistant Cancer Cells and in Blood–Brain Barrier Endothelial Cells

Symmetry ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 1221
Author(s):  
Ziad Omran ◽  
Chloe Whitehouse ◽  
Majed Halwani ◽  
Mazin A. Zamzami ◽  
Othman A. Baothman ◽  
...  
Keyword(s):  
Surface Tension ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Membrane Surface ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Brain Barrier ◽  
Major Drawback ◽  
Blood Brain ◽  
Wide Range

Cancer is the second leading cause of death worldwide. Chemotherapy has shown reasonable success in treating cancer. However, multidrug resistance (MDR), a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents, is a major drawback in the effective use of chemotherapeutic agents in the clinic. Overexpression of P-glycoprotein (Pgp) is a major cause of MDR in cancer as it actively effluxes a wide range of structurally and chemically unrelated substrates, including chemotherapeutic agents. Interestingly, Pgp is also overexpressed in the endothelial cells of blood–brain barrier (BBB) restricting the entry of 98% small molecule drugs to the brain. The efficacy of Pgp is sensitive to any impairment of the membrane structure. A small increase of 2% in the membrane surface tension, which can be caused by a very low drug concentration, is enough to block the Pgp function. We demonstrate in this work by mathematical equations that the incorporation of drugs does increase the surface tension as expected, and the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within only 4.5 s.

scholarly journals Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

2021 ◽  
Vol 22 (9) ◽  
pp. 4725
Author(s):  
Karina Vargas-Sanchez ◽  
Monica Losada-Barragán ◽  
Maria Mogilevskaya ◽  
Susana Novoa-Herrán ◽  
Yehidi Medina ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Specific Interaction ◽  
Brain Barrier ◽  
Mass Spectrometry Analysis ◽  
Peptide Ligand ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
Potential Biomarker

Neurodegenerative diseases are characterized by increased permeability of the blood–brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1β-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope–receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit β-1. Among them, only laminin subunit β-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit β-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

scholarly journals Iron Uptake in Blood-Brain Barrier Endothelial Cells Cultured in Iron-Depleted and Iron-Enriched Media

2002 ◽  
Vol 71 (3) ◽  
pp. 1134-1140 ◽  
Author(s):  
W. Van Gelder ◽  
M. I. E. Huijskes-Heins ◽  
M. I. Cleton-Soeteman ◽  
J. P. Van Dijk ◽  
H. G. Van Eijk
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Iron Uptake ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cells Cultured

scholarly journals Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 2007-2014 ◽  
Author(s):  
Richard S. Beard ◽  
Jason J. Reynolds ◽  
Shawn E. Bearden
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Junction Protein ◽  
Brain Barrier Permeability

Abstract Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change in expression of the adherens junction protein VE-cadherin with Hcy treatment, but there was a significant decrease in the amount of β-catenin at the membrane. Moreover, Hcy caused nuclear translocation of β-catenin and attachment to the promoter for the tight junction protein claudin-5, with concomitant reduction in claudin-5 expression. Using a murine model of HHcy (cbs+/−), treatment for 2 weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of claudin-5 and blood-brain barrier permeability to both exogenous sodium fluorescein and endogenous IgG. Memantine had no effect on these parameters in wild-type littermates. The same results were obtained using an in vitro model with brain microvascular endothelial cells. These data provide the first evidence that the NMDAr is required for Hcy-mediated increases in blood-brain barrier permeability. Modulating cerebral microvascular NMDAr activity may present a novel therapeutic target in diseases associated with opening of the blood-brain barrier in HHcy, such as stroke and dementia.

Neural precursor cell influences on blood–brain barrier characteristics in rat brain endothelial cells

2007 ◽  
Vol 1159 ◽  
pp. 67-76 ◽  
Author(s):  
Joseph C. Lim ◽  
Adam J. Wolpaw ◽  
Maeve A. Caldwell ◽  
Stephen B. Hladky ◽  
Margery A. Barrand
Keyword(s):  
Endothelial Cells ◽  
Rat Brain ◽  
Blood Brain Barrier ◽  
Precursor Cell ◽  
Brain Barrier ◽  
Neural Precursor ◽  
Brain Endothelial Cells ◽  
Neural Precursor Cell ◽  
Blood Brain ◽  
Rat Brain Endothelial Cells

Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells

1996 ◽  
Vol 270 (4) ◽  
pp. H1149-H1158 ◽  
Author(s):  
L. Descamps ◽  
M. P. Dehouck ◽  
G. Torpier ◽  
R. Cecchelli
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Bovine Brain ◽  
Brain Barrier ◽  
Double Labeling ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
A Cell

A cell culture model of the blood-brain barrier consisting of a coculture of bovine brain capillary endothelial cells (BBCECs) and astrocytes has been used to examine the mechanism of iron transport to the brain. Binding experiments showed that BBCECs express 35,000 high-affinity (concn at 50% receptor saturation = 11.3 +/- 2.1 nM) transferin (Tf) receptors per cell. In contrast to apo-transferrin (apoTf) we observed a specific transport of holo-transferrin (holoTf) across BBCECs. This transport was inhibited completely at low temperature. Moreover, the anti-Tf receptor antibody (OX-26) competitively inhibited holoTf uptake by BBCECs. Pulse-chase experiments demonstrated that only 10% of Tf was recycled to the luminal side of the cells, whereas the majority of Tf was transcytosed to the abluminal side; double-labeling experiments clearly demonstrated that iron crosses BBCECs bound to Tf. No intraendothelial degradation of Tf was observed, suggesting that the intraendothelial pathway through BBCECs bypasses the lysosomal compartment. These results clearly show that the iron-Tf complex is transcytosed across brain capillary endothelial cells by a receptor-mediated pathway without any degradation.

scholarly journals Characterization of a Primate Blood-Brain Barrier Co-Culture Model Prepared from Primary Brain Endothelial Cells, Pericytes and Astrocytes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1484
Author(s):  
Daisuke Watanabe ◽  
Shinsuke Nakagawa ◽  
Yoichi Morofuji ◽  
Andrea E. Tóth ◽  
Monika Vastag ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Brain Endothelial Cells ◽  
Monkey Brain ◽  
Blood Brain ◽  
Culture Model ◽  
Culture Models ◽  
Human Primate

Culture models of the blood-brain barrier (BBB) are important research tools. Their role in the preclinical phase of drug development to estimate the permeability for potential neuropharmaceuticals is especially relevant. Since species differences in BBB transport systems exist, primate models are considered as predictive for drug transport to brain in humans. Based on our previous expertise we have developed and characterized a non-human primate co-culture BBB model using primary cultures of monkey brain endothelial cells, rat brain pericytes, and rat astrocytes. Monkey brain endothelial cells in the presence of both pericytes and astrocytes (EPA model) expressed enhanced barrier properties and increased levels of tight junction proteins occludin, claudin-5, and ZO-1. Co-culture conditions also elevated the expression of key BBB influx and efflux transporters, including glucose transporter-1, MFSD2A, ABCB1, and ABCG2. The correlation between the endothelial permeability coefficients of 10 well known drugs was higher (R2 = 0.8788) when the monkey and rat BBB culture models were compared than when the monkey culture model was compared to mouse in vivo data (R2 = 0.6619), hinting at transporter differences. The applicability of the new non-human primate model in drug discovery has been proven in several studies.

scholarly journals Intravenous injection of cyclophilin A realizes the transient and reversible opening of barrier of neural vasculature through basigin in endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Narumi Nakada-Honda ◽  
Dan Cui ◽  
Satoshi Matsuda ◽  
Eiji Ikeda
Keyword(s):  
Endothelial Cells ◽  
Single Dose ◽  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Cyclophilin A ◽  
Brain Barrier ◽  
Blood Brain ◽  
Neural Tissues ◽  
Neural Diseases

AbstractNeural vasculature forms the blood–brain barrier against the delivery of systemically administered therapeutic drugs into parenchyma of neural tissues. Therefore, procedures to open the blood–brain barrier with minimal damage to tissues would lead to the great progress in therapeutic strategy for intractable neural diseases. In this study, through analyses with mouse in vitro brain microvascular endothelial cells and in vivo neural vasculature, we demonstrate that the administration of cyclophilin A (CypA), a ligand of basigin which is expressed in barrier-forming endothelial cells, realizes the artificial opening of blood–brain barrier. Monolayers of endothelial cells lost their barrier properties through the disappearance of claudin-5, an integral tight junction molecule, from cell membranes in a transient and reversible manner. Furthermore, the intravenous injection of a single dose of CypA into mice resulted in the opening of blood–brain barrier for a certain period which enabled the enhanced delivery of systemically administered doxorubicin into the parenchyma of neural tissues. These findings that the pre-injection of a single dose of CypA realizes an artificial, transient as well as reversible opening of blood–brain barrier are considered to be a great step toward the establishment of therapeutic protocols to overcome the intractability of neural diseases.

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