Blood–Brain Barrier Transporters and Neuroinflammation: Partners in Neuroprotection and in Pathology

Makrides, Victoria; Dolgodilina, Elena; Virgintino, Daniela

doi:10.1007/978-3-319-45514-3_6

Cited by 5 publications

(5 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results on P-gp cellular immunolocalization, carried out in human developing telencephalon, seem to confirm data on a possible astrocyte de-differentiation. In fact, the P-gp immunosignal was revealed on GFAP-reactive RG-like NPCs, located in the proliferative VZ of the future neocortex [97] (Fig. 6A-C) and was demonstrated to progressively decrease during cortical histogenesis (Fig.…”

Section: P-glycoprotein Immunolocalization On Radial-glia-like Neural...mentioning

confidence: 98%

Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Trizio

Errede

d’Amati

et al. 2020

CPD

View full text Add to dashboard Cite

P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while ‘outer’ RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.

show abstract

Section: P-glycoprotein Immunolocalization On Radial-glia-like Neural...mentioning

confidence: 98%

Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Trizio

Errede

d’Amati

et al. 2020

CPD

View full text Add to dashboard Cite

show abstract

“…They may impede normal cellular processes such as cell division and programmed cell death, associated with malignant transformation. One of the prototypical oncogenes affected by nsSNPs is the RAS gene family, encompassing HRAS, which encodes small GTPases involved in signalling pathways that control cellular proliferation, differentiation, and survival (Khan and Bisen, 2013;Makrides et al, 2017). Mutations in RAS genes, including nsSNPs, can activate these pathways and subvert normal cellular regulation, thereby instigating tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Ali¹,

Ali²,

Qamar³

et al. 2023

Front. Chem.

View full text Add to dashboard Cite

The HRAS gene plays a crucial role in regulating essential cellular processes for life, and this gene's misregulation is linked to the development of various types of cancers. Nonsynonymous single nucleotide polymorphisms (nsSNPs) within the coding region of HRAS can cause detrimental mutations that disrupt wild-type protein function. In the current investigation, we have employed in-silico methodologies to anticipate the consequences of infrequent genetic variations on the functional properties of the HRAS protein. We have discovered a total of 50 nsSNPs, of which 23 were located in the exon region of the HRAS gene and denoting that they were expected to cause harm or be deleterious. Out of these 23, 10 nsSNPs ([G60V], [G60D], [R123P], [D38H], [I46T], [G115R], [R123G], [P11OL], [A59L], and [G13R]) were identified as having the most delterious effect based on results of SIFT analysis and PolyPhen2 scores ranging from 0.53 to 69. The DDG values −3.21 kcal/mol to 0.87 kcal/mol represent the free energy change associated with protein stability upon mutation. Interestingly, we identified that the three mutations (Y4C, T58I, and Y12E) were found to improve the structural stability of the protein. We performed molecular dynamics (MD) simulations to investigate the structural and dynamic effects of HRAS mutations. Our results showed that the stable model of HRAS had a significantly lower energy value of −18756 kj/mol compared to the initial model of −108915 kj/mol. The RMSD value for the wild-type complex was 4.40 Å, and the binding energies for the G60V, G60D, and D38H mutants were −107.09 kcal/mol, −109.42 kcal/mol, and −107.18 kcal/mol, respectively as compared to wild-type HRAS protein had −105.85 kcal/mol. The result of our investigation presents convincing corroboration for the potential functional significance of nsSNPs in augmenting HRAS expression and adding to the activation of malignant oncogenic signalling pathways.

show abstract

“…The barrier to paracellular diffusion contributed by TJs potentially isolates the brain from many essential polar nutrients such as glucose and amino acids necessary for metabolism and therefore the CNS endothelium forming the BBB express a large number of specific transporters, including solute carriers and ABC (ATP-binding cassette) transporter proteins, for a wide variety of solutes and nutrients, mediating flux into and out of the brain [92][93][94][95][96][97][98][99][100][101]. Classification and roles of BBB transporters can be found in [102][103][104].…”

Section: Transporters or Solute Carriersmentioning

confidence: 99%

Epigenetics in blood–brain barrier disruption

Ihezie¹,

Mathew²,

McBride³

et al. 2021

Fluids Barriers CNS

View full text Add to dashboard Cite

The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood–brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.

show abstract

Blood–Brain Barrier Transporters and Neuroinflammation: Partners in Neuroprotection and in Pathology

Cited by 5 publications

References 153 publications

Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Epigenetics in blood–brain barrier disruption

Contact Info

Product

Resources

About