Browsing by Author "Mentor, Shireen"
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Item Are claudin-5 tight-junction proteins in the blood-brain barrier porous?(Wolters Kluwer Health, 2020) Fisher, David W.; Mentor, ShireenThe capillaries of the brain are particularly special, as they are not simply conduits for blood, but are primarily responsible to ensure that the neurons function in a strictly regulated homeostatic interstitium. Brain endothelial cells (BECs) express a plethora of ion channels on its luminal and abluminal surfaces, namely: potassium (K+ ) channels (i.e., Kir2 and Kv1), chloride (Cl–)/bicarbonate (HCO3–) channels, as well as a number of ion-solute exchangers (Redzic et al., 2011). These channels essentially prioritize vectorial transendothelial transport, especially for the regulation of K+ flux across the blood-brain barrier (BBB) (Redzic et al., 2011). The differences between the K+ concentration of the brain interstitium and plasma is only 2 mM to 4 mM, but the maintenance of this ionic concentration difference provides a constancy for the neuronal resting membrane potential, their associated firing thresholds and the preservation of a constant level of neuronal excitability.Item Exosomes form tunneling nanotubes (TUNTs) in the blood-brain barrier: A nano-anatomical perspective of barrier genesis(Frontiers Media, 2022) Mentor, Shireen; Fisher, DavidThe blood-brain barrier (BBB) is a robust interface between the blood and the central nervous system. Barrier type endothelium is able to limit paracellular (PC) movement, relegating molecular flux to the transendothelial pathways of brain endothelial cells (BECs). It is, therefore, apparent that any leakage via the PC shunts would effectively nullify the regulation of molecular flux across the transcellular pathways. The application of higher-resolution scanning electron microscopy (HR-SEM) illuminates the heterogenous, morphological profile that exists on the surface of BEC membranes and the relationship between these ultrastructures during the molecular construction of the PC space between adjacent BECs. In this study developing BEC monolayers were grown on mixed, cellulose esters insert membranes in a bicameral system.Item High-resolution insights into the in vitro developing blood-brain barrier: Novel morphological features of endothelial nanotube function(Frontiers Media, 2021) Mentor, Shireen; Fisher, DavidHigh-resolution electron microscopy (HREM) imaging of the in vitro blood-brain barrier (BBB), is a promising modality for investigating the dynamic morphological interplay underpinning BBB development. The successful establishment of BBB integrity is grounded in the brain endothelial cells (BEC’s) ability to occlude its paracellular spaces of brain capillaries through the expression of the intercellular tight junction (TJ) proteins. The impermeability of these paracellular spaces are crucial in the regulation of transcellular transport systems to achieve homeostasis of the central nervous system. To-date research describing morphologically, the dynamics by which TJ interaction is orchestrated to successfully construct a specialized barrier remains undescribed. In this study, the application of HREM illuminates the novel, dynamic and highly restrictive BEC paracellular pathway which is founded based on lateral membrane alignment which is the functional imperative for the mechanical juxtapositioning of TJ zones that underpin molecular bonding and sealing of the paracellular space.Item The Ism between endothelial cilia and endothelial nanotubules is an evolving concept in the genesis of the BBB(MDPI, 2022) Mentor, Shireen; Fisher, DavidThe blood–brain barrier (BBB) is fundamental in maintaining central nervous system (CNS) homeostasis by regulating the chemical environment of the underlying brain parenchyma. Brain endothelial cells (BECs) constitute the anatomical and functional basis of the BBB. Communication between adjacent BECs is critical for establishing BBB integrity, and knowledge of its nanoscopic landscape will contribute to our understanding of how juxtaposed zones of tight-junction protein interactions between BECs are aligned. The review discusses and critiques types of nanostructures contributing to the process of BBB genesis. We further critically evaluate earlier findings in light of novel high-resolution electron microscopy descriptions of nanoscopic tubules.Item Next generation precision medicine: Crispr-mediated genome editing for the treatment of neurodegenerative disorders(Springerlink, 2019) Mentor, ShireenDespite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etcItem The Role of Cytoskeletal Proteins in the Formation of a Functional In Vitro Blood-Brain Barrier Model(MDPI, 2022) Mentor, Shireen; Makhathini, Khayelihle Brian; David, FischerThe brain capillary endothelium is highly regulatory, maintaining the chemical stability of the brain’s microenvironment. The role of cytoskeletal proteins in tethering nanotubules (TENTs) during barrier-genesis was investigated using the established immortalized mouse brain endothelial cell line (bEnd5) as an in vitro blood-brain barrier (BBB) model. The morphology of bEnd5 cells was evaluated using both high-resolution scanning electron microscopy and immunofluorescence to evaluate treatment with depolymerizing agents Cytochalasin D for F-actin filaments and Nocodazole for α-tubulin microtubules. The effects of the depolymerizing agents were investigated on bEnd5 monolayer permeability by measuring the transendothelial electrical resistance (TEER). The data endorsed that during barrier-genesis, F-actin and α-tubulin play a cytoarchitectural role in providing both cell shape dynamics and cytoskeletal structure to TENTs forming across the paracellular space to provide cell-cell engagement. Western blot analysis of the treatments suggested a reduced expression of both proteins, coinciding with a reduction in the rates of cellular proliferation and decreased TEER. The findings endorsed that TENTs provide alignment of the paracellular (PC) spaces and tight junction (TJ) zones to occlude bEnd5 PC spaces. The identification of specific cytoskeletal structures in TENTs endorsed the postulate of their indispensable role in barrier-genesis and the maintenance of regulatory permeability across the BBB. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.