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Nanomedicine for the Treatment of Neurological Disorders
Published in Sarwar Beg, Mahfoozur Rahman, Md. Abul Barkat, Farhan J. Ahmad, Nanomedicine for the Treatment of Disease, 2019
BBB is the major barrier to prevent crossing of most circulatory cells and other molecules from blood to brain. Along with pericytes, perivascular astrocytes, neurons, and basal lamina, microvessel epithelial cells form structural component of BBB (Bendayan et al., 2002; Obermeier et al., 2013; Zhao et al., 2015; Freese et al., 2017). This structure and transportation of endogenous compounds are maintained by tight junction and proteins present within it: claudins and occludin, along with adherent junction proteins (made up of cadherins and catenins) (Weksler et al., 2005). Other than these structural units, few specific efflux/influx channels, receptors, and protein transporters also act as metabolism-driven barrier at BBB; which includes ATP-Binding cassette (ABC) associated transporters, multidrug resistance-associated proteins (MRPs), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP, ABCG2), organic anion transporters (OATs) and organic anion transporting polypeptide family (OATPs), where OATs and OATPs act as both influx and efflux system for brain (Kusuhara and Sugiyama, 2001; Loscher and Potschka, 2005; Bendayan et al., 2006; Dallas et al., 2006).
Solid Lipid Nanoparticles for Brain Targeting
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nanocarriers for Brain Targeting, 2019
M. M. de Araujo, L. B. Tofani, I. L. Suzuki, P. D. Marcato, M. V. L. B. Bentley
The BBB restricts solute entry into the brain via the transcellular route due to an increased electrical resistance between the ECs at the tight junctions (TJ) (Roney et al., 2005). Indispensable proteins, including claudin and the junctional adhesion molecule (JAM), compose the TJ. The claudins form the seal of the TJ by homotypically binding to each other on adjacent EC cells (Wolburg et al., 2003). The JAM regulates leukocyte transmigration at the BBB (Martin-Padura et al., 1998). Between the ECs, there is an expression of TJ, which is one of the most critical characteristics, because of their consequences on the function of the BBB (Reichel et al., 2003). These features provide almost complete restriction of the paracellular pathway, control over the CNS penetration, differential expression of transporters, receptors and enzymes at the luminal or abluminal cell surface, allowing the BBB to act as a dynamic interface between the periphery of the body (blood) and the central compartment (brain) (Roney et al., 2005).
Comparative study of two isothiazolinone biocides, 1,2-benzisothiazolin-3-one (BIT) and 4,5-dichloro-2-n-octyl-isothiazolin-3-one (DCOIT), on barrier function and mitochondrial bioenergetics using murine brain endothelial cell line (bEND.3)
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Donghyun Kim, Eun-Hye Kim, Ok-Nam Bae
To determine the effective concentration ranges of DCOIT on the barrier function of brain ECs, the influence of exposure time and concentration of DCOIT was examined on mitochondrial metabolic capacity and membrane integrity, as measured by MTT reduction and LDH activity, respectively. DCOIT significantly elevated released LDH activity after 6 hr treatment at 5 μM, and significantly decreased MTT reduction following 3 hr incubation at 5 μM (Figure 2(b,c)). After 24 hr treatment with 0, 1, 2, 5, or 10 μM DCOIT, the IC50 of MTT reduction was calculated as 4.93 μM (Figure 2d). The significantly lowered expression levels of claudin-5 and ZO-1, the TJ proteins, was observed in confocal microscopy images (Figure 2e) and western blot analysis (Figure 2(f,g)). The protein levels of claudin-5 and ZO-1 were reduced approximately 0.41-fold (Figure 2f) and 0.08-fold (Figure 2g), respectively. DCOIT-induced TJ degradation leads to a diminished BBB integrity. TEER values were significantly decreased by approximately 0.55-fold (Figure 2h) and permeability was also significantly enhanced by approximately 1.59-fold (Figure 2i) after DCOIT treatment.
Review on the current treatment status of vein of Galen malformations and future directions in research and treatment
Published in Expert Review of Medical Devices, 2021
Panagiotis Primikiris, Georgios Hadjigeorgiou, Maria Tsamopoulou, Alessandra Biondi, Christina Iosif
In the study of Duran et al. [137], the reported EPHB4 missense mutations altered some of the amino acid residues in the tyrosine kinase domain of the vein-specific EPHB4 receptor [109,137]. Interestingly, all patients affected by EPHB4 mutations suffered from choroidal VOGM. There were also seven non-VOGM family members who carried these mutations and three of them presented a cutaneous vascular pathology (port-wine stain and capillary malformations). The above findings suggest a mechanism of incomplete penetrance and variable expressivity for EPHB4 mutations. Duran et al. also reported mutations in the CLDN14 gene (P= 6.44 × 10−7) in approximately 5% of VOGM. The CLDN14 gene encodes the tight junction protein, Claudin-14. It is also to point out that non-VOGM family members of CLDN14-mutated probands were also diagnosed with cutaneous vascular pathology. Using Ingenuity Pathway Analysis, which analyzes common shared signaling pathways, it was also identified in this study that the most commonly affected pathway by the de novo and rare transmitted mutations was the Ephrin receptor signaling pathway. .
Effects of ambient particulate matter on vascular tissue: a review
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Kristina Shkirkova, Krista Lamorie-Foote, Michelle Connor, Arati Patel, Giuseppe Barisano, Hans Baertsch, Qinghai Liu, Todd E. Morgan, Constantinos Sioutas, William J. Mack
The precise inflammatory mechanisms resulting from PM exposure remain unclear. Experimental evidence suggests parallel endothelial dysfunction from inflammatory substrates and blood-brain barrier (BBB) disruption. In particular, activation of the nitric oxide pathways through uncoupling of the endothelial nitric oxide enzyme and subsequent reduction in local expression of nitrogen oxide in the vascular endothelium is associated with reduction in tight junction protein expression (Saura et al. 2006). Mice exposed to mixed vehicle (gasoline and diesel engine) exhaust for 30 days were injected with the molecular tracer, sodium fluorescein, on the final day of exposure. Elevated levels of inflammatory biomarkers (iNOS by 300% and IL-1b by 200%) in cerebral tissue and arteries correlated with decreased levels of tight junction proteins, including a 200% fall in occludin and claudin-5. Elevated endothelial monolayer tracer transfer suggestive of a leaky BBB was observed in mice exposed to vehicle exhaust (Oppenheim et al. 2013). These findings indicated that vehicular pollutants might increase inflammation and endothelial monolayer permeability of peripheral vessels through modification of intracellular gaps and alterations in protein structure of endothelial tight junctions. Evidence suggests that PM-induced endothelial cell and vascular flow changes are multifactorial, which contribute to systemic inflammatory responses through circulating plasma proteins, decreased vascular tone, changes in endothelial cell dynamics, and BBB alterations.