Intercellular Interactomics of Human Brain Endothelial Cells and Th17 Lymphocytes: A Novel Strategy for Identifying Therapeutic Targets of CNS Inflammation

Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells) possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC) communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration

Multilocus ISSR Markers Reveal Two Major Genetic Groups in Spanish and South African Populations of the Grapevine Fungal Pathogen Cadophora luteo-olivacea

Cadophora luteo-olivacea is a lesser-known fungal trunk pathogen of grapevine which has been recently isolated from vines showing decline symptoms in grape growing regions worldwide. In this study, 80 C. luteo-olivacea isolates (65 from Spain and 15 from South Africa) were studied. Inter-simple-sequence repeat-polymerase chain reaction (ISSR-PCR) generated 55 polymorphic loci from four ISSR primers selected from an initial screen of 13 ISSR primers. The ISSR markers revealed 40 multilocus genotypes (MLGs) in the global population. Minimum spanning network analysis showed that the MLGs from South Africa clustered around the most frequent genotype, while the genotypes from Spain were distributed all across the network. Principal component analysis and dendrograms based on genetic distance and bootstrapping identified two highly differentiated genetic clusters in the Spanish and South African C. luteo-olivacea populations, with no intermediate genotypes between these clusters. Movement within the Spanish provinces may have occurred repeatedly given the frequent retrieval of the same genotype in distant locations. The results obtained in this study provide new insights into the population genetic structure of C. luteo-olivacea in Spain and highlights the need to produce healthy and quality planting material in grapevine nurseries to avoid the spread of this fungus throughout different grape growing regions

Free radical mediated damage to the brain during ischaemia-reperfusion : A phase concept

NRC publication: Ye

Pathophysiology of the neurovascular unit: disease cause or consequence?

Pathophysiology of the neurovascular unit (NVU) is commonly seen in neurological diseases. The typical features of NVU pathophysiology include tissue hypoxia, inflammatory and angiogenic activation, as well as initiation of complex molecular interactions between cellular (brain endothelial cells, astroctyes, pericytes, inflammatory cells, and neurons) and acellular (basal lamina) components of the NVU, jointly resulting in increased blood\u2013brain barrier permeability, brain edema, neurovascular uncoupling, and neuronal dysfunction and damage. The evidence of important role of the brain vascular compartment in disease pathogenesis has elicited the debate whether the primary vascular events may be a cause of the neurological disease, as opposed to a mere participant recruited by a primary neuronal origin of pathology? Whereas some hereditary and acquired cerebral angiopathies could be considered a primary cause of neurological symptoms of the disease, the epidemiological studies showing a high degree of comorbidity among vascular disease and dementias, including Alzheimer's disease, as well as migraine and epilepsy, suggested that primary vascular pathology may be etiological factor causing neuronal dysfunction or degeneration in these diseases. This review focuses on recent hypotheses and evidence, suggesting that pathophysiology of the NVU may be initiating trigger for neuronal pathology and subsequent neurological manifestations of the disease.Peer reviewed: YesNRC publication: Ye

The Transport Systems of the Blood\u2013Brain Barrier

Peer reviewed: YesNRC publication: Ye

Glutathione reductase during and after brain ischemia in gerbils: Metab.Brain Dis.

NRC publication: Ye

MPTP-indukovan parkinsonizam kao model Parkinsonove bolesti i indikator moguce terapije (MPTP-induced parkinsonism as a model for Parkinson's disease and indicator of therapeutical approach

NRC publication: Ye

Integrated platform for brain imaging and drug delivery across the blood-brain barrier

Peer reviewed: YesNRC publication: Ye

Receptor-mediated transcytosis for brain delivery of therapeutics: receptor classes and criteria

The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands

Excitatory amino acid receptors, oxido-reductive processes and brain edema following transient ischemia in gerbils: Acta Neurochir.

NRC publication: Ye