Polychlorinated biphenyls (PCBs) are lipophilic and persistent environmental toxicants, which pose health threats to the exposed population. Among several organs and cell types, vascular tissue and endothelial cells are especially prone to PCB-induced toxicity. Exposure to PCBs can exert detrimental impacts on biological pathways, expression of transcription factors, and tight junction proteins that are integral to the functionality of endothelial cells. Because biological and cellular processes are tightly regulated by circadian rhythms, and disruption of the circadian system may cause several diseases, we evaluated if exposure to PCBs can alter the expression of the major endothelial circadian regulators. In addition, we studied if dysregulation of circadian rhythms by silencing the brain and muscle ARNT-like 1 (Bmal1) gene can contribute to alterations of brain endothelial cells in response to PCB treatment. We demonstrated that diminished expression of Bmal1 enhances PCB-induced dysregulation of tight junction complexes, such as the expression of occludin, JAM-2, ZO-1, and ZO-2 especially at pathologically relevant longer PCB exposure times. Overall, the obtained results imply that dysregulation of the circadian clock is involved in endothelial toxicity of PCBs. The findings provide new insights for toxicological studies focused on the interactions between environmental pollutants and regulation of circadian rhythms.

Many plant-derived flavonoids are known for their anti-neuroinflammatory and anti-neurodegenerative effects. The fruits and leaves of the black currant (BC, Ribes nigrum) contain these phytochemicals with therapeutic benefits. The current study presents a report on a standardized BC gemmotherapy extract (BC-GTE) that is prepared from fresh buds. It provides details about the phytoconstituent profile specific to the extract as well as the associated antioxidant and anti-neuroinflammatory properties. The reported BC-GTE was found to contain approximately 133 phytonutrients, making it unique in its composition. Furthermore, this is the first report to quantify the presence of significant flavonoids such as luteolin, quercetin, apigenin, and kaempferol. Drosophila melanogaster-based tests revealed no cytotoxic but nutritive effects. We also demonstrated that adult male Wistar rats, pretreated with the analyzed BC-GTE and assessed after lipopolysaccharide (LPS) injection, did not show any apparent increase in body size in the microglial cells located in the hippocampal CA1 region, while in control experiments, the activation of microglia was evident. Moreover, no elevated levels of serum-specific TNF-α were observed under the LPS-induced neuroinflammatory condition. The analyzed BC-GTE’s specific flavonoid content, along with the experimental data based on an LPS-induced inflammatory model, suggest that it possesses anti-neuroinflammatory/neuroprotective properties. This indicates that the studied BC-GTE has the potential to be used as a GTE-based complementary therapeutic approach.

SUMMARY: Occludin (ocln) is one of the main regulatory cells of the blood-brain barrier (BBB). Ocln silencing resulted in alterations of the gene expression signatures of a variety of genes of the innate immunity system, including IFN-stimulated genes (ISGs) and the antiviral retinoic acid-inducible gene-1 (RIG-1) signaling pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein (MAVS). Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy in our system. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected ocln deficient mice. Overall, these results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of ocln as a key factor in the control of innate immune responses and mitochondrial dynamics, which affect cerebral vascular diseases such as ischemic stroke.