Since cyclooxygenase (COX) isozymes discovery, many papers and reviews have been published to describe the structural bases of COX inhibition, and to debate on the therapeutic and adverse effects of worldwide clinically used nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective inhibitors (well known as Coxibs). COX-2 inhibition has been widely investigated, whereas the role of COX-1 in human pathophysiology is mostly not yet well ascertained. As time goes on, the cliche that the constitutively expressed isoform COX-1 is only involved in normal physiological functions, such as platelet aggregation, gastric mucosa protection and renal electrolyte homeostasis is going to be shattered. Low-dose aspirin, behaving as a preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by this isoenzyme in many mammalian cell types. This review would elucidate the most recent findings on selective COX-1 inhibition and their relevance to human pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain. It would also focus on the design and development of new highly selective COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a deeper insight of the role of COX-1 in human health and disease. Among the traditional NSAIDs, other then aspirin and indomethacin, only few examples of selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have been so far identified. This review has also the scope to stimulate the development of novel drugs, which activity is COX-1 mediated.

Crosstalk mechanisms between pericytes, endothelial cells, and astrocytes preserve integrity and function of the blood-brain-barrier (BBB) under physiological conditions. Long intercellular channels allowing the transfer of small molecules and organelles between distant cells called tunneling nanotubes (TNT) represent a potential substrate for energy and matter exchanges between the tripartite cellular compartments of the BBB. However, the role of TNT across BBB cells under physiological conditions and in the course of BBB dysfunction is unknown. In this work, we analyzed the TNT’s role in the functional dialog between human brain endothelial cells, and brain pericytes co-cultured with human astrocytes under normal conditions or after exposure to ischemia/reperfusion, a condition in which BBB breakdown occurs, and pericytes participate in the BBB repair. Using live time-lapse fluorescence microscopy and laser-scanning confocal microscopy, we found that astrocytes form long TNT with pericytes and endothelial cells and receive functional mitochondria from both cell types through this mechanism. The mitochondrial transfer also occurred in multicellular assembloids of human BBB that reproduce the three-dimensional architecture of the BBB. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and astrocytes exposed to oxygen-glucose deprivation were rescued from apoptosis by healthy pericytes through TNT-mediated transfer of functional mitochondria, an effect that was virtually abolished in the presence of TNT-destroying drugs. The results establish a functional role of TNT in the crosstalk between BBB cells and demonstrate that TNT-mediated mitochondrial transfer from pericytes rescues astrocytes from ischemia/reperfusion-induced apoptosis. Our data confirm that the pericytes might play a pivotal role in preserving the structural and functional integrity of BBB under physiological conditions and participate in BBB repair in brain diseases.

The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton.Significance: This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.