Prostaglandin [KLH]

Epilepsy is one of the most common neurological diseases. It adversely affects cognitive function. Neuroinflammation has been widely recognized as an important factor involved in the pathophysiology of epilepsy. Cyclooxygenase (COX) is a type of oxidoreductase enzyme that acts in the metabolic pathway converting arachidonic acid to prostaglandins, which mediate inflammatory reactions. The activation of inducible cyclooxygenase-2 (COX-2) is considered to be a precipitating factor of neuroinflammation in the brain. Neuroinflammatory processes in the brain are known to contribute to the cascade of events leading to neuronal injury, which may consequently cause cognitive decline. Here in this study, we showed that pentylenetetrazole (PTZ)-kindled mice exhibited an increased level of COX-2 and its main product prostaglandin E2 (PGE(2)) along with neuroinflammation and neuronal injury in the hippocampus. Pharmacological inhibition of COX-2 by celecoxib, however, significantly reduced hippocampal neuroinflammation and neuronal injury. Furthermore, inhibition of COX-2 by celecoxib attenuated cognitive impairment in the PTZ-kindled mice, suggesting that COX2-PGE(2) signaling pathway mediated neuroinflammation and neuronal injury contributes to cognitive dysfunction in the PTZ-kindled epilepsy mice. Targeting COX-2-PGE(2) signaling pathway in the epileptic brain appears to be a viable strategy for attenuating neuronal injury and preventing cognitive deficits in epilepsy patients.

Mesenchymal stromal cells (MSCs) hold great therapeutic potential, in part because of their immunomodulatory properties. However, these properties can be transient and depend on multiple factors. Here, we developed a multifunctional hydrogel system to synergistically enhance the immunomodulatory properties of MSCs, using a combination of sustained inflammatory licensing and three-dimensional (3D) encapsulation in hydrogels with tunable mechanical properties. The immunomodulatory extracellular matrix hydrogels (iECM) consist of an interpenetrating network of click functionalized-alginate and fibrillar collagen, in which interferon gamma (IFN-gamma) loaded heparin-coated beads are incorporated. The 3D microenvironment significantly enhanced the expression of a wide panel of pivotal immunomodulatory genes in bone marrow-derived primary human MSCs (hMSCs), compared to two-dimensional (2D) tissue culture. Moreover, the inclusion of IFN-gamma loaded heparin-coated beads prolonged the expression of key regulatory genes upregulated upon licensing, including indoleamine 2,3-dioxygenase 1 (IDO1) and galectin-9 (GAL9). At a protein level, iECM hydrogels enhanced the secretion of the licensing responsive factor Gal-9 by hMSCs. Its presence in hydrogel conditioned media confirmed the correct release and diffusion of the factors secreted by hMSCs from the system. Furthermore, co-culture of iECMencapsulated hMSCs and activated human T cells resulted in suppressed proliferation, demonstrating direct regulation on immune cells. These data highlight the potential of iECM hydrogels to enhance the immunomodulatory properties of hMSCs in cell therapies.