Liposomal 9-Aminoacridine for Treatment of Ischemic Stroke: From Drug Discovery to Drug Delivery.

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.

Association between bullying victimization and depressive symptoms in children: The mediating role of self-esteem.

BACKGROUND: Bullying victimization is becoming an increasing problem among children. This longitudinal study examined the relation of bullying victimization (both traditional and cyberbullying victimization) to subsequent depressive symptoms and the possible mediating role of self-esteem among children. METHODS: A total of 4043 Chinese elementary school children in Grades 3 and 4 comprised the sample. Assessments were conducted every six months on five occasions. Latent growth curve modeling was applied to examine the longitudinal relations among the variables. RESULTS: Results showed that (a) bullying victimization was positively and significantly associated with subsequent depressive symptoms; (b) self-esteem played an important mediating role in the relation between bullying victimization and depressive symptoms. LIMITATIONS: The study only considered self-esteem as a mediator. The generalizability of the results should be made cautiously. CONCLUSIONS: The results highlight the relation between bullying victimization and depressive symptoms among children, suggesting that intervention programs target bullying victimization and self-esteem to reduce the likelihood of depressive symptoms among children.

Self-regulated hirudin delivery for anticoagulant therapy.

Pathological coagulation, a disorder of blood clotting regulation, induces a number of cardiovascular diseases. A safe and efficient system for the delivery of anticoagulants to mimic the physiological negative feedback mechanism by responding to the coagulation signal changes holds the promise and potential for anticoagulant therapy. Here, we exploit a "closed-loop" controlled release strategy for the delivery of recombinant hirudin, an anticoagulant agent that uses a self-regulated nanoscale polymeric gel. The cross-linked nanogel network increases the stability and bioavailability of hirudin and reduces its clearance in vivo. Equipped with the clot-targeted ligand, the engineered nanogels promote the accumulation of hirudin in the fibrous clots and adaptively release the encapsulated hirudin upon the thrombin variation during the pathological proceeding of thrombus for potentiating anticoagulant activity and alleviating adverse effects. We show that this formulation efficiently prevents and inhibits the clot formation on the mouse models of pulmonary embolism and thrombosis.