Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.

Background: Tumor recurrence and metastasis occur at a high rate in patients with colon cancer. Identification of effective strategies for the treatment of colon cancer is critical. Recently, poly (lactic-co-glycolic acid) (PLGA) has been shown to have potential as a broad therapeutic drug delivery system. We designed a dual-loaded nanoparticle drug delivery system to overcome the limitations of chemotherapeutic drugs used to treat colon cancer. Methods: We developed epidermal growth factor (EGF) functionalized PLGA nanoparticles (NPs) co-loaded with 5fluorouracil (5Fu) and perfluorocarbon (PFC) (EGF-PLGA@5Fu/PFC) for targeted treatment of colon cancer. CCK-8 assay, Hoechst33342 staining and flow cytometry were performed to investigate the functions of EGF-PLGA@5Fu/ PFC NPs in SW620 cells. Beside, animal experiment, histological analysis and immunofluorescence staining were adopted to further confirm the role of EGF-PLGA@5Fu/PFC NPs in vivo. Results: The findings showed that EGF-PLGA@5Fu /PFC NPs had an average size 200 nm and a 5Fu-loading efficiency of 7.29%. Furthermore, in vitro release was pH-sensitive. Targeted EGF-PLGA@5Fu/PFC NPs exhibited higher cellular uptake than non-targeted NPs into colon cancer cells. In addition, EGF-PLGA@5Fu/PFC NPs suppressed cell viability and induced apoptosis in SW620 cells to a greater extent than non-targeted NPs. In tumor xenografted mice, EGF-PLGA@5Fu/PFC NPs suppressed tumor growth more effectively than 5Fu, PLGA@5Fu or PLGA@5Fu/PFC NPs. Histopathological analysis further demonstrated that EGF-targeted NPs inhibited tumor growth to a greater extent than non-targeted or non-NP treatments. The improved therapeutic outcomes observed in this study were due to relief of tumor hypoxia by transport of oxygen by PFC to the tumors. Conclusion: We constructed a biocompatible nanodrug delivery system based on functionalized nanoparticles that provided a novel strategy for selective delivery of chemotherapy drugs to tumors.

Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell‐to‐cell communication. The present study focused on investigating whether EV‐delivered miR‐370‐3p affects breast cancer. Initially, the miR‐370‐3p expression pattern was examined in the cancer‐associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells‐derived EVs. The relation of miR‐370‐3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF‐7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro‐inflammatory factors and nuclear factor‐kappa B (NF‐κB) signaling‐related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell‐derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR‐370‐3p from breast cancer cells to NFs, and EV‐encapsulated miR‐370‐3p was also found to facilitate fibroblast activation. Mechanistically, EV‐encapsulated miR‐370‐3p downregulated the expression of CYLD through binding to its 3′UTR and activated the NF‐κB signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR‐370‐3p to aggravate breast cancer through downregulating CYLD expression and activating the NF‐κB signaling pathway.