Impaired Phagocytosis in Localized Aggressive Periodontitis: Rescue by Resolvin E1

Resolution of inflammation is an active temporally orchestrated process demonstrated by the biosynthesis of novel proresolving mediators. Dysregulation of resolution pathways may underlie prevalent human inflammatory diseases such as cardiovascular diseases and periodontitis. Localized Aggressive Periodontitis (LAP) is an early onset, rapidly progressing form of inflammatory periodontal disease. Here, we report increased surface P-selectin on circulating LAP platelets, and elevated integrin (CD18) surface expression on neutrophils and monocytes compared to healthy, asymptomatic controls. Significantly more platelet-neutrophil and platelet-monocyte aggregates were identified in circulating whole blood of LAP patients compared with asymptomatic controls. LAP whole blood generates increased pro-inflammatory LTB4 with addition of divalent cation ionophore A23187 (5 µM) and significantly less, 15-HETE, 12-HETE, 14-HDHA, and lipoxin A4. Macrophages from LAP subjects exhibit reduced phagocytosis. The pro-resolving lipid mediator, Resolvin E1 (0.1–100 nM), rescues the impaired phagocytic activity in LAP macrophages. These abnormalities suggest compromised resolution pathways, which may contribute to persistent inflammation resulting in establishment of a chronic inflammatory lesion and periodontal disease progression

Combined intracranial Acriflavine, temozolomide and radiation extends survival in a rat glioma model

Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF) regulatory pathways, recent evidence has shown that Acriflavine (ACF) can effectively target glioma invasiveness and recurrence. However, local delivery of ACF and its combinatory effects with Temozolomide (TMZ) and radiation therapy (XRT) have not yet been optimized. In this study we test a novel polymeric matrix that can gradually release ACF at the tumor bed site in combination with systemic TMZ and XRT. In vitro cytotoxicity assays of ACF in combination with TMZ and XRT were performed on rodent and human cell lines with CCK-8 and flow cytometry. In vitro drug release was measured and intracranial safety was assessed in tumor-free animals. Finally, efficacy was assessed in an intracranial gliosarcoma model and combination therapy with TMZ and XRT evaluated. Combination therapy of ACF, TMZ, and XRT was able to reduce cell viability and induce apoptosis in glioma cells. In vitro and in vivo release of ACF was measured in benchtop and animal models. Efficacy was established in an in vivo gliosarcoma model in which intracranial ACF (p < 0.01) significantly improved median survival and the combination therapy of ACF, TMZ and XRT (p < 0.01) significantly improved median survival and led to long-term survival (LTS). We provide evidence that ACF, combined with TMZ and XRT, led to LTS in an intracranial model of rat gliosarcoma. These findings, in combination with the use of a novel polymeric matrix that allows more gradual drug delivery, constitute a first step in the translation of this novel strategy to human use