Background Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox-tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear. Methods In vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor (VEGF) A levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) expressions in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, RT-qPCR, and ELISA. The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and Transwell assays. Results In vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as Albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12–0.5 µM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 µM SU11248 entirely inhibited EPC migration to the supernatants of liver cell and protoscolex cocultures. Conclusions Our results indicated that SU11248 may primarily inhibit E. multilocularis-associated angiogenesis by suppressing the host VEGFA/VEGFR2 signaling pathway, thus decelerating parasite growth. Inhibition of VEGFA-induced angiogenesis is may thus be a novel approach for treating AE.
Background: Cell-based therapeutics bring great hope in areas of unmet medical needs. Mesenchymal stem cells (MSCs) has been suggested to facilitate neovascularization mainly by paracrine action, and endothelial progenitor cells (EPCs) can differentiate into mature endothelial cells. Studies have demonstrated that a combination cell therapy that includes MSCs and EPCs has a favorable effect on ischemic limbs. However, the mechanism of combination cell therapy remains unclear. Herein, we investigate whether stromal cell-derived factor (SDF)-1 secreted by MSCs contributes to. Furthermore, we examined whether SDF-1 affects EPC migration via Phosphoinositide 3-Kinases (PI3K)/protein kinase B (termed as Akt) signaling pathway.Methods: First, intramuscular MSC injections were supplemented with intravenous EPC injections in the mouse model of hind limb ischemia. The incorporation of Qdot® 525 labeled-EPC into the vasculature and capillary density was evaluated by CD31 immunohistochemistry and immunofluorescence, respectively. Then, the concentration of SDF-1 secreted by MSCs was detected via quantitative immunoassay. Flow cytometry was performed to quantify CXC chemokine receptor (CXCR) 4-positive EPCs. The effect of MSCs on EPC migration was measured by a transwell system and a tube-like structure formation on Matrigel. The SDF-1 antagonist AMD3100 and the PI3K inhibitor wortmannin were separately used to determine the participation of CXCR4 and PI3K into EPC migration. Finally, western blot assay was performed to detect the effect of SDF-1 secreted by MSCs on Akt phosphorylation in EPCs.Results: The combination delivery of MSCs and EPCs via a “dual-administration” approach enhanced the incorporation of EPCs into the vasculature and increased the capillary density in mouse ischemic hind limb. The SDF-1 concentration secreted by MSCs was 2.61 ng/ml after 48 h. CXCR4-positive EPCs increased after incubation with MSC-conditioned medium (CM). MSCs contributed to EPC migration and tube-like structure formation, both of which were suppressed by AMD3100 and wortmannin. Phospho-Akt induced by MSC-CM was attenuated when EPCs were pretreated with AMD3100 and wortmannin.Conclusions: The paracrine action of MSCs contributes to EPC migration. Furthermore, SDF-1 secreted by MSCs induces EPC migration. The mechanism of this migration is related to the activation of the Akt pathway
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