Bone marrow-derived mesenchymal stem cells (BMSCs) are promising gene vehicles for cancer gene therapy. In our previous study, we reported that BMSCs expressing interleukin (IL)-18 effectively inhibit the growth of glioma in rats. In the present study, we further detected the effect of BMSCs co-expressing IL-18 and interferon (IFN)-β, both of which are immunostimulatory cytokines. BMSCs were genetically engineered to express IL-18 and IFN-β by transfection of recombinant lentivirus-mediated gene transfer. Results showed that BMSCs co-expressing the two cytokines displayed more significant inhibition effect on glioma cell growth in vitro when compared with BMSCs solely expressing IL-18 or IFN-β. Treatment of BMSCs co-expressing IL-18 and IFN-β significantly prolonged the survival and inhibited tumor growth in a rat intracranial glioma model. Furthermore, these genetically engineered BMSCs remarkably promoted cell apoptosis, antitumor cytokine production and CD4+ and CD8+ T-cell infiltration in intracranial glioma tissues than BMSCs solely expressing IL-18 or IFN-β. Results of the present study suggested that IL-18 and IFN-β had a synergistic effect on glioma inhibition. Moreover, results provided evidence that delivery of IL-18 and IFN-β by BMSCs may be an excellent and promising approach to develop an effective treatment protocol for glioma therapy.

Study design: Experimental study. Objectives: To investigate the effects of endothelin-receptor antagonist Bosentan on the spinal neural apoptosis in rats with ischemic reperfusion (IR) injury. Setting: Department of Neurosurgery, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medcine, Xi'an, Shaanxi Province, China Methods: Sprague-Dawley Rats were randomly divided into two groups, saline (IRS, n ¼ 48) and Bosentan (IRB, n ¼ 48) treatment, respectively, when reperfused in 6 h, 12 h, 24 h, 3 days, 5 days and 7 days. Immunohistochemical staining was used to assess endothelin-1 (ET-1), endothelin receptor type A (ETR A ), endothelin receptor type B (ETR B ), Bcl-2, Bax, Caspase-8, Caspase-9 and Caspase-3 expression. ET-1 and its receptor in spinal cord tissue were evaluated by real-time PCR. Plasma ET-1 concentration was also detected using radioimmunoassay. Results: Compared with the group IRS, plasma concentration of ET-1 in group IRB was significantly increased at each time point (Po0.05) and peaked at 24 h (Po0.01). ETR B expression in group IRB was significantly higher than group IRS at each time point (Po0.05) and peaked at day 3 (Po0.01). The difference in the expression of ETR A was not statistically significant in the group IRS and IRB (P40.05). The apoptosis rate in group IRB was significantly decreased at each time point (Po0.05). The protein expressions of Bcl-2, Bax, Caspase-8, Caspase-9 and Caspase-3 were significantly increased in response to Bosentan treatment after IR. Conclusion: These results suggest Bosentan decreases apoptosis rate after IR injury in the spinal cord, possibly through the ET-1-ETR B signaling pathway.

Study design: Experimental study. Objectives: To investigate whether Bosentan, an endothelin-A/-B dual receptor antagonist, could protect neurons after spinal cord ischemia reperfusion (SCIR) injury in rats and its underlying signaling pathway. Setting: Department of Neurosurgery, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi Province, China. Methods: Sprague-Dawley rats were randomly divided into two groups, saline group (IRS, n ¼ 48) and Bosentan group (IRB, 5 mg kg À1 , n ¼ 48). After ischemia for 1 h with occlusion of the infrarenal aorta, spinal cord were reperfused for 6h, 12h, 24h, 3d, 5d, and 7d separately. Enzyme-linked immunosorbent assay was used to detect vascular endothelial growth factor (VEGF) in serum. Immunohistochemistry was performed to detect protein expression of VEGF, VEGF receptor 1 (FLT-1) and VEGF receptor 2 (FLK-1). Gene expressions of VEGF and its receptors were evaluated using the quantitative reverse transcription polymerase chain reaction. Results: Compared with the IRS group, gene and protein expressions of VEGF, FLT-1 and FLK-1 were significantly increased (Po0.05), so was the concentration of VEGF in plasma (Po0.05). FLK-1 was expressed on spinal cord neurons.

Angiomotin-like 1 (AMOTL1) is reportedly a pivotal tumor-associated protein that is strongly associated with the tumorigenesis of multiple malignant tumors. However, the issue of whether AMOTL1 plays a role in the tumorigenesis of glioma remains unclear.The aim of this work was to explore the possible relationship between AMOTL1 and glioma progression. Results demonstrated that high levels of AMOTL1 in glioma tissues were associated with a reduced survival rate in patients with glioma. Cellular functional assays revealed that silencing of AMOTL1 in glioma cell lines substantially decreased cell proliferation and invasion and increased cell apoptosis. Further investigation revealed that silencing of AMOTL1 inhibited the activation of yes-associated protein 1 (YAP1) and decreased the expression of YAP1 target genes. Reactivation of YAP1 reversed AMOTL1-silencing-induced antitumor effects, whereas inhibition of YAP1 abolished AMOTL1-overexpression-induced tumor-promoting effects in glioma cells.Silencing of AMOTL1 also retarded the growth of glioma cell-derived xenograft tumors in vivo. In conclusion, these findings suggested that AMOTL1 may exert a tumorpromoting function in glioma by enhancing the activation of YAP1 signaling. This work suggested AMOTL1 as a potential target for the development of antiglioma therapy.