YAP promotes self-renewal of gastric cancer cells by inhibiting expression of L-PTGDS and PTGDR2
INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY
Authors: Bie, Qingli; Li, Xiaozhe; Liu, Shiqi; Yang, Xiao; Qian, Zhenwen; Zhao, Rou; Zhang, Xiaobei; Zhang, Bin
Abstract
Introduction Cancer stem cells have been implicated angiogenesis of tumor and invasiveness, drug resistance in tumors. Yes-associated protein 1 (YAP) owns carcinogenic roles in various organs, but the role of YAP in cancer stem cells of gastric cancer (GC) remains unclear. In this study, we explored the function and mechanism of YAP in GC cancer stem cells. Materials and methods, and results First, we confirmed that the expression of YAP mRNA and protein in GC tissues was higher than in adjacent tissues by RT-PCR, western blot and immunohistochemistry. Immunofluorescence staining of the GC tissues revealed that the region of YAP expression coincided with the region of expression of the cancer stem cell marker SALL4 but did not overlap with that of the epithelial marker cytokeratin 14 (CK14). Additional research revealed that spherical cells expressed relatively high levels of YAP protein, and YAP overexpression reinforced self-renewal and expression of stem cell markers in the GC cells. Knockdown the expression of YAP reversed this phenomenon. Second, we examined the expression patterns of lipocalin-type prostaglandin D2 synthase (L-PTGDS) and prostaglandin D2 receptor 2 (PTGDR2) in GC tissues and proved that there was negatively correlation between the expression of L-PTGDS and PTGDR2 and YAP in GC tissues. Finally, we confirmed that YAP inhibited the expression of L-PTGDS and PTGDR2 by gain- and loss-of-function experiments. Moreover, the overexpression of L-PTGDS and PTGDR2 suppressed the proliferation and self-renewal induced by YAP in vitro and reversed the pro-tumor effect of YAP in vivo. Conclusion Our results revealed a novel function of YAP and the mechanism underlying cancer stem cell regulation by YAP.
Intranasal delivery of icariin via a nanogel-thermoresponsive hydrogel compound system to improve its antidepressant-like activity
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Authors: Xu, Dong; Lu, Yu-Ren; Kou, Na; Hu, Meng-Jiao; Wang, Qiang-Song; Cui, Yuan-Lu
Abstract
Although icariin has been reported to have antidepressant-like effects in different animal models, its poor oral bioavailability and low efficiency of delivery to the brain limit its application. In this study, icariin nanogels were prepared by reverse microemulsion methods to improve its poor water solubility. Then, we developed an icariin nanogel loaded self-assembled thermosensitive hydrogel system (icariin-NGSTH) to deliver icariin via a noninvasive, direct nose-to-brain delivery route for the treatment of depression. The in vivo distribution was investigated by fluorescence imaging with rhodamine B-labeled nanogels. The antidepressant efficacy of icariinNGSTH was evaluated in behavioral despair tests and the chronic unpredictable mild stress (CUMS) model. The results showed that icariin-NGSTH had a zero-order kinetics release in the first 10 h. Icariin-NGSTH led to rapid brain distribution within 30 min. Icariin-NGSTH significantly reduced the duration of immobility in the tail suspension test (TST) and forced swim test (FST). Compared with oral administration, intranasally administered icariin-NGSTH had a fast-acting antidepressant effect in the TST and FST. Moreover, icariin-NGSTH increased body weight and sucrose preference, reversed abnormal plasma levels of testosterone, interleukin-6 (IL-6) and prostaglandin E-2 (PGE(2)), and repaired neuronal damage in the hippocampi of CUMS rats. These results indicated that icariin-NGSTH at a low dose produced a significant antidepressant effect. As a complex drug delivery system, intranasally administered icariin-NGSTH is a rapid and effective treatment for depression, increasing the antidepressant-like activity of icariin.