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Changgui Shi, Ping Huang, Hui Kang, Bo Hu, Jin Qi, Min Jiang, Hanbing Zhou, Lei Guo, and Lianfu Deng

The inhibition of osteoblast proliferation by glucocorticoids (GCs) is very important in the etiology of GC-induced osteoporosis. The mechanisms of this process are still not fully understood. The results of recent studies have indicated an important role for microRNAs in GC-mediated responses in various cellular processes, including cell proliferation and apoptosis. Therefore, we developed the hypothesis that these regulatory molecules might be involved in GC-decreased osteoblast proliferation. Western blotting, quantitative real-time PCR, cell proliferation assays, and luciferase assays were employed to investigate the role of miRNAs in GC-inhibited osteoblast proliferation. microRNA-199a-5p was significantly increased in osteoblasts treated with dexamethasone (Dex). To delineate the role of microRNA-199a-5p, we silenced and overexpressed microRNA-199a-5p in osteoblasts. We found that overexpressing microRNA-199a-5p remarkably increased the inhibition effect of Dex on osteoblast proliferation, and depleting microRNA-199a-5p significantly attenuated Dex-inhibited osteoblast proliferation. Results of mechanistic studies indicated that microRNA-199a-5p inhibited FZD4 and WNT2 expression through a microRNA-199a-5p binding site within the 3′-UTR of FZD4 and WNT2. The post-transcriptional repression of FZD4 and WNT2 were further confirmed by luciferase reporter assay. These results indicated that microRNA-199a-5p may play a significant role in GC-inhibited osteoblast proliferation by regulating the WNT signaling pathway.

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Feng Wang, Lu Wang, Yifeng Wang, Dai Li, Tianpeng Hu, Manyi Sun, and Ping Lei

Insulin-like growth factor-1 (IGF-1) improves cognitive function, but its mechanism has not been elucidated. The aim of the study was to explore whether IGF-1 exerted its protective effect on cognitive function and anxiety behavior through the activation of PI3K/Akt/CREB pathway in high-fat diet rats. Neuronal cells HT22 were treated with nothing, IGF-1, IGF-1 + LY294002 or IGF-1 + 666-15. Expressions of p-PI3K, p-Akt and p-CREB were measured using Western blot analysis. Thirty C57BL/6J rats were used. After feeding with high-fat diet, normal saline, PEG-IGF-1, PEG-IGF-1 + LY294002 or PEG-IGF-1 + 666-15 was treated. Cognitive function and anxiety behavior were assessed by Morris water maze and open field test. Several inflammation and oxidative stress biomarkers were measured using recognized methods. Expressions of p-PI3K and p-CREB were also measured using Western blot analysis. After IGF-1 treatment in cells, expressions of p-PI3K, p-Akt and p-CREB were increased. Furthermore, LY294002 downregulated the expressions of these three proteins, but 666-15 only inhibited the expression of CREB in the cells. Compared with the control rats, we found abnormalities of cognitive function and anxiety behavior, inhibition of PI3K/Akt/CREB pathway and increase of oxidative stress and inflammation in high-fat diet rats. After PEG-IGF-1 treatment, the changes in high-fat diet rats were reversed. Then, we blocked the pathway and found that these blockers attenuated the protective effects of PEG-IGF-1. In conclusion, IGF-1 improved cognitive function and anxiety behavior in high-fat diet rats and inhibited inflammation and oxidative stress in hippocampus tissue through the activation of PI3K/Akt/CREB pathway.

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He-jun Zhao, Xia Jiang, Li-juan Hu, Lei Yang, Lian-dong Deng, Ya-ping Wang, and Zhi-peng Ren

This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.