ABSTRACT
ß-Elemene, a compound extracted from Chinese herb Curcuma wenyujin, has been demonstrated with antitumor effects in various cancers, including glioblastoma (GBM), a primary brain tumor with high morbidity and mortality. In this study, we reported a bisamino derivative of ß-Elemene, 2, 2'-((1R, 3R, 4S)-4-methyl-4-vinylcyclohexane-1, 3-diyl) bis(prop-2-en-1-amine) (compound 1), displayed a better anti-GBM effect than ß-Elemene with lower concentration. GBM cell lines (C6 and U87) were treated with compound 1 and subsequently analyzed by several assays. Compound 1 significantly inhibited the migration of C6 and U87 cells based on wound healing assay, transwell assay and inverted migration assay. Furthermore, colony formation assay, immunostaining and flow cytometry assays revealed that compound 1 significantly inhibited the proliferation of GBM cells. In addition, compound 1 induced the apoptosis of GBM cells. Mechanistically, we found Yes-associated protein (YAP) was down-regulated in compound 1-treated GBM cells, and the overexpression of YAP partially rescued the anti-GBM effects of compound 1. Finally, compound 1 suppresses the GBM growth in xenograft model through inactivation YAP signaling. Taken together, these results reveal that a novel derivative of ß-Elemene, compound 1, exhibits more potent anti-GBM activity than ß-Elemene through inactivating YAP signaling pathway, which will provide novel strategies for the treatment of GBM.
ABSTRACT
Pancreatic cancer is a highly malignant type of cancer and its treatment remains a major challenge. The novel recombinant protein TNF-related apoptosis-inducing ligand (TRAIL)-Mu3 has been shown to exert stronger tumor inhibitory effects in colon cancer in vitro and in vivo compared with TRAIL. The present study investigated the antitumor effects of TRAIL-Mu3 on pancreatic cancer cells, and the possible mechanisms were further examined. Compared with TRAIL, TRAIL-Mu3 exhibited significantly higher cytotoxic effects on pancreatic cancer cell lines. The inhibitory effect of TRAIL-Mu3 on the viability of PANC-1 cells was shown to be a caspase-dependent process. The affinity of TRAIL-Mu3 to PANC-1 cell membranes was significantly enhanced compared with TRAIL. In addition, TRAIL-Mu3 upregulated death receptor (DR) expression in PANC-1 cells and promoted the redistribution of DR5 in lipid rafts. Western blotting results demonstrated that TRAIL-Mu3 activated the caspase cascade in a faster and more efficient manner compared with TRAIL in PANC-1 cells. Therefore, TRAIL-Mu3 enhanced the antitumor effects in pancreatic cancer cells by strengthening the apoptotic signaling pathway. The present study indicated the potential of TRAIL-Mu3 for the treatment of pancreatic cancer.
ABSTRACT
Objective To investigate the relationship between cholinergic pathway damage and the executive dysfunction of patients with different degrees of cognitive impairment caused by cerebral white matter lesions(WML). Methods From March,2016 to December,2017,115 patients were recruited,whose characteristics,such as age,gender, education,and history of hypertension,diabetes and stroke were recorded.According to the T2-weighted MRI,80 patients were defined as WML.WML patients were divided into cognitively normal(CN)group(n=41),vascular cognitive impairment of none dementia(VCIND)group(n=21)and vascular dementia(VaD)group(n=18)ac-cording to the result of Montreal Cognitive Assessment(MoCA)and Clinical Dementia Rating(CDR).Other 35 cases without WML and cognitive impairment were as control group.WML under MRI were evaluated with Cho-linergic Pathways Hyperintensities Scale(CHIPS).All the WML patients were assessed with Stroop Color-Word Test,Trail Making Test, Symbol Digital Modalities Test, and Verbal Fluence Test.The correlation between the scores of CHIPS and the executive tests were analysed. Results There was no significant difference in age, gender, level of education, and cardiovascular disease risk factors among four groups(P>0.05),but there were significant differences in scores of MoCA and CHIPS(F>25.781,P<0.001),while the score of MoCA was the least(P<0.01)and the scores of CHIPS were the most in VaD group (P<0.001).The CHIPS scores of left and bilateral hemisphere negatively correlated with all the scores of execu-tive tests(P<0.05),while that of the right hemisphere just correlated with the scores of some executive tests(P<0.05). Conclusion For cognitive impairment after WML,cholinergic pathway damage may relate with the executive function impairment,especially the damage in left cerebral hemisphere.
