Brain metastases (BMs) usually develop in breast cancer (BC) patients. Thus, the molecular mechanisms of breast cancer brain metastasis (BCBM) are of great importance in designing therapeutic strategies to treat or prevent BCBM. The present study attempted to identify novel diagnostic and prognostic biomarkers of BCBM. Two datasets (GSE125989 and GSE100534) were obtained from the Gene Expression Omnibus (GEO) database to find differentially expressed genes (DEGs) in cases of BC with and without brain metastasis (BM). A total of 146 overlapping DEGs, including 103 up-regulated and 43 down-regulated genes, were identified. Functional enrichment analysis showed that these DEGs were mainly enriched for functions including extracellular matrix (ECM) organization and collagen catabolic fibril organization. Using protein–protein interaction (PPI) and principal component analysis (PCA) analysis, we identified ten key genes, including LAMA4, COL1A1, COL5A2, COL3A1, COL4A1, COL5A1, COL5A3, COL6A3, COL6A2, and COL6A1. Additionally, COL5A1, COL4A1, COL1A1, COL6A1, COL6A2, and COL6A3 were significantly associated with the overall survival of BC patients. Furthermore, COL6A3, COL5A1, and COL4A1 were potentially correlated with BCBM in human epidermal growth factor 2 (HER2) expression. Additionally, the miR-29 family might participate in the process of metastasis by modulating the cancer microenvironment. Based on datasets in the GEO database, several DEGs have been identified as playing potentially important roles in BCBM in BC patients.

Although the memory- improving effect of crocin has been suggested by previous evidences, the association between this effect and hippocampal acetylcholine (Ach) level and apoptosis is not well investigated. This study aimed to determine the protective effects of crocin on memory, hippocampal Ach level, and apoptosis in a rat model of cerebral ischemia. Male Wistar rats were divided into sham group received saline, and other 3 groups underwent 4-vessel occlusion brain ischemia (4VOI), received oral administration of either saline or crocin in doses of 30 mg/day and 60 mg/day for 7 days. Outcomes were memory, determined by radial eight-arm maze (RAM) task and Morris water maze (MWM) test, Ach release in the dorsal hippocampus (evaluated by microdialysis-HPLC) and apoptosis (investigated by TUNEL assay). 4VOI impaired memory reduced dorsal hippocampus Ach level, and induced apoptosis. Crocin, significantly improved the memory (F = 343.20; P < 0.001 for RAM error choices and F = 182.5; P < 0.0001 for MWM), increased Ach level (F = 115.1; P < 0.001) and prevented hippocampal neuronal apoptosis (W = 183.50; P < 0.001) as compared statistically by ANOVA test. Crocin can be suggested as a promising therapy for ischemic cerebrovascular accidents by its memory preserving, Ach-increasing, and neuroprotective effects.

Epithelial-mesenchymal transition (EMT) is a pivotal event in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. In this study, we found that nobiletin, a polymethoxylated flavone, suppressed migration and invasion in both U87 and U251 glioma cells. Expression of epithelial markers (E-cadherin and occludin) was upregulated; mesenchymal markers (N-cadherin, fibronectin) and the transcriptional factor Slug were downregulated after nobiletin treatment. Transforming growth factor β (TGF-β) was applied to stimulate EMT and the results showed that nobiletin not only influenced basal level cell migration but also prevented TGF-β-triggered migration and EMT, with the AKT/GSK3β/β-catenin signaling pathway greatly involved. Furthermore, nobiletin remarkably diminished TGF-β-induced β-catenin nuclear translocation and the binding to the Slug promoter. It is worth noting that nobiletin almost blocked invasion in Slug-expressing U87 and U251 cells, and only exhibiting faint effect on non-Slug-expressing U343 glioma cells. Reinforced Slug expression in U343 cells by transfecting Slug plasmid was significantly attenuated by nobiletin, demonstrating the essential role of Slug in the anti-metastasis effect of nobiletin. Nobiletin repressed tumor growth in vivo and abrogated EMT in nude mice bearing U87-Luc xenografts, as demonstrated by Xenogen IVIS imaging and immunohistochemistry assay. Our findings suggested that nobiletin might have a great potential for treating glioblastoma.