Identification of Hub genes with prognostic values in colorectal cancer by integrated bioinformatics analysis.

BACKGROUND: Our study aimed to investigate the Hub genes and their prognostic value in colorectal cancer (CRC) via bioinformatics analysis. METHODS: The data set of colorectal cancer was downloaded from the GEO database (GSE21510, GSE110224 and GSE74602) for differential expression analysis using the GEO2R tool. Hub genes were screened by protein-protein interaction (PPI) comprehensive analysis. GEPIA was used to verify the expression of Hub genes and evaluate its prognostic value. The protein expression of Hub gene in CRC was analyzed using the Human Protein Atlas database. The cBioPortal was used to analyze the type and frequency of Hub gene mutations, and the effects of mutation on the patients' prognosis. The TIMER database was used to study the correlation between Hub genes and immune infiltration in CRC. Gene set enrichment analysis (GSEA) was used to explore the biological function and signal pathway of the Hub genes and corresponding co-expressed genes. RESULTS: We identified 346 differentially expressed genes (DEGs), including 117 upregulated and 229 downregulated. Four Hub genes (AURKA, CCNB1, EXO1 and CCNA2) were selected by survival analysis and differential expression validation. The protein and mRNA expression levels of AURKA, CCNB1, EXO1 and CCNA2 were higher in CRC tissues than in adjacent tissues. There were varying degrees of immune cell infiltration and gene mutation of Hub genes, especially B cells and CD8+ T cells. The results of GSEA showed that Hub genes and their co-expressed genes mainly participated in chromosome segregation, DNA replication, translational elongation and cell cycle. CONCLUSION: Overexpression of AURKA, CCNB1, CCNA2 and EXO1 had a better prognosis for CRC and this effect was correlation with gene mutation and infiltration of immune cells.

Tripchlorolide Attenuates ß-amyloid Generation via Suppressing PPARγ-Regulated BACE1 Activity in N2a/APP695 Cells.

Due to its apparent rate-limiting function, BACE1 (ß-secretase) appears to be a prime target for prevention of amyloid-ß (Aß) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor binding site of the BACE1 promoter, indicating that PPARγ may be a potential target for AD treatment. Several studies have demonstrated that PPARγ activation is involved in the immunostimulation of amyloid-ß precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T4), with a similar chemical structure to that of NSAIDs, decreased the levels of Aß secreted in N2a-APP695 cells. T4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPPß, a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARγ from cytoplasm to nuclear. Intriguingly, T4, like pioglitazone (a PPARγ agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARγ antagonist). These results indicate that T4 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of Aß. Due to its capability to alter Aß generation and to protect central neural system against the neurotoxicity of Aß, T4 may serve as a promising agent in modulating Aß-related pathology in Alzheimer's disease.

Ginsenoside Rg1 attenuates amyloid-beta content, regulates PKA/CREB activity, and improves cognitive performance in SAMP8 mice.

It is well established that the presence of soluble amyloid-beta protein (Abeta) correlates with the severity of dementia in Alzheimer's disease (AD). Several lines of evidence indicate that cyclic AMP responsive element binding protein (CREB) and protein kinase A (PKA) are involved in soluble Abeta-trigged disruption of synaptic plasticity in early AD. Previously we demonstrated the beneficial effects of ginsenoside Rg1 on Abeta-induced neuronal insult. Therefore, in the present study, we examined the effects of long-term consumption of Rg1 on the cerebral Abeta content and PKA/CREB signaling molecules, as well as cognitive performance in senescence-accelerated mouse prone 8 (SAMP8). Notably, a significant dose-dependent reduction of soluble Abeta(1-40) was shown in the hippocampus of SAMP8 mice after administration with ginsenoside Rg1 for 3 months. Furthermore, Rg1 treatment resulted in a significant decrease of hippocampal PKA RIIalpha level (isoform IIalpha of the regulatory subunit of PKA). In contrast, phospho-CREB and brain derived neurotrophic factor (BDNF) levels were dramatically increased in the hippocampus of SAMP8 treated with Rg1. Additionally, administration of ginsenoside Rg1 consequently improved learning and memory outcomes in SAMP8 mice. These data suggest that long-term consumption of ginsenoside Rg1 may delay cognitive decline, associated with significant effects on Abeta generation, PKA/CREB activity, as well as BDNF content in the brain. These data provide further support for the therapeutic or intervention potency of ginsenoside Rg1 in the early stage of AD.