ABSTRACT
Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent types of malignant tumours. Metastasis is the leading cause of cancer-related mortality, with lung metastases accounting for 32.9% of all metastatic CRCs. However, since the biological mechanism of lung metastatic CRC is poorly understood, limited therapeutic targets are available. In the present study, we aimed to identify the key genes and molecular processes involved in CRC lung metastasis. METHODS: The differentially expressed genes (DEGs) between primary and lung metastatic CRC patients were obtained from the Gene Expression Omnibus (GEO) database via the GEO2R tool. The enriched biological processes and pathways modulated by the DEGs were determined with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome Gene Sets analyses. The search tool Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct a protein-protein interaction (PPI) network among DEGs. RESULTS: The DEGs were enriched in surfactant metabolism, cell-cell communication and chemokine signaling pathways. The defined hub genes were included CLU, SFTPD, CCL18, SPP1, APOE, BGN and MMP3. Among them, CLU, SFTPD and CCL18 might be associated with the specific lung tropism metastasis in CRC. In addition, the expression and prognostic values of the hub genes in CRC patients were verified in database of The Cancer Genome Atlas (TCGA) and GEO. Moreover, the protein levels of the hub genes were detected in primary and lung metastatic CRC cells, serum or tissues. Furthermore, SFTPD was confirmed to facilitate cellular proliferation and lung metastasis in CRC. CONCLUSION: This bioinformatics study may provide a better understanding of the candidate therapeutic targets and molecular mechanisms for CRC lung metastasis.
