RESUMEN
BACKGROUND: Intracranial aneurysm (IA) is a cerebrovascular disease with a high mortality rate due to ruptured subarachnoid hemorrhage. While Krüppel-like factor 6 (KLF6) dysregulation has been implicated in cancer and cardiovascular diseases, its role in IA remains unclear. MATERIALS AND METHODS: The GSE122897 and GSE15629 datasets were downloaded from the Gene Expression Omnibus database. Immune cell infiltration and hypoxia analysis were performed to explore the effects of KLF6 on IA. Weighted gene co-expression network analysis was used to identify hub genes related to KLF6 expression for subsequent analyses. Hypoxia-related genes were identified. Drug prediction was performed for IA. Samples from healthy individuals and patients with IA were collected to detect the expression of endothelin-1 (ET-1), vascular hematoma factor (vWF), and KLF6. A model of H2O2-induced human brain vascular smooth muscle cells (HBVSMC) injury was constructed to explore the effects of KLF6 and melatonin to treat IA. RESULTS: T cells CD4 memory resting and monocytes were significantly different in the KLF6 high and low expression groups. Four hypoxia-related gene sets were significantly enriched in the KLF6 high-expression group. Six hypoxia-related hub genes were obtained, which were significantly associated with KLF6. Drug prediction showed that melatonin may be a potential drug for IA. The levels of ET-1, vWF, and KLF6 were significantly upregulated in patients with IA. KLF6 exacerbates H2O2-induced injury in HBVSMC, ameliorated by melatonin. CONCLUSION: KLF6 may be a potential target for IA treatment, with melatonin-mediated KLF6 effects playing a crucial role in the development of IA.
KLF6 was associated with infiltrated immune cells and hypoxia genes in intracranial aneurysm.KLF6 was significantly upregulated in patients with intracranial aneurysm.KLF6 exacerbates H2O2-induced injury in HBVSMC, ameliorated by melatonin.
Asunto(s)
Aneurisma Intracraneal , Factor 6 Similar a Kruppel , Melatonina , Humanos , Factor 6 Similar a Kruppel/genética , Factor 6 Similar a Kruppel/metabolismo , Aneurisma Intracraneal/genética , Aneurisma Intracraneal/metabolismo , Aneurisma Intracraneal/tratamiento farmacológico , Endotelina-1/metabolismo , Endotelina-1/genética , Masculino , Músculo Liso Vascular/metabolismo , FemeninoRESUMEN
The epidermal growth factor receptor (EGFR) has been well validated as a therapeutic target for anticancer drug discovery. Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy. However, a tertiary Cys797 to Ser797 (C797S) point mutation has hampered osimertinib treatment in patients with advanced EGFR-mutated NSCLC. Several classes of fourth-generation EGFR inhibitors were consequently discovered with the aim of overcoming the EGFRC797S mutation-mediated resistance. However, no clinical efficacy data of the fourth-generation EGFR inhibitors were reported to date, and EGFRC797S mutation-mediated resistance remains an "unmet clinical need." Proteolysis-targeting chimeric molecules (PROTACs) obtained from EGFR-TKIs have been developed to target drug resistance EGFR in NSCLC. Some PROTACs are from nature products. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.