The design of a cross-acridine scaffold mimicking the i, i+3, i+5, and i+7 residues distributed over a two-face, two-turn α-helix is described. Docking studies and 2D (1)H, (15)N HSQC NMR spectroscopy provide compelling evidence that compound 3 d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl-1 and Bcl-2 proteins (Ki 0.079 and 0.056 μM, respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold.
Purpose
The aim of this study was to screen survival‐related genes for glioblastoma (GBM).
Methods
GSE53733 was downloaded from Gene Expression Omnibus (GEO) database, including 16 short‐term (ST), 31 intermediate (IM), and 23 long‐term (LT) survivors. Analysis of variance was used to analyze the expression in three groups. The genes with P < .01 were screened as differentially expressed genes (DEGs). Soft clustering was performed using Mfuzz to mine the expression patterns of differential genes in three groups of overall survival (OS) classification. The cytoscape plugin clueGO was used for functional enrichment analysis. The protein interaction between differential genes was extracted from the STRING V10 database, and the protein‐protein interaction (PPI) network was constructed and displayed with cytoscape. The hub genes were verified by quantitative reverse‐transcription polymerase chain reaction.
Results
Total 662 DEGs were obtained among three groups and enriched in 12 clusters. The overlap analysis between clusters could classify these 12 clusters Cluster A and B. Total 264 OS.DEGs were contained in Cluter A and Cluster B, and enriched in 28 Gene Ontology terms, such as trophoblast giant cell differentiation (P value = 6.18E−04), muscle fiber development (P value = 9.09E−04), and negative regulation of stem cell differentiation (P value = 1.76E−03). The top five nodes with highest degree in OS.PPI were HDAC1, DECR1, RASL11A, PDIA3, and POLR2F. The expression of DECR1 and POLR2F was significantly lower, while the levels of HDAC1 and PDIA3 were highly expressed in GBM tissues.
Conclusion
DECR1, POLR2F, HDAC1, and PDIA3 might be potential key genes affected the overall survival time of patients with GBM.
Ginsenoside Rb1 is a potential anti-inflammatory natural molecule, but its therapeutic efficacy was tremendously hampered by the low solubility and non-targeted delivery. In this study, we innovatively developed a mannose (Man)-modified albumin bovine serum albumin carrier (Man-BSA) to overcome the previously mentioned dilemmas of Rb1. The constructed Man-BSA@Rb1 NPs could improve the solubility and increase the cellular uptake of Rb1, finally leading to the enhanced anti-inflammatory effects. The robust therapeutics of Man-BSA@Rb1 NPs were measured in terms of nitrite, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels, which might be achieved by potently inhibiting nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in lipopolysaccharide (LPS)-induced Raw264.7 cells. Moreover, the therapeutic efficacy of Man-BSA@Rb1 NPs was further confirmed in the d-Gal/LPS-induced liver injury model. The results indicated that Man-BSA may offer a promising system to improve the anti-inflammatory therapy of Rb1.
Background: Manoalide (MA), a proven natural inhibitor of PLA2 has anticancer effects, but its potential application and mechanism as an anticancer drug to promote EGFR-TKI sensitivity in lung cancer cells have not been studied.Methods: KRAS-mutated lung cancer cells and organoids, acquired osimertinib-resistant lung cancer cell lines HCC827OR, were used as EGFR-TKI-resistant models. CCK-8, clone formation, apoptosis assays, and calcein-AM staining were performed to investigate the inhibitory effects of MA in lung cancer cells and organoids. The flow cytometry or confocal microscope was used to detect lipid droplets, ROS, lipid peroxidation, mitochondria Ca2+, and iron content. The oxygen consumption rate (OCR) and fatty acid oxidation (FAO) were used to estimate the effect of MA on mitochondrial function.Results: MA inhibits the proliferation of KRAS-mutated lung cancer cells and organoids. In addition, MA induces ER stress in a ROS-dependent mechanism. The ROS induced by MA is mainly in mitochondrial and causes lipid peroxidation, thereby inhibiting mitochondrial FAO metabolism and promoting the accumulation of lipid droplets. MA also suppresses the KRAS-ERK pathway through ROS and promotes the sensitivity of KRAS-mutated lung cancer cells and organoids to osimertinib. Furthermore, MA induces ferroptosis by suppressing the NRF2-SLC7A11 axis and mitochondrial Ca2+ overload induced-FTH1 pathways to promote the sensitivity of osimertinib-resistant lung cancer cells to osimertinib.Conclusions: MA is a candidate EGFR-TKI sensitizer in KRAS-mutated and osimertinib-resistant lung cancer cells.
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