Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future.
Selective separation and enrichment of phosphoproteins are essential for understanding their important functions in almost all cellular processes. Here, taking advantage of the feature that cadmium ion (Cd2+) has an overwhelming preference for phosphates, we developed a robust and simple Cd2+ co‐precipitation strategy for the selective isolation of intact phosphoproteins. After evaluating the feasibility of Cd2+ in phosphoprotein precipitation, we compared the washing protocols for the removal of non‐specific binding proteins and then used the best‐performing protocol for the isolation of phosphoproteins from different complex samples. It was found that phosphoproteins can be specifically enriched from artificial protein mixtures containing α‐casein, β‐casein, and bovine serum albumin or plasma, in which bovine serum albumin or plasma were served as interferences with very high molar ratios. Applying this method to enrich phosphoproteins from complex cell lysates, a high specificity was confirmed by western blotting analysis with a phosphoprotein‐specific kit. Finally, we successfully applied this method to the purification of caseins from drinking milk, highlighting its potential application in the studies where purified phosphoproteins were required. In a word, this Cd2+ co‐precipitation method enables universal and effective capture, enrichment, and detection of intact phosphoproteins, making it a powerful tool for the comprehensive analysis of the phosphoproteome.
Fully polarimetric synthetic aperture radar (PolSAR) data are represented by four channels and the coherences between two arbitrary channels are important descriptors for the interpretation of polarimetric scattering mechanisms. However, there exists a scattering ambiguity between oriented urban and natural areas since they both contribute to the cross-polarised (HV) scattering. A polarimetric correlation coefficient ratio is proposed to overcome this scattering ambiguity in PolSAR imagery. First, the polarimetric coherences of urban areas with various orientation angles were analysed. Subsequently, it was found that the proposed coherence parameter considers the reflection asymmetry of buildings and also the scattering divergence between co-polarised and cross-polarised channels, which is beneficial to the scattering analysis in urban areas. The effectiveness of the proposed parameter is demonstrated using the Phased Array type L-band Synthetic Aperture Radar dataset.
Background: Xiao-Xian-Xiong decoction is a useful formula in the treatment of atherosclerosis in traditional Chinese medicine. In this study, we aimed to investigate the function of Xiao-Xian-Xiong decoction in the treatment of atherosclerosis. Methods: In this study, we conducted the method of network pharmacology and molecular docking to discover the mechanism of Xiao-Xian-Xiong decoction against atherosclerosis. Then, we validated the function of Xiao-Xian-Xiong decoction in atherosclerosis in vitro. We investigated the function and mechanism of Xiao-Xian-Xiong decoction in RAW264.7 macrophage-derived foam cells.Results: We identified 213 targets of Xiao-Xian-Xiong decoction and 331 targets of atherosclerosis. The PPI networks of Xiao-Xian-Xiong decoction and atherosclerosis were constructed. Furthermore, the two PPI networks were merged and the core PPI network was obtained. Then, functional enrichment analysis was conducted with GO and KEGG signaling pathway analysis. KEGG analysis indicated Xiao-Xian-Xiong decoction was correlated with ubiquitin mediated proteolysis pathway, PI3K-AKT pathway, MAPK pathway, Notch signaling pathway, and TGF-β signaling pathway. At last, we validated the function of Xiao-Xian-Xiong decoction with atherosclerosis in vitro. Xiao-Xian-Xiong decoction reduced lipid accumulation and promoted the outflow of cholesterol in RAW264.7-derived foam cells. Xiao-Xian-Xiong decoction increased the expression of ABCA1 and ABCG1 protein in foam cells. ABCA1 and ABCG1 were related with regulation of the inflammatory pathway and cell proliferation in atherosclerosis.Conclusions: Combined the mechanism of available treatments of atherosclerosis, we inferred Xiao-Xian-Xiong decoction could alleviate atherosclerosis by inhibiting inflammatory response and cell proliferation.
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