Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA.

Endometrial cancer (EC) is a prevalent gynecological malignancy worldwide, and 5-methylcytosine (m5C) modification of mRNA is a crucial epigenetic modification associated with the development and occurrence of several cancers. However, the precise function of m5C modification in EC remains elusive. This study aimed to investigate the expression and clinical significance of the primary m5C modification writer, NSUN2, in EC. Our findings indicated that NSUN2 exhibited a substantial up-regulation in EC as a result of an epigenetic augmentation in H3K4me3 levels within the promoter region, which was triggered by the down-regulation of KDM5A. Moreover, gain- and loss-of-function experiments revealed the role of NSUN2 in enhancing m5C modification of mRNA, thereby promoting EC cell proliferation. RNA bisulfite sequencing and transcriptomic sequencing were employed to elucidate the involvement of NSUN2 in the regulation of ferroptosis. Subsequent in vitro experiments confirmed that the knockdown of NSUN2 significantly up-regulated the levels of lipid peroxides and lipid ROS in EC cells, thereby augmenting the susceptibility of EC to ferroptosis. Mechanistically, NSUN2 stimulated the m5C modification of SLC7A11 mRNA, and the m5C reader YBX1 exhibited direct recognition and binding to the m5C sites on SLC7A11 mRNA via its internal cold shock domain (CSD), leading to an increase in SLC7A11 mRNA stability and elevated levels of SLC7A11. Additionally, rescue experiments showed that NSUN2 functioned as a suppressor of ferroptosis, which was dependent on SLC7A11. Overall, targeting the NSUN2/SLC7A11 axis inhibited tumor growth by increasing lipid peroxidation and ferroptosis of EC cells both in vitro and in vivo. Therefore, our study provides new insight into the role of NSUN2, suggesting that NSUN2 may serve as a prognostic biomarker and therapeutic target in patients with EC.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

Quaternary ammonium chitosan derivative dynamic coating for the separation of veterinary sulfonamide residues by CE with field-amplified sample injection.

A quaternary ammonium chitosan, 2-hydroxypropyltrimethylammonium chloride chitosan (HACC), has been developed for the dynamic coating material in CE for the first time. It presented many advantages such as favorable water solubility, satisfactory coating efficiency, and EOF toward the anode at pH >7.0. Using the modified fused-silica capillary, sulfonamides (SAs), an important group of veterinary drugs, were separated and detected by CE combined with field-amplified sample injection (FASI). The LODs of sulfonamides with UV detection were less than 0.5 ng/mL. The proposed method has been applied to the determination of veterinary sulfonamide residues in samples such as chicken, beef, and honey with fast separation (15 sulfonamides within 20 min), low LODs (0.1-0.5 ng/mL), and good reliability compared to the criteria of China (GB/T 18932.17-2003).