Abstract The regulatory mechanism of long non-coding RNAs (lncRNAs) in autophagy is as yet not well established. In this research, we show that the long non-coding RNA MLLT4 antisense RNA 1 (lncRNA MLLT4-AS1) is induced by the MTORC inhibitor PP242 and rapamycin in cervical cells. Overexpression of MLLT4-AS1 promotes autophagy and inhibits tumorigenesis and the migration of cervical cancer cells, whereas knockdown of MLLT4-AS1 attenuates PP242-induced autophagy. Mass spectrometry, RNA fluorescence in situ hybridization (RNA-FISH), and immunoprecipitation assays were performed to identify the direct interactions between MLLT4-AS1 and other associated targets, such as myosin-9 and autophagy-related 14(ATG14). MLLT4-AS1 was upregulated by H3K27ac modification with PP242 treatment, and knockdown of MLLT4-AS1 reversed autophagy by modulating ATG14 expression. Mechanically, MLLT4-AS1 was associated with the myosin-9 protein, which further promoted the transcription activity of the ATG14 gene. In conclusion, we demonstrated that MLLT4-AS1 acts as a potential tumor suppressor in cervical cancer by inducing autophagy, and H3K27ac modification-induced upregulation of MLLT4-AS1 could cause autophagy by associating with myosin-9 and promoting ATG14 transcription.
Objectives: To investigate the Relationship between visit-to-visit blood pressure variability and vascular elasticity and endothelial function in hypertensive patients. Methods: Collecting 169 cases of essential hypertensive patients and all participants were followed every three months. VBPV was indicated by a standard deviation of visit-to-visit blood pressure .According to tertile of visit-to-visit systolic blood pressure variability (VSBPV), all participants were divided into low VSBPV group (n = 56), medium VSBPV group (n = 57) and high VSBPV group (n = 56). Results: The changes of FMD and NO in low VSBPV group was significantly higher than that of medium and high VSBPV group, the difference was statistically significant (P < 0.05). The changes of ET-1, cfPWV and AIx in the low VSBPV group, was significantly higher than that of medium and high VSBPV group, the difference was statistically significant (P < 0.05). The difference was statistically significant (P < 0.05). The change of IMT in high VSBPV group was significantly higher than that in medium VSBPV group, the difference was statistically significant (P < 0.05). Changes of FMD and NO were significantly negatively correlated with VSBPV (P < 0.05).Yet,Changes of ET-1, cfPWV, IMT and AIx were significantly positively correlated with VSBPV (P < 0.05).Changes of FMD and NO were negatively correlated with VDBPV (P < 0.05). Changes of ET-1 and cfPWV were positively correlated with VDBPV (P < 0.05). Controlling other variables, VSBPV was independently related to the rate of change of AIx, IMT, cfPWV, NO, ET-1 and FMD. Conclusion: The variability of visit-to-visit blood pressure is closely correlated with vascular elasticity and endothelial function in essential hypertension patients.
Robust allogeneic immune reactions after transplantation impede the translational pace of human embryonic stem cells (hESCs)-based therapies. Selective genetic editing of human leucocyte antigen (HLA) molecules has been proposed to generate hESCs with immunocompatibility, which, however, has not been specifically designed for the Chinese population yet. Herein, we explored the possibility of customizing immunocompatible hESCs based on Chinese HLA typing characteristics. We generated an immunocompatible hESC line by disrupting HLA-B, HLA-C, and CIITA genes while retaining HLA-A*11:01 (HLA-A*11:01-retained, HLA-A11R ), which covers ~21% of the Chinese population. The immunocompatibility of HLA-A11R hESCs was verified by in vitro co-culture and confirmed in humanized mice with established human immunity. Moreover, we precisely knocked an inducible caspase-9 suicide cassette into HLA-A11R hESCs (iC9-HLA-A11R ) to promote safety. Compared with wide-type hESCs, HLA-A11R hESC-derived endothelial cells elicited much weaker immune responses to human HLA-A11+ T cells, while maintaining HLA-I molecule-mediated inhibitory signals to natural killer (NK) cells. Additionally, iC9-HLA-A11R hESCs could be induced to undergo apoptosis efficiently by AP1903. Both cell lines displayed genomic integrity and low risks of off-target effects. In conclusion, we customized a pilot immunocompatible hESC cell line based on Chinese HLA typing characteristics with safety insurance. This approach provides a basis for establishment of a universal HLA-AR bank of hESCs covering broad populations worldwide and may speed up the clinical application of hESC-based therapies.
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