LncRNA IRAIN overcomes imatinib resistance in chronic myeloid leukemia via NF-κB/CD44 pathway inhibition.

The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

CircSEC11A knockdown alleviates oxidative stress and apoptosis and promotes cell proliferation and angiogenesis by regulating miR-29a-3p/SEMA3A axis in OGD-induced human brain microvascular endothelial cells (HBMECs).

BACKGROUND: Circular RNA (circRNA) has been found to play an important role in the progression of many diseases, including ischemic stroke. However, the regulatory mechanism of circSEC11A in ischemic stroke progression need to further investigation. METHODS: Human brain microvascular endothelial cells (HBMECs) were stimulated by oxygen glucose deprivation (OGD). CircSEC11A, SEC11A mRNA and miR (microRNA)-29a-3p were quantified by quantitative real-time PCR (qRT-PCR). SEMA3A, BAX and BCL2 protein level was quantified by western blot. Oxidative stress, cell proliferation, angiogenesis and apoptosis abilities were gauged by oxidative stress assay kit, 5-Ethynyl-2'-Deoxyuridine (EdU) staining, tube formation assay and flow cytometry assays, respectively. Direct relationship between miR-29a-3p and circSEC11A or SEMA3A was validated by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. RESULTS: CircSEC11A was upregulated in OGD-induced HBMECs. OGD promoted the oxidative stress and apoptosis and inhibited cell proliferation and angiogenesis, while circSEC11A knockdown relieved the effects. CircSEC11A functioned as the sponge for miR-29a-3p, and miR-29a-3p inhibitor reversed the effects of si-circSEC11A on OGD-induced HBMECs oxidative injuries. Moreover, SEMA3A served as the target gene of miR-29a-3p. MiR-29a-3p inhibition ameliorated OGD-induced HBMECs oxidative injuries, while SEMA3A overexpression rescued the impacts of miR-29a-3p mimic. CONCLUSION: CircSEC11A promoted the malignant progression in OGD-induced HBMECs through the mediation of miR-29a-3p/SEMA3A axis. This study has provided the new insight into the underlying application of circSEC11A in cell model of ischemic stroke.

Effects of Vestibular Damage on the Sleep and Expression Level of Orexin in the Hypothalamus of Rats and Its Correlation with Autophagy and Akt Tumor Signal Pathway.

The aim of this study was to investigate the effect of vestibular disruption on autophagy-related proteins and the tumour-associated pathway P13K/Akt in rat sleep and its hypothalamus tissue and to examine whether catechins trigger tumour autophagy. Healthy adult male rats were randomly selected and divided into the vestibular damage group, the sham operation group, and the control group, with 8 rats in each group. A vestibular damage model was established through penetrating the tympanic membrane of the external auditory canal by injecting sodium p-aminophenylarsonate. The electroencephalogram (EGG) activity was used to record the sleep-wakefulness cycle of rats, and the expression levels of hypothalamic orexin (orexin) mRNA and autophagy proteins were detected. Primary hippocampal neurons were intervened with orexin at different concentrations and at different times to detect cell viability and the expression of autophagy protein and P13K/Akt signal pathway protein. The results showed that compared with the control group and the sham operation group, NREM duration in the vestibular damage group decreased significantly (P < 0.05), while its W time increased significantly (P < 0.05). The expression level of orexin mRNA in the hypothalamus of the vestibular damage group was significantly higher than that of the other two groups (P < 0.05), the expression of autophagy microtubule-related proteins LC3B and Beclin-1 increased significantly (P < 0.05), and the protein expression level of p62 decreased significantly (P < 0.05). After orexin intervention, compared with the control group, the expression of Beclin-1 protein that positively correlated with autophagy decreased significantly (P < 0.05) and the expression of mTOR, PDK1, and Akt protein increased significantly (P < 0.05). Compared with the orexin intervention group, the expression of Beclin-1 and LC3B proteins in cells of the orexin receptor inhibitor (Almorexant) group, the autophagy activator (Rapamycin) group, the orexin + Almorexant group, and the orexin + Rapamycin group increased significantly (P < 0.05), and the expression of mTOR, PDK1, and Akt proteins decreased significantly (P < 0.05). Catechins trigger autophagy in part by regulating the p-Akt/p-mTOR and P13K pathways and by stimulating the MAPK pathway. Catechins initiate apoptosis in common tumour types of hepatocellular carcinoma cells by activating autophagy-related pathways. The conclusion is that vestibular damage can affect the sleep-wakefulness cycle of rats; the level of autophagy in hypothalamic tissue is upregulated and may affect cell proliferation and activity through mTOR-P13K/Akt, which has a certain reference value for tumor formation and provides a basis for the research of insomnia or sleep disorders caused by tumors. Autophagy activation is a key process by which catechins promote apoptosis in tumour cells, providing an avenue for more research on the use of catechins-rich diets for cardiovascular protection in the treatment of tumours.

Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis.

Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( -) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABABR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( -) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.