Aim Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique showing improvement effects on Parkinson’s disease (PD). Multiple microRNAs (miRs) are dys-expressed during the progression of PD. In the current study, the potential involvement of miRs in the anti-PD effects of rTMS was explored.Methods PD symptoms were induced in mice with 6-OHDA. The expression profile of miRs influenced by rTMS in PD mice was detected by microarray technique and validated by RT-qPCR detection. The PD mice were treated with rTMS and the changes in cognitive behaviors, substantia nigra neuron number, brain histology, and Aβ1-42 level were detected. The activity of miR-409-3p/PDHB axis was also detected to preliminarily explain the interaction between miRs and rTMS.Results The detection of microarray showed that 266 miRs were dys-expressed in PD mice after the administration of rTMS, including 101 up-regulated ones and 146 down-regulated ones. With validation by RT-qPCR detection, miR-409-3p was selected for subsequent assays. Administrations of rTMS improved cognitive behaviors of mice, increased neuron number, and attenuated brain injuries induced by 6-OHDA. The cerebrospinal fluid (CSF) level of Aβ1-42 was induced, while the brain level of Aβ1-42 was suppressed by rTMS. Regarding miR-409-3p/PDHB axis, rTMS administrations suppressed miR-409-3p level and increased the expression of PDHB.Conclusion Administrations of rTMS showed considerable protective effects on brain tissues against PD-induced injuries, which was associated with the changes in miR levels. The current study demonstrated that the inhibition of miR-409-3p by rTMS contributed to the attenuation of PD by inducing PDHB.
Background Radiotherapy is commonly used for locoregionally advanced NSCLC, but radioresistance is a clinical challenge. The long non-coding RNA CBR3-AS1 mediates radioresistance in NSCLC, yet the underlying molecular mechanism is unclear. This study aims to explore whether and how N6-methyladenosine (m6A) modification regulates CBR3-AS1 expression and promotes NSCLC radioresistance. Methods Integrative bioinformatics analyses were used to investigate the m6A methyltransferases that were associated with CBR3-AS1 expression and radioresistance of patients using data from The Cancer Genome Atlas of lung adenocarcinoma and squamous cell carcinoma. Clinical samples of 133 patients with NSCLC was collected to validate the correlation of the methyltransferase with radioresistance. The functional role and molecular mechanism of the methyltransferase in radioresistance was investigated through a series of in vitro experiments including m6A MeRIP-PCR, lentivirus transfection, RNA immunoprecipitation, Luciferase reporter, Colony formation, Transwell invasion, Flow cytometry, ELISA and TUNEL assay and in vivo experiments. Results The methyltransferase RNA binding motif protein 15 (RBM15) was identified as it was significantly positively correlated with CBR3-AS1 expression and overall survival of NSCLC patients receiving radiotherapy. The clinical samples demonstrated that the high protein expression of RBM15 was significantly enriched in patients with radioresistance as well as associated with poor prognosis of patients receiving radiotherapy. In vitro, RBM15 silencing enhanced the effects of radiation on the growth and invasion inhibition, and apoptosis induction of NSCLC cells; RBM15 overexpression had the opposite effects. Mechanistically, RBM15 induced CBR3-AS1 upregulation via an m6A-IGF2BP3-dependent mechanism, inducing CXCL1 expression by sponging miR-409-3p to recruit myeloid-derived suppressor cells (MDSCs) and inhibit T cell activity. In vivo, RBM15 silencing suppressed MDSC invasiveness and enhanced CD8 + and CD4 + T cell infiltration, causing NSCLC cells to overcome radioresistance. Conclusion Our study identifies methyltransferase RBM15 as a potential therapeutic target for NSCLC radioresistance whose inhibition reverses resistance through limiting MDSC recruitment via the m6A-IGF2BP3-CBR3-AS1/miR-409-3p/CXCL1 axis. Graphical
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