One of modern biology’s great surprises is that the human genome encodes only ~20,000 protein-coding genes, which represents less than 2% of the total genome sequence, and the majority of them are transcribed into non-coding RNAs (ncRNAs). Increasing evidence has shown that ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating a wide range of biological processes of the human brain. They not only regulate the pathogenesis of brain tumors, but also the development of neuropsychiatric diseases. This review provides an integrated overview of the roles of ncRNAs in normal human brain function, brain tumor development, and neuropsychiatric disease. We discussed the functions and molecular mechanisms of miRNAs, lncRNAs, and circRNAs in normal brain function and glioma, respectively, including those in exosome vesicles that can act as a molecular information carrier. We also discussed the regulatory roles of ncRNAs in the development of neuropsychiatric diseases. Lastly, we summarized the currently available platforms and tools that can be used for ncRNA identification and functional exploration in human diseases. This study will provide comprehensive insights for the roles of ncRNAs in human brain function and disease.

Anaplastic thyroid cancer is an extremely lethal malignancy without reliable treatment. BRAFV600E point mutation is common in ATCs, which leads to MAPK signaling activation and is regarded as a therapeutic target. Resveratrol inhibits ATC cell growth, while its impact on BRAF-MAPK signaling remains unknown. This study aims to address this issue by elucidating the statuses of BRAF-MAPK and STAT3 signaling activities in resveratrol-treated THJ-11T, THJ-16T, and THJ-21T ATC cells and Nthyori 3-1 thyroid epithelial cells. RT-PCR and Sanger sequencing revealed MKRN1-BRAF fusion mutation in THJ-16T, BRAF V600E point mutation in THJ-21T, and wild-type BRAF genes in THJ-11T and Nthyori 3-1 cells. Western blotting and immunocytochemical staining showed elevated pBRAF, pMEK, and pERK levels in THJ-16T and THJ-21T, but not in THJ-11T or Nthyori 3-1 cells. Calcein/PI, EdU, and TUNEL assays showed that compared with docetaxel and doxorubicin and MAPK-targeting dabrafenib and trametinib, resveratrol exerted more powerful inhibitory effects on mutant BRAF-harboring THJ-16T and THJ-21T cells, accompanied by reduced levels of MAPK pathway-associated proteins and pSTAT3. Trametinib- and dabrafenib-enhanced STAT3 activation was efficiently suppressed by resveratrol. In conclusion, resveratrol acts as dual BRAF-MAPK and STAT3 signaling inhibitor and a promising agent against ATCs with BRAF mutation.

Glioblastoma multiforme (GBM) is the most common lethal primary brain malignancy without reliable therapeutic drugs. IL-13Rα2 is frequently expressed in GBMs as a molecular marker. Resveratrol (Res) effectively inhibits GBM cell growth but has not been applied in vivo because of its low brain bioavailability when administered systemically. A sustained-release and GBM-targeting resveratrol form may overcome this therapeutic dilemma. To achieve this goal, encapsulated Res 30 ± 4.8 nm IL-13Rα2-targeting nanoparticles (Pep-PP@Res) were constructed. Ultraviolet spectrophotometry revealed prolonged Res release (about 25%) from Pep-PP@Res in 48 h and fluorescent confocal microscopy showed the prolonged intracellular Res retention time of Pep-PP@Res (>24 h) in comparison with that of free Res (<4 h) and PP@Res (<4 h). MTT and EdU cell proliferation assays showed stronger suppressive effects of Pep-PP@Res on rat C6 GBM cells than that of PP@Res (p = 0.024) and Res (p = 0.009) when used twice for 4 h/day. Pep-PP@Res had little toxic effect on normal rat brain cells. The in vivo anti-glioblastoma effects of Res can be distinctly improved in the form of Pep-PP@Res nanoparticles via activating JNK signaling, upregulating proapoptosis gene expression and, finally, resulting in extensive apoptosis. Pep-PP@Res with sustained release and GBM-targeting properties would be suitable for in vivo management of GBMs.

Glioblastoma multiforme (GBM) is the commonest primary brain malignancy with extremely poor prognosis. Resveratrol posseses anti-cancer effects, while GBM cells respond differently to it due to certain unknown reason(s). Because the tumor-derived exosomes are supposed to influence chemosensitivity, the exosomic proteins released from resveratrol-sensitive U251 and resveratrol-resistant glioblastoma LN428 cells are profiled before (N/Exo) and after drug treatment (Res/Exo) by label-free liquid chromatography-mass spectrometry (LC-MS). The therapeutic implications of the proteomic findings are estimated by gene ontology enrichment analysis (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG)-based bioinformatic analyses and further elucidated by exosome co-incubating. The results reveal that U251/N/Exo but not U251/Res/Exo enhances resveratrol sensitivity of resveratrol-resistant LN428 cells. The resveratrol sensitive properties of U251 cells are not altered by either LN428/N/Exo or LN428/Res/Exo. U251/N/Exo contains higher levels of chromatin silencing and epidermis development proteins, while U251/Res/Exo has more oxygen transport and G protein-coupled receptor. Both of LN428/N/Exo and LN428/Res/Exo are rich in the proteins related with nucleosome assembly, microtubule-based process and chromatin silencing. In conclusion, U251/N/Exo sensitizes LN428 cells to resveratrol via delivering drug sensitizing signals, suggesting the presence of additional factor(s) that may determine the resveratrol sensitivities of glioblastoma cells.