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.

Breast cancer (BC) is the most prevalent malignancy among women worldwide. Traditional research models such as primary cancer cell and patient-derived tumor xenografts (PDTXs) have limitations. Cancer cells lack a tumor microenvironment (TME) and genetic diversity, whereas PDTXs are expensive and have a time-consuming preparation protocol. Therefore, alternative research models are warranted. Patient-derived organoids (PDOs) are a promising in vitro model. They mimic the TME, gene expression, and cell types of original cancer tissues. PDOs have been successfully developed from various cancers, including BC. In this review, we focused on the value and limitations of PDOs in BC research, including their characteristics and potential in drug development, personalized therapy, immunotherapy, and the application prospects of PDOs in drug testing and prognosis.

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.

Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican‐3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti‐GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer‐targeted next‐generation sequencing (NGS) and three‐dimensional patient‐derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT‐PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti‐GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS‐08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3‐positive cells was variable in the focal (+; 10%–30%; 8/45), partial (++; 31%–70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10⁻¹⁰). The anti‐GPC3 antibody efficiently inhibits Wnt/β‐catenin signaling and induces apoptosis in GPC3‐positive PDOs and PDXs, as opposed to GPC3‐negative PDOs and PDXs. The high frequency of GPC3 and CD133 co‐expression and the effectiveness of anti‐wild‐type GPC3‐Ab therapy in GPC3‐positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma.

Glioblastoma multiforme (GBM) cells show different responses to resveratrol, for unknown reasons. Our data from human medulloblastoma cells and primary cultures of rat brain cells revealed an inverse correlation of sulfonation activity with resveratrol sensitivities, providing a clue to the underlying mechanisms of the variable sensitivities of GBM cells to resveratrol. In this study, we found that U251 cells were sensitive and LN229 cells were insensitive to resveratrol. Thus, these two cell lines were taken as comparable models for elucidating the influence of sulfonation activities on resveratrol sensitivity. HPLC showed identical resveratrol metabolic patterns in both cell lines. LC/MS and high‐resolution mass MS analyses further demonstrated that resveratrol monosulfate generated by sulfotransferases (SULTs) was the major metabolite of human GBM cells. The levels of brain‐associated SULT (SULT1A1, SULT1C2, and SULT4A1) expression in U251 cells were lower than those in LN229 cells, suggesting the inverse relationship of SULT‐mediated sulfonation activity with high intracellular resveratrol bioavailability and resveratrol sensitivity of human GBM cells. Furthermore, immunohistochemical staining revealed reductions in expression of the three brain‐associated SULTs in 72.8%, 47.5% and 66.3% of astrocytomas, respectively. Therefore, the levels of brain‐associated SULTs and sulfonation activity mediated by them could be important parameters for evaluating the potential response of human GBM cells to resveratrol, and may have value in the personalized treatment of GBMs with resveratrol.Database Nucleotide sequence data for SULT1A1, SULT1C2 and SULT4A1 are available in the GenBank database under the accession numbers BC110887, BC005353, and BC028171.

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.