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Glioblastomas (GBM) are malignant tumours with poor prognosis. Treatment involves chemotherapy and/or radiotherapy; however, there is currently no standard treatment for recurrence, and prognosis remains unfavourable. Inflammatory mediators and microRNAs (miRNAs) influence the aggressiveness of GBM, being involved in the communication with the cells of the tumour parenchyma, including microglia/macrophages, and maintaining an immunosuppressive microenvironment. Hence, the modulation of miRNAs and inflammatory factors may improve GBM treatments. In this study, we investigated the effects of agathisflavone, a biflavonoid purified from Cenostigma pyramidale (Tul.), on the growth and migration of GBM cells, on the expression of inflammatory cytokines and microRNAs, as well on the response of microglia. Agathisflavone (5–30 μM) induced a dose- and time-dependent reduction in the viability of both human GL-15 and rat C6 cells, as determined by the MTT test, and reduced cell migration, as determined by cell scratch assay. RT-qPCR analysis revealed that agathisflavone (5 μM) down-regulated the expression of miR-125b and miR-155 in the secretome derived from GL-15 cells, which was associated with upregulation of the mRNA expression of IL-6 and arginase-1 immunoregulatory factors. Exposure of human microglia/macrophage to the secretome from GL-15 GMB cells modulated proliferation and morphology, effects that were modulated by agathisflavone treatment. These results demonstrate the effect of flavonoids on the growth of GBM cells, which impacts cells in the microenvironment and can be considered for preclinical studies for adjuvant treatments. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, endogenous, single-stranded RNAs that act on gene silencing at the post-transcriptional level by binding to a target messenger RNA (mRNA), leading to its degradation or inhibiting translation into functional proteins. The key role of miRNAs in development, proliferation, differentiation andapoptosis has been deeply investigated, revealing that deregulation in their expression is critical in various diseases, such as metabolic disorders and cancer. Since these small molecules initially evolved as a mechanism of protection against viruses and transposable elements, the fascinating hypothesis that they can move between organisms both of the same or different species has been postulated. Trans-kingdom is the term used to define the migration that occurs between species. This mechanism has been well analyzed between plants and their pests, in order to boost defense and increase pathogenicity, respectively. Intriguingly, in the last decades, the plant–human trans-kingdom migration via food intake hypothesis arose. In particular, various studies highlighted the ability of exogenous miRNAs, abundant in the mainly consumed plant-derived food, to enter the human body affecting gene expression. Notably, plant miRNAs can resist the strict conditions of the gastrointestinal tract through a methylation step that occurs during miRNA maturation, conferring high stability to these small molecules. Recent studies observed the anti-tumoral, immune modulator and anti-inflammatory abilities of trans-kingdom interaction between plant and human. Here, we depict the existing knowledge and discuss the fascinating plant–human trans-kingdom interaction, highlighting first the eventual role of plant miRNAs from foods on our somatic gene identity card and then the potential impact of using plant miRNAs as novel therapeutic avenues. [ABSTRACT FROM AUTHOR]