Martina Nespoli

Glioblastoma remains a highly aggressive and therapy-resistant brain tumor, with limited benefit from the current standard-of-care regimen combining surgery, radiotherapy, and temozolomide. Overcoming chemoresistance therefore represents a critical unmet clinical need. Here, we investigate the anticancer potential of Succisa pratensis and its ability to enhance TMZ efficacy in GBM models. Treatment with S. pratensis markedly reduced cell proliferation and migration while significantly increasing sensitivity to TMZ. Integrated multi-omics analyses revealed extensive metabolic rewiring, characterized by suppression of central carbon metabolism and activation of stress-adaptive pathways. Mechanistically, we identify the Pregnane X Receptor, a key regulator of drug metabolism and chemoresistance, as a central node affected by treatment. Although S. pratensis increased PXR expression, this was not accompanied by induction of canonical downstream targets, including MDR1 and ALDH1A1, indicating a functional impairment of PXR transcriptional activity. Consistently, pharmacological inhibition of PXR using the antagonist SPA70 further potentiated the cytotoxic effects of S. pratensis and TMZ. Docking analyses suggest that specific secondary metabolites, including apigenin-derived compounds, may interact with the PXR ligand-binding domain, providing a potential molecular basis for this effect. Collectively, our findings indicate that S. pratensis enhances TMZ efficacy by inducing metabolic vulnerability and functionally impairing PXR signaling. These results highlight the therapeutic potential of plant-derived metabolites as adjuvant strategies to overcome chemoresistance in glioblastoma.

Chronic gastrointestinal disorders such as inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS) impose significant health burdens globally. IBDs, encompassing Crohn’s disease and ulcerative colitis, are multifactorial disorders characterized by chronic inflammation of the gastrointestinal tract. On the other hand, IBS is one of the principal gastrointestinal tract functional disorders and is characterized by abdominal pain and altered bowel habits. Although the precise etiopathogenesis of these disorders remains unclear, mounting evidence suggests that non-coding RNA molecules play crucial roles in regulating gene expression associated with inflammation, apoptosis, oxidative stress, and tissue permeability, thus influencing disease progression. miRNAs have emerged as possible reliable biomarkers, as they can be analyzed in the biological fluids of patients at a low cost. This review explores the roles of miRNAs in IBDs and IBS, focusing on their involvement in the control of disease hallmarks. By an extensive literature review and employing bioinformatics tools, we identified the miRNAs frequently studied concerning these diseases. Ultimately, specific miRNAs could be proposed as diagnostic biomarkers for IBDs and IBS. Their ability to be secreted into biofluids makes them promising candidates for non-invasive diagnostic tools. Therefore, understanding molecular mechanisms through the ways in which they regulate gastrointestinal inflammation and immune responses could provide new insights into the pathogenesis of IBDs and IBS and open avenues for miRNA-based therapeutic interventions.