Fernanda Vidal Carvalho

Introduction: Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system and is highly resistant to temozolomide (TMZ). Rutin is a potent antioxidant with immunomodulatory and anti-glioma effects in vitro, although its mechanisms of action remain incompletely understood. This study investigated the effects of rutin on morphology, viability, redox balance, and pro-tumoral signaling in GBM 2D cultures and 3D spheroids, as well as its association with TMZ sensitivity. Methods: GL15 and U343 human GBM cell lines and primary astrocytes were treated with rutin (5–30 μM) and/or TMZ (125–4000 μM). Cell metabolic activity and viability were assessed by MTT, PI/DiOC18(3) or PI/Hoechst. Cell migration was assessed from spheroid-derived cells, and extracellular matrix (ECM) components (fibronectin and laminin) were evaluated by immunofluorescence. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA fluorescence. IL-6, STAT3, NOS2, and IDO1 gene expression were determined by RT-qPCR, and protein expression of MMP2, fibronectin, STAT3, PI3K, and AKT by Western blotting. Nitric oxide (NO) and L-kynurenine levels were quantified in the supernatant by colorimetric assays. Results: Rutin reduced cell viability and enhanced TMZ cytotoxicity in both 2D and 3D cultures, while exerting selective effects by increasing metabolic activity and attenuating TMZ-induced effects in non-tumoral primary astrocytes. In 3D spheroids, rutin affected structural organization and reduced spheroid-derived cell migration, accompanied by changes in ECM components, including MMP2, fibronectin, and laminin. Rutin decreased intracellular ROS levels and suppressed the TMZ-induced increase in ROS and NOS signaling. These effects were accompanied by modulation of IL-6/STAT3 signaling, along with reduced STAT3, PI3K, and AKT protein levels. Rutin also modulated immunometabolic parameters, including extracellular L-kynurenine and nitric oxide levels, and enhanced TMZ responsiveness following pre-sensitization. Conclusions: Rutin enhances TMZ responsiveness by modulating interconnected pro-tumoral mechanisms, including redox balance, pro-survival signaling, ECM remodeling and migratory behavior, and immunometabolic pathways linked to chemoresistance, supporting its potential as an adjuvant therapeutic strategy.

Lepidium meyenii (maca) is a nutraceutical plant widely recognized for its diverse bioactive compounds and associated biological activities. In this study, a bio-guided fractionation approach combined with UHPLC-Q-TOF-MS/MS-based metabolomics and chemometric analysis was applied to identify bioactive fractions associated with antiglioma activity. Cytotoxicity against C6 glioma cells was used as the biological endpoint to guide fractionation. Among the obtained fractions, subfractions F6.5.7 and F6.5.9 exhibited the highest activity, reducing cell viability by 99% and 67%, respectively. Metabolomic profiling revealed that these active subfractions were enriched in macamides and mono- and polyunsaturated fatty acids. Chemometric analysis indicated a strong association between antiglioma activity and specific metabolites, particularly 9-oxo-10E,12E-octadecadienoic acid, linolenic acid, and macamide B. These compounds are proposed as candidate contributors to the observed bioactivity. The results highlight the potential of targeted fractionation combined with metabolomics as a strategy to identify bioactive constituents from functional foods. This study provides a chemical basis for further investigations into maca-derived compounds with antiglioma potential.

Three new polyprenylated benzophenone derivatives named burlemarxiones G−I ( 1‐3 ) were isolated from C. burle‐marxii trunks (compound 1 ) and leaves (compounds 2 and 3 ), along with the known compound burlemarxione F. Burlemarxione G ( 1 ) was isolated after methylation with diazomethane and it is the keto‐enol tautomeric pair of burlemarxione F. Burlemarxione H ( 2 ) derives from burlemarxiones F and G, but it has additional rings due to cyclization of the prenyl group attached to C‐5 that establishes new single bonds between C‐1 and C‐23, as well as, between C‐24 and C‐29. Burlemarxione I ( 3 ) has two additional cyclizations: the first encompasses the cyclization of the former isopentenyl group into an 11,11‐dimethyl‐six‐membered ring, whereas the second produces additional rings due to the cyclization of the prenyl group attached to C‐5 that establishes new single bonds between C‐1 and C‐23, as well as, between C‐24 and C‐29. All three compounds showed moderate anti‐glioma activity. These results show that C. burle‐marxii is an important source of sophisticated polyprenylated benzophenone derivatives.

Lepidium meyenii is a medicinal edible plant that have nutritional and therapeutic benefits due to synthesis of bioactive compounds.