Biology subjects

Bertoli, G. R.

Publications and source records attributed to Bertoli, G. R..

3 recordsLinked to original sources

bioRxiv2026

Disrupting Pregnane X Receptor Signaling Overcomes Temozolomide Resistance in Glioblastoma via Succisa pratensis-Derived Metabolites

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. Article HighlightsO_LISuccisa pratensis enhances temozolomide efficacy in glioblastoma by reducing proliferation, migration, and clonogenic growth. C_LIO_LIIntegrated proteomic and metabolomic analyses reveal extensive metabolic rewiring, with suppression of central carbon metabolism and induction of stress-adaptive pathways. C_LIO_LIPregnane X Receptor (PXR), a key regulator of chemoresistance, is functionally impaired despite increased expression, resulting in reduced activation of drug-resistance genes. C_LIO_LIPharmacological inhibition of PXR further potentiates the antitumor effects of Succisa pratensis and temozolomide, promoting apoptotic cell death. C_LIO_LIApigenin-derived metabolites show high affinity for the PXR ligand-binding domain and emerge as promising candidates to overcome temozolomide resistance in glioblastoma. C_LI

cancer biology↗

bioRxiv2019

Chronic pain alters microvascular architectural organization of somatosensory cortex

Chronic pain (CP) represents a complex pathology profoundly involving both neural and glial compartments of the central nervous system. While most CP studies have also investigated the macroscopic brain vascular system, its microstructural architecture still remains largely unexplored. Further, the adaptive modifications of the vascular microstructure as consequence of diseases or pathological insults, did not receive adequate attention. Here we show microtomographic signs of diffuse and conspicuous microvascular neogenesis in somatosensory cortex of CP animal models already peaking at 15 days from the model instantiation. Progressive fading of this microvessel neogenesis then ensued in the next six months yet maintaining higher vascular density with a preserved small fraction of them. Due to the important consequences on the neuron-glial-vessel arrangements and on the resulting metabolic and functional disorders of the local networks, novel additional scenarios of CP are thus conceivable with profound consequences of potential future CP diagnostic and therapeutic appraisals.

neuroscience↗

bioRxiv2019

Removal of behavioural and electrophysiological signs of chronic pain by in vivo microsections of rat somatosensory cortex with parallel X-ray microbeams

Chronic pain (CP) is a condition characterized by a wide spectrum of clinical signs and symptoms, missing a sound modelling at the neuronal network scale. Recently, we presented a general theory showing common electrophysiological traits in different CP rat models, i.e. a collapse of relevant functional connectivity network properties, such as modularity, in the somatosensory thalamo-cortical (TC) network. In this work, we preliminary investigated by an in silico accurate simulator of the six-layer mammalian cortical networks that evidenced the crucial collapse of network modularity in CP simulated conditions and the consequent reduction of network adaptive processes. On this track, in studies on CP experimental animals affected by sciatic nerve multiple ligature (Bennett-Xie model), by synchrotron-generated X-ray microbeam (MB) irradiations (7 parallel beams, 100um width), we targeted in vivo the CP involved hindlimb somatosensory projection cortex that, because of the doses radiation (360 Gy, peak at each beam), non-invasively produced fast and precise tissue destruction along the 7 beam projections. These parcellated the cortical tissue and restored the cortical network statistics related to modularity and information processing efficiency as evidenced from post irradiation in vivo electrophysiological recordings. In addition, by MB treatment there was an ensuing removal of behavioral signs of allodynia and hyperalgesia accompanied by recovered normal gait schemes yet preserving the normal sensory thresholds of the experimental rats up to three months after the MB irradiation. Finally, novel and unprecedented therapeutic appraisals for CP are devised. Significance StatementChronic pain (CP) is an excruciating condition with severe effects on patients life. Apart from many clinical and experimental studies no current theory on CP is generally accepted. Recently, we proposed a general theory of CP in experimental animals as characterized by strong alteration of the connections among neurons in different brain regions. We show here on in silico simulations that specific connectivity changes in the somatosensory cortex recover the lost functional integrity. Concurrently, in experimental animals, we re-modulated, in vivo, some anatomical connections of the somatosensory cortex by extremely thin synchrotron generated X-ray microbeam irradiations. The resulting behavioral and electrophysiological signs of CP disappeared yet maintaining normal sensory responses. No adverse or pathological effects on blank animals were observable.

neuroscience↗