The extracellular matrix HA promotes the YAP/hypoxia axis of glioblastoma cells on 3D agar/HA scaffolds Nicole Fratini, Carolina Castillo, Roberta Grillo, Stefania D'Amone, Luca Pacini, Maddalena Grieco, Maria Grazia Lolli, Sara Maria Giannitelli, Francesco Brasili, Ornella Ursini, Claudia Bearzi, Roberto Rizzi, Barbara Cortese Biomaterials Advances, 2026 The tumour microenvironment of glioblastoma (GBM) as defined by mechanical heterogeneity, hypoxia, and hyaluronic acid (HA)-rich extracellular matrix (ECM), is a highly dynamic milieu which influences tumour progression and therapeutic resistance. Yet, how these cues converge to regulate mechanosensitive pathways in 3D remains poorly understood. Here, we engineered agar-based porous hydrogels functionalized with HA to independently tune stiffness and ECM composition, creating biomimetic 3D niches for GBM cells. The presence of HA coating showed to increase hydrogel stiffness, promote YAP/TAZ nuclear localisation, and elevate total LATS1/2 expression, consistent with Hippo pathway feedback regulation. Over time, however, hypoxic niches emerged that destabilised this feedback, enabling sustained YAP nuclear activity. HA also modulated OCT4 and Sox2 localisation and attenuated HIF-1α nuclear accumulation, indicating that HA also modulates the spatial distribution and nuclear accumulation of HIF-1α. Also, a cooperative regulation through the HA-CD44-CXCR4 axis, showed integrated biochemical and mechanical signals to reinforce YAP/HIF crosstalk. Together, these results reveal a dynamic interplay between ECM stiffness, HA signalling, and hypoxia in shaping YAP/HIF crosstalk and stem-like phenotypes in GBM and establish our hydrogel platform as a powerful tool to dissect and therapeutically exploit these interactions.
Doxorubicin and NFL-TBS.40-63 peptide loaded gold nanoparticles as a multimodal therapy of glioblastoma Myriam El Moutaoukil, Maria Grazia Lolli, Stefania D’Amone, Memona Khan, Roberta Grillo, Joel Eyer, Maddalena Grieco, Ornella Ursini, Jolanda Spadavecchia, Barbara Cortese Discover Nano, 2025 Conventional treatments for glioblastoma (GBM) are hindered by systemic toxicity, limited blood-brain barrier penetration, and therapeutic resistance. To address these challenges, we developed dual-functionalized gold nanoparticles (AuNPs) conjugated with a biotinylated NFL-TBS.40-63 peptide and the chemotherapeutic agent doxorubicin. This platform integrates targeted delivery and therapeutic action to enhance efficacy while minimising off-target effects. Our findings reveal superior cellular uptake, dose- and time-dependent cytotoxicity, and apoptosis induction in GBM cells compared to mono-functionalized counterparts. Furthermore, pH-sensitive drug release profiles underscore the system's potential to exploit the tumour microenvironment's acidic conditions for precise drug delivery. Comprehensive characterisation confirmed the stability, biocompatibility, and functional efficacy of the dual-functionalized AuNPs. This study highlights the promise of these nanoconjugates as a multimodal approach to GBM therapy, paving the way for further translational research in nanomedicine.
Anti-IL-17 and Anti-IL-23 Therapies Modulate Serum Biomarkers of Intestinal Dysbiosis and Oxidative Stress Linked to Cardiovascular Risk in Patients with Psoriasis Giuseppe Annunziata, Emanuele Scala, Laura Mercurio, Luca Sanna, Anna Dattolo, Gianluca Pagnanelli, Maria Grazia Lolli, Roberta Belli, Gaia Moretta, Silvia Savastano, Giovanna Muscogiuri, Maria Maisto, Roberto Ciampaglia, Vincenzo Piccolo, Gian Carlo Tenore, Cristina Albanesi, Stefania Madonna, Luigi Barrea Life, 2025 Psoriasis is a chronic inflammatory skin disease whose pathogenesis involves not only cutaneous inflammation but also intestinal dysbiosis and oxidative stress (OxS). Monoclonal antibodies targeting interleukin (IL)-17 and IL-23 have demonstrated significant immunomodulatory effects; however, their impact on systemic parameters requires further investigation. We conducted a study on 33 patients with plaque psoriasis treated with anti-IL-17 or anti-IL-23 monoclonal antibodies. Dermatological parameters (Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI)), biomarkers of intestinal dysbiosis (trimethylamine-N-oxide (TMAO)) and OxS (reactive oxygen metabolites (d-ROMs) and oxidized LDL (oxLDL)) were evaluated. Anthropometric, metabolic, and adipose-derived hormonal parameters (adipokines) were also monitored. After 16 weeks of therapy, significant improvements were observed in PASI and DLQI scores (p < 0.001). TMAO levels were significantly reduced (p = 0.02), as were d-ROMs and oxLDL (p < 0.001). No significant changes were found in weight, body mass index, lipid profile, or adipokine levels (visfatin, leptin and adiponectin). Our data indicate that monoclonal antibody therapy not only improves psoriasis severity but also exerts beneficial effects on systemic biomarkers of dysbiosis and OxS, independent of metabolic or hormonal changes. These findings suggest a systemic mechanism of action, supporting a multifactorial therapeutic effect with potential implications for the prevention of cardiovascular risk.
Leptin: a gender and obesity-related marker predictive of metabolic comorbidities and therapeutic response to anti-IL-23 biologic drugs in psoriatic patients Roberta Belli, Anna Dattolo, Francesca Sampogna, Emanuela Gubinelli, Daniela Lulli, et al. Frontiers in Immunology, 2025 Introduction Psoriasis is a chronic immune-mediated inflammatory skin disorder, frequently associated with comorbidities such as obesity, which can exacerbate its severity and hinder treatment efficacy. Psoriasis pathogenesis involves complex interactions among genetic, environmental, hormonal factors, and is characterized by dysregulated immune responses. In this study, we investigated the relationship between obesity and psoriasis, exploring the impact of circulating levels of adipokines on disease severity, comorbidities, and treatment response to anti-IL-17 and anti-IL-23 biologics. Methods We conducted an observational study that included 91 patients with psoriasis eligible for biological therapy, as well as 26 healthy controls. Disease severity was assessed using PASI, along with the measurement of body composition. Serum samples were analyzed for the measurement of adipokine levels and lipid profiles. Clinical parameters, bioelectrical impedance analysis (BIA), serum adipokine levels (leptin, visfatin, adiponectin) and lipid profile were assessed at baseline and after 16 weeks of biologic treatments. Results Clinical parameters and adiposity-related indices were analyzed in 76 patients at both T0 and 16 weeks of anti-IL-17 and anti-IL-23 biological treatments, while serum adipokine levels were assessed in 66 patients. Psoriatic patients exhibited higher body mass index (BMI), waist circumference, fat mass (FM), and levels of visfatin (a pro-inflammatory adipokine), whereas adiponectin levels (an anti-inflammatory adipokine) were lower compared to controls. Circulating leptin (a pro-inflammatory adipokine) was significantly higher in female psoriatic patients and showed a positive correlation with the PASI score. Leptin also positively correlated with adiposity indices, while adiponectin showed negative correlations. Furthermore, in women, leptin levels were also associated with psoriatic arthritis, hypertension and, at lower extent, with type II diabetes. Finally, treatment with anti-IL-23 led to a reduction in visfatin levels in female psoriatic patients and resulted in a significant decrease in fat mass percentage in men. Notably, higher baseline leptin levels were associated with the failure to achieve an 90% improvement in baseline PASI at W16 of anti-IL-23 biologic treatments. Conclusions This study highlights significant sex-specific differences in the relationships between adipokines, body composition indices, psoriasis severity, comorbidities, and clinical outcome to therapies. Leptin, in particular, may serve as a predictive biomarker for response to anti-IL-23 therapies.
Severely Damaged Freeze-Injured Skeletal Muscle Reveals Functional Impairment, Inadequate Repair, and Opportunity for Human Stem Cell Application Daniela Fioretti, Mario Ledda, Sandra Iurescia, Raffaella Carletti, Cira Di Gioia, Maria Grazia Lolli, Rodolfo Marchese, Antonella Lisi, Monica Rinaldi Biomedicines, 2024 Background: The regeneration of severe traumatic muscle injuries is an unsolved medical need that is relevant for civilian and military medicine. In this work, we produced a critically sized nonhealing muscle defect in a mouse model to investigate muscle degeneration/healing phases. Materials and methods: We caused a freeze injury (FI) in the biceps femoris of C57BL/6N mice. From day 1 to day 25 post-injury, we conducted histological/morphometric examinations, an analysis of the expression of genes involved in inflammation/regeneration, and an in vivo functional evaluation. Results: We found that FI activates cytosolic DNA sensing and inflammatory responses. Persistent macrophage infiltration, the prolonged expression of eMHC, the presence of centrally nucleated myofibers, and the presence of PAX7+ satellite cells at late time points and with chronic physical impairment indicated inadequate repair. By looking at stem-cell-based therapeutic protocols of muscle repair, we investigated the crosstalk between M1-biased macrophages and human amniotic mesenchymal stem cells (hAMSCs) in vitro. We demonstrated their reciprocal paracrine effects where hAMSCs induced a shift of M1 macrophages into an anti-inflammatory phenotype, and M1 macrophages promoted an increase in the expression of hAMSC immunomodulatory factors. Conclusions: Our findings support the rationale for the future use of our injury model to exploit the full potential of in vivo hAMSC transplantation following severe traumatic injuries.
Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling Annalisa Crema, Mario Ledda, Daniela Fioretti, Maria Grazia Lolli, Massimo Sanchez, Elisabetta Carico, Rodolfo Marchese, Monica Rinaldi, Antonella Lisi Journal of Tissue Engineering and Regenerative Medicine, 2019 Cell therapy represents a promising alternative strategy for end‐stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/β‐catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated β‐catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/β‐catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent colocalization with β‐catenin and colocalized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition‐related markers showed enhanced expression and wider distribution, and the hepato‐mesenchymal population Thy1 + CK19− was also present. Control animals injected with hepatogenic factors alone exhibited higher β‐catenin, decreased Wnt5a levels, and persistent proliferation of the hepato‐mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process, and improves the rescue of hepatic function by modulating the Wnt/βcatenin signaling and activating hepato‐mesenchymal population.
Array of disordered silicon nanowires coated by a gold film for combined NIR photothermal treatment of cancer cells and Raman monitoring of the process evolution Annalisa Convertino, Valentina Mussi, Luca Maiolo, Mario Ledda, Maria Grazia Lolli, Fabio Antonio Bovino, Guglielmo Fortunato, Massimiliano Rocchia, Antonella Lisi Nanotechnology, 2018 Photothermal therapy (PTT) assisted by nanomaterials is a promising minimally invasive technique for cancer treatment. Here, we explore the PTT properties of a silicon- and gold-based nanostructured platform suitable for being directly integrated in fibre laser systems rather than injected into the human body, which occurs for the most commonly unreported PTT nanoagents. In particular, the photothermal properties of an array of disordered silicon nanowires coated by a thin gold film (Au/SiNWs) were tested on a monolayer of human colon adenocarcinoma cells (Caco-2) irradiated with a 785 nm laser. Au/SiNWs allowed an efficient photothermal action and simultaneous monitoring of the process evolution through the Raman signal coming from the irradiated cellular zone. Strong near infra-red (NIR) absorption, overlapping three biological windows, cell-friendly properties and effective fabrication technology make Au/SiNWs suitable both to be integrated in surgical laser tools and as an in vitro platform to develop novel PTT protocols using different cancer types and NIR sources.
