36 results on '"Guarnaccia, L"'
Search Results
2. Frontiers in anti-cancer drug discovery: Challenges and perspectives of metformin as anti-angiogenic add-on therapy in glioblastoma
- Author
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Guarnaccia, L, Marfia, G, Masseroli, M, Navone, S, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Garzia, E, Riboni, L, Locatelli, M, Guarnaccia L., Marfia G., Masseroli M. M., Navone S. E., Balsamo M., Caroli M., Valtorta S., Moresco R. M., Campanella R., Garzia E., Riboni L., Locatelli M., Guarnaccia, L, Marfia, G, Masseroli, M, Navone, S, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Garzia, E, Riboni, L, Locatelli, M, Guarnaccia L., Marfia G., Masseroli M. M., Navone S. E., Balsamo M., Caroli M., Valtorta S., Moresco R. M., Campanella R., Garzia E., Riboni L., and Locatelli M.
- Abstract
Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovas-cularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various onco-promoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
- Published
- 2022
3. P-425 Premature follicular-phase progesterone increase in ART cycles and endometrial receptivity: evaluation of new, more reliable predictors
- Author
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Cappellini, C, primary, Garzia, E, additional, Galiano, V, additional, Guarnaccia, L, additional, Riparini, J, additional, Sulpizio, P, additional, and Marconi, A.M, additional
- Published
- 2022
- Full Text
- View/download PDF
4. P-644 The Δ4-Androstenedione baseline serum level reflects the ovarian response to stimulation: set-up of a novel index to predict the outcomes of IVF cycles
- Author
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Galiano, V, primary, Cappellini, C, additional, Guarnaccia, L, additional, Guermandi, E, additional, Sulpizio, P, additional, and Garzia, E, additional
- Published
- 2022
- Full Text
- View/download PDF
5. Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics
- Author
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Guarnaccia, L, Navone, S, Masseroli, M, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Schisano, L, Fiore, G, Galiano, V, Garzia, E, Appiani, G, Locatelli, M, Riboni, L, Marfia, G, Guarnaccia, L, Navone, S, Masseroli, M, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Schisano, L, Fiore, G, Galiano, V, Garzia, E, Appiani, G, Locatelli, M, Riboni, L, and Marfia, G
- Abstract
Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and mu-dependent ability of MET to decrease cell viability and proliferatio
- Published
- 2022
6. Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department
- Author
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Campanella, R, Guarnaccia, L, Caroli, M, Zarino, B, Carrabba, G, La Verde, N, Gaudino, C, Rampini, A, Luzzi, S, Riboni, L, Locatelli, M, Navone, S, Marfia, G, Campanella R., Guarnaccia L., Caroli M., Zarino B., Carrabba G., La Verde N., Gaudino C., Rampini A., Luzzi S., Riboni L., Locatelli M., Navone S. E., Marfia G., Campanella, R, Guarnaccia, L, Caroli, M, Zarino, B, Carrabba, G, La Verde, N, Gaudino, C, Rampini, A, Luzzi, S, Riboni, L, Locatelli, M, Navone, S, Marfia, G, Campanella R., Guarnaccia L., Caroli M., Zarino B., Carrabba G., La Verde N., Gaudino C., Rampini A., Luzzi S., Riboni L., Locatelli M., Navone S. E., and Marfia G.
- Abstract
Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the “one-size-fits-all” approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory.
- Published
- 2020
7. Tumor-educated platelets and angiogenesis in glioblastoma : another brick in the wall for novel prognostic and targetable biomarkers, changing the vision from a localized tumor to a systemic pathology
- Author
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Campanella, R, Guarnaccia, L, Cordiglieri, C, Trombetta, E, Caroli, M, Carrabba, G, La Verde, N, Rampini, P, Gaudino, C, Costa, A, Luzzi, S, Mantovani, G, Locatelli, M, Riboni, L, Navone, S, Marfia, G, Campanella, Rolando, Guarnaccia, Laura, Cordiglieri, Chiara, Trombetta, Elena, Caroli, Manuela, Carrabba, Giorgio, La Verde, Nicla, Rampini, Paolo, Gaudino, Chiara, Costa, Antonella, Luzzi, Sabino, Mantovani, Giovanna, Locatelli, Marco, Riboni, Laura, Navone, Stefania Elena, Marfia, Giovanni, Campanella, R, Guarnaccia, L, Cordiglieri, C, Trombetta, E, Caroli, M, Carrabba, G, La Verde, N, Rampini, P, Gaudino, C, Costa, A, Luzzi, S, Mantovani, G, Locatelli, M, Riboni, L, Navone, S, Marfia, G, Campanella, Rolando, Guarnaccia, Laura, Cordiglieri, Chiara, Trombetta, Elena, Caroli, Manuela, Carrabba, Giorgio, La Verde, Nicla, Rampini, Paolo, Gaudino, Chiara, Costa, Antonella, Luzzi, Sabino, Mantovani, Giovanna, Locatelli, Marco, Riboni, Laura, Navone, Stefania Elena, and Marfia, Giovanni
- Abstract
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.
- Published
- 2020
8. Potential therapeutic effects of milk thistle
- Author
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LI VOLTI, Giovanni, CASTRUCCIO CASTRACANI, Carlo, Guarnaccia, L, and Barbagallo, IGNAZIO ALBERTO
- Published
- 2015
9. AMICO: the Asset Management for Industrial Complex Enterprise
- Author
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Alì, S., Cantali, G., Salvatore Cavalieri, Chiacchio, F., Guarnaccia, L., Scibilia, F., and Scuderi, A.
- Published
- 2013
10. Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma
- Author
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Laura Guarnaccia, Giovanni Marfia, Matteo Maria Masseroli, Stefania Elena Navone, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, Rosa Maria Moresco, Rolando Campanella, Emanuele Garzia, Laura Riboni, Marco Locatelli, Guarnaccia, L, Marfia, G, Masseroli, M, Navone, S, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Garzia, E, Riboni, L, and Locatelli, M
- Subjects
Brain tumor ,Angiogenesi ,Cancer Research ,angiogenesis ,Angiogenesis ,brain tumors ,glioblastoma ,metformin ,Oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Review ,RC254-282 ,oncology_oncogenics - Abstract
Simple Summary Glioblastoma is the most aggressive primary brain tumor, with the highest incidence and the worst prognosis. Life expectancy from diagnosis remains dismal, at around 15 months, despite surgical resection and treatment with radiotherapy and chemotherapy. Given the aggressiveness of the tumor and the inefficiency of the treatments adopted to date, the scientific research investigates innovative therapeutic approaches. Importantly, angiogenesis represents one of the main features of glioblastoma, becoming in the last few years a major candidate for target therapy. Metformin, a well-established therapy for type 2 diabetes, offered excellent results in preventing and fighting tumor progression, particularly against angiogenic mechanisms. Therefore, the purpose of this review is to summarize and discuss experimental evidence of metformin anti-cancer efficacy, with the aim of proposing this totally safe and tolerable drug as add-on therapy against glioblastoma. Abstract Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
- Published
- 2022
- Full Text
- View/download PDF
11. Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics
- Author
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Laura Guarnaccia, Stefania E. Navone, Matteo M. Masseroli, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, Rosa M. Moresco, Rolando Campanella, Luigi Schisano, Giorgio Fiore, Valentina Galiano, Emanuele Garzia, Giuseppe C. Appiani, Marco Locatelli, Laura Riboni, Giovanni Marfia, Guarnaccia, L, Navone, S, Masseroli, M, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Schisano, L, Fiore, G, Galiano, V, Garzia, E, Appiani, G, Locatelli, M, Riboni, L, and Marfia, G
- Subjects
Cancer Research ,glioblastoma ,metformin ,brain tumors ,angiogenesis ,Oncology ,angiogenesi ,brain tumor - Abstract
Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and mu-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.
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- 2022
- Full Text
- View/download PDF
12. Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology
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Nicla La Verde, Giorgio Carrabba, Laura Riboni, Rolando Campanella, Laura Guarnaccia, Elena Trombetta, Antonella Costa, Marco Locatelli, Paolo Rampini, Stefania Elena Navone, Giovanna Mantovani, Giovanni Marfia, Chiara Gaudino, Chiara Cordiglieri, Sabino Luzzi, Manuela Caroli, Campanella, R, Guarnaccia, L, Cordiglieri, C, Trombetta, E, Caroli, M, Carrabba, G, La Verde, N, Rampini, P, Gaudino, C, Costa, A, Luzzi, S, Mantovani, G, Locatelli, M, Riboni, L, Navone, S, and Marfia, G
- Subjects
Adult ,Blood Platelets ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Platelet Membrane Glycoproteins ,Immunofluorescence ,Flow cytometry ,03 medical and health sciences ,angiogenesis ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,Platelet ,Receptor ,Sphingosine-1-Phosphate Receptors ,lcsh:QH301-705.5 ,Cells, Cultured ,S1PR1 ,Aged ,platelet ,Vascular Endothelial Growth Factor Receptor-1 ,Neovascularization, Pathologic ,medicine.diagnostic_test ,Brain Neoplasms ,Cell growth ,business.industry ,Communication ,glioblastoma ,Endothelial Cells ,angiogenesi ,General Medicine ,Middle Aged ,Prognosis ,Vascular Endothelial Growth Factor Receptor-2 ,Peptide Fragments ,Adenosine Diphosphate ,Blot ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,lcsh:Biology (General) ,platelets ,sphingosine-1-phosphate ,Female ,business ,030217 neurology & neurosurgery - Abstract
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.
- Published
- 2020
13. Testing calpain inhibition in tumor endothelial cells: novel targetable biomarkers against glioblastoma malignancy.
- Author
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Guarnaccia L, Navone SE, Begani L, Barilla E, Garzia E, Campanella R, Miozzo M, Fontana L, Alotta G, Cordiglieri C, Gaudino C, Schisano L, Ampollini A, Riboni L, Locatelli M, and Marfia G
- Abstract
Introduction: Glioblastoma IDH -wildtype (GBM) is the most malignant brain tumor in adults, with a poor prognosis of approximately 15 months after diagnosis. Most patients suffer from a recurrence in <1 year, and this renders GBM a life-threatening challenge. Among molecular mechanisms driving GBM aggressiveness, angiogenesis mediated by GBM endothelial cells (GECs) deserves consideration as a therapeutic turning point. In this scenario, calpains, a family of ubiquitously expressed calcium-dependent cysteine proteases, emerged as promising targets to be investigated as a novel therapeutic strategy and prognostic tissue biomarkers., Methods: To explore this hypothesis, GECs were isolated from n=10 GBM biopsies and characterized phenotypically by immunofluorescence. The expression levels of calpains were evaluated by qRT-PCR and Western blot, and their association with patients' prognosis was estimated by Pearson correlation and Kaplan-Meier survival analysis. Calpain targeting efficacy was assessed by a time- and dose-dependent proliferation curve, MTT assay for viability, caspase-3/7 activity, migration and angiogenesis in vitro , and gene and protein expression level modification., Results: Immunofluorescence confirmed the endothelial phenotype of our primary GECs. A significant overexpression was observed for calpain-1/2/3 (CAPN) and calpain-small-subunits-1/2 (CAPNS1), whereas calpastatin gene, the calpain natural inhibitor, was reported to be downregulated. A significant negative correlation was observed between CAPN1/CAPNS1 and patient overall survival. GEC challenging revealed that the inhibition of calpain-1 exerts the strongest proapoptotic efficacy, so GEC mortality reached the 80%, confirmed by the increased activity of caspase-3/7. Functional assays revealed a strong affection of in vitro migration and angiogenesis. Gene and protein expression proved a downregulation of MAPK, VEGF/VEGFRs, and Bcl-2, and an upregulation of caspases and Bax-family mediators., Conclusion: Overall, the differential expression of calpains and their correlation with patient survival suggest a novel promising target pathway, whose blockade showed encouraging results toward precision medicine strategies., Competing Interests: Authors EB, GA, LR have been involved, as researchers, thanks to the participation of Andremacon Srl in the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Guarnaccia, Navone, Begani, Barilla, Garzia, Campanella, Miozzo, Fontana, Alotta, Cordiglieri, Gaudino, Schisano, Ampollini, Riboni, Locatelli and Marfia.)
- Published
- 2024
- Full Text
- View/download PDF
14. Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat.
- Author
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Navone SE, Guarnaccia L, Rizzaro MD, Begani L, Barilla E, Alotta G, Garzia E, Caroli M, Ampollini A, Violetti A, Gervasi N, Campanella R, Riboni L, Locatelli M, and Marfia G
- Subjects
- Humans, Luteolin pharmacology, Phosphatidylinositol 3-Kinases, Ceramides, Sphingolipids, Glioblastoma drug therapy, Lysophospholipids, Sphingosine analogs & derivatives
- Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.
- Published
- 2023
- Full Text
- View/download PDF
15. Microgravity and the intervertebral disc: The impact of space conditions on the biomechanics of the spine.
- Author
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Marfia G, Guarnaccia L, Navone SE, Ampollini A, Balsamo M, Benelli F, Gaudino C, Garzia E, Fratocchi C, Di Murro C, Ligarotti GK, Campanella C, Landolfi A, Perelli P, Locatelli M, and Ciniglio Appiani G
- Abstract
The environmental conditions to which astronauts and other military pilots are subjected represent a unique example for understanding and studying the biomechanical events that regulate the functioning of the human body. In particular, microgravity has shown a significant impact on various biological systems, such as the cardiovascular system, immune system, endocrine system, and, last but not least, musculoskeletal system. Among the potential risks of flying, low back pain (LBP) has a high incidence among astronauts and military pilots, and it is often associated with intervertebral disc degeneration events. The mechanisms of degeneration determine the loss of structural and functional integrity and are accompanied by the aberrant production of pro-inflammatory mediators that exacerbate the degenerative environment, contributing to the onset of pain. In the present work, the mechanisms of disc degeneration, the conditions of microgravity, and their association have been discussed in order to identify possible molecular mechanisms underlying disc degeneration and the related clinical manifestations in order to develop a model of prevention to maintain health and performance of air- and space-travelers. The focus on microgravity also allows the development of new proofs of concept with potential therapeutic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marfia, Guarnaccia, Navone, Ampollini, Balsamo, Benelli, Gaudino, Garzia, Fratocchi, Di Murro, Ligarotti, Campanella, Landolfi, Perelli, Locatelli and Ciniglio Appiani.)
- Published
- 2023
- Full Text
- View/download PDF
16. Incidence of intra-procedural complications according to the timing of endovascular treatment in ruptured intracranial aneurysms.
- Author
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Gaudino C, Navone SE, Da Ros V, Guarnaccia L, Marfia G, Pantano P, Peschillo S, Triulzi FM, and Biraschi F
- Abstract
Background: Although endovascular treatment of ruptured intracranial aneurysms is well-established, some critical issues have not yet been clarified, such as the effects of timing on safety and effectiveness of the procedure. The aim of our study was to analyze the incidence of intra-procedural complications according to the timing of treatment, as they can affect morbidity and mortality., Materials and Methods: We retrospectively analyzed all patients who underwent endovascular treatment for ruptured intracranial aneurysms at three high flow center. For all patients, imaging and clinical data, aneurysm's type, mean dimension and different treatment techniques were analyzed. Intra-procedural complications were defined as thrombus formation at the aneurysm's neck, thromboembolic events, and rupture of the aneurysm. Patients were divided into three groups according to time between subarachnoid hemorrhage and treatment (<12 h hyper-early, 12-36 h early, and >36 h delayed)., Results: The final study population included 215 patients. In total, 84 patients (39%) underwent hyper-early, 104 (48%) early, and 27 (13%) delayed endovascular treatment. Overall, 69% of the patients were treated with simple coiling, 23% with balloon-assisted coiling, 1% with stent-assisted coiling, 3% with a flow-diverter stent, 3% with an intrasaccular flow disruptor device, and 0.5% with parent vessel occlusion. Delayed endovascular treatment was associated with an increased risk of total intra-procedural complications compared to both hyper-early ( p = 0.009) and early ( p = 0.004) treatments with a rate of complications of 56% (vs. 29% in hyper-early and 26% in early treated group- p = 0.011 and p = 0.008). The delayed treatment group showed a higher rate of thrombus formation and thromboembolic events. The increased risk of total intra-procedural complications in delayed treatment was confirmed, also considering only the patients treated with simple coiling and balloon-assisted coiling ( p = 0.005 and p = 0.003, respectively, compared to hyper-early and early group) with a rate of complications of 62% (vs. 28% in hyper-early and 26% in early treatments- p = 0.007 and p = 0.003). Also in this subpopulation, delayed treated patients showed a higher incidence of thrombus formation and thromboembolic events., Conclusions: Endovascular treatment of ruptured intracranial aneurysms more than 36 h after SAH seems to be associated with a higher risk of intra-procedural complications, especially thrombotic and thromboembolic events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gaudino, Navone, Da Ros, Guarnaccia, Marfia, Pantano, Peschillo, Triulzi and Biraschi.)
- Published
- 2023
- Full Text
- View/download PDF
17. Space flight and central nervous system: Friends or enemies? Challenges and opportunities for neuroscience and neuro-oncology.
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Marfia G, Navone SE, Guarnaccia L, Campanella R, Locatelli M, Miozzo M, Perelli P, Della Morte G, Catamo L, Tondo P, Campanella C, Lucertini M, Ciniglio Appiani G, Landolfi A, and Garzia E
- Subjects
- Astronauts, Humans, Central Nervous System physiology, Space Flight, Weightlessness adverse effects
- Abstract
Space environment provides many challenges to pilots, astronauts, and space scientists, which are constantly subjected to unique conditions, including microgravity, radiations, hypoxic condition, absence of the day and night cycle, etc. These stressful stimuli have the potential to affect many human physiological systems, triggering physical and biological adaptive changes to re-establish the homeostatic state. A particular concern regards the risks for the effects of spaceflight on the central nervous system (CNS), as several lines of evidence reported a great impact on neuroplasticity, cognitive functions, neurovestibular system, short-term memory, cephalic fluid shift, reduction in motor function, and psychological disturbances, especially during long-term missions. Aside these potential detrimental effects, the other side of the coin reflects the potential benefit of applicating space-related conditions on Earth-based life sciences, as cancer research. Here, we focused on examining the effect of real and simulated microgravity on CNS functions, both in humans and in cellular models, browsing the different techniques to experience or mime microgravity on-ground. Increasing evidence demonstrate that cancer cells, and brain cancer cells in particular, are negatively affected by microgravity, in terms of alteration in cell morphology, proliferation, invasion, migration, and apoptosis, representing an advancing novel side of space-based investigations. Overall, deeper understandings about the mechanisms by which space environment influences CNS and tumor biology may be promisingly translated into many clinical fields, ranging from aerospace medicine to neuroscience and oncology, representing an enormous pool of knowledge for the implementation of countermeasures and therapeutic applications., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)
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- 2022
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18. Basal serum level of Δ4-androstenedione reflects the ovaries' ability to respond to stimulation in IVF cycles: setting up a new reliable index of both ovarian reserve and response.
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Garzia E, Galiano V, Guarnaccia L, Marfia G, Murru G, Guermandi E, Riparini J, Sulpizio P, and Marconi AM
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- Androgens, Androstenedione, Anti-Mullerian Hormone, Female, Fertilization in Vitro methods, Follicle Stimulating Hormone, Follicular Atresia, Gonadotropins, Humans, Ovarian Follicle physiology, Ovary, Ovulation Induction methods, Reproducibility of Results, Ovarian Reserve
- Abstract
Purpose: Adequate androgen levels are necessary for regular follicular growth, progression beyond the pre-antral stage, and prevention of follicular atresia. The main purpose of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. The secondary purpose was to compare the possible predictive value of androgens with that of already known markers., Methods: The study included 91 infertile patients aged 30-45 years awaiting the first IVF cycle. All women underwent the same stimulation protocol and the same starting dose of recombinant FSH. As stimulation outcomes, the number of follicles recruited, estradiol and progesterone levels on the day of trigger, the total dose of gonadotropins administered, and the number of oocytes collected were recorded. Multiple linear regression and multivariate logistic regression were used to evaluate the significant predictive value of the variables for response to controlled ovarian stimulation (COS). By studying the reliability of different markers, an attempt was made to develop a single index with the highest predictive value., Results: Pearson's correlation revealed a statistically significant inverse correlation between oocytes collected and age (r = - 0.333, p < 0.001) and a positive correlation with AMH (anti-müllerian hormone) (r = 0.360, p < 0.001), antral follicle count (AFC) (r = 0.639, p < 0.001), and androstenedione (Δ4-A) (r = 0.359, p < 0.001). No significant correlation was reported with FSH (r = - 0.133, p = 0.207) and total testosterone (r = 0.180, p = 0.088). In COS good responders, the G-index (= AMH ng/mL*AFC/Δ4-A ng/dL) revealed a significantly higher level (p < 0.001) than AMH, AFC, and Δ4-A alone., Conclusion: Baseline serum Δ4-A, presumably crucial for ensuring a regular follicular growth, is a reliable marker of ovarian response to stimulation. Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles, we suggest a new index, the G-index, able to contemplate both the ovarian reserve and the Δ4-A level., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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19. A Targeted Next-Generation Sequencing Panel to Genotype Gliomas.
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Guarnaccia M, Guarnaccia L, La Cognata V, Navone SE, Campanella R, Ampollini A, Locatelli M, Miozzo M, Marfia G, and Cavallaro S
- Abstract
Gliomas account for the majority of primary brain tumors. Glioblastoma is the most common and malignant type. Based on their extreme molecular heterogeneity, molecular markers can be used to classify gliomas and stratify patients into diagnostic, prognostic, and therapeutic clusters. In this work, we developed and validated a targeted next-generation sequencing (NGS) approach to analyze variants or chromosomal aberrations correlated with tumorigenesis and response to treatment in gliomas. Our targeted NGS analysis covered 13 glioma-related genes ( ACVR1 , ATRX , BRAF , CDKN2A , EGFR , H3F3A , HIST1H3B , HIST1H3C , IDH1 , IDH2 , P53 , PDGFRA , PTEN ), a 125 bp region of the TERT promoter, and 54 single nucleotide polymorphisms (SNPs) along chromosomes 1 and 19 for reliable assessment of their copy number alterations (CNAs). Our targeted NGS approach provided a portrait of gliomas' molecular heterogeneity with high accuracy, specificity, and sensitivity in a single workflow, enabling the detection of variants associated with unfavorable outcomes, disease progression, and drug resistance. These preliminary results support its use in routine diagnostic neuropathology.
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- 2022
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20. Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics.
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Guarnaccia L, Navone SE, Masseroli MM, Balsamo M, Caroli M, Valtorta S, Moresco RM, Campanella R, Schisano L, Fiore G, Galiano V, Garzia E, Appiani GC, Locatelli M, Riboni L, and Marfia G
- Abstract
Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated., Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively., Results: Data resulting revealed a time- and μ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide., Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.
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- 2022
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21. Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma.
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Guarnaccia L, Marfia G, Masseroli MM, Navone SE, Balsamo M, Caroli M, Valtorta S, Moresco RM, Campanella R, Garzia E, Riboni L, and Locatelli M
- Abstract
Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin's potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
- Published
- 2021
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22. Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine-1-phosphate signaling.
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Navone SE, Campanella R, Guarnaccia L, Ouellet JA, Locatelli M, Cordiglieri C, Gualtierotti R, Gaudino C, Ciniglio Appiani G, Luzzi S, Borsa S, Rampini P, Pluderi M, Haglund L, Riboni L, Alini M, and Marfia G
- Subjects
- Animals, Cell Line, Cellular Microenvironment, Chemotaxis, Female, Humans, Male, Mice, Middle Aged, Nitric Oxide metabolism, Receptor Cross-Talk, Sphingosine metabolism, Intervertebral Disc Degeneration metabolism, Lysophospholipids metabolism, Microglia metabolism, Sphingosine analogs & derivatives
- Abstract
The etiology of intervertebral disc degeneration is largely unknown, but local neuroinflammation may exert a crucial role through activation of cells as microglia and pro-inflammatory cytokines production. We aimed to compare the effect of degenerated and normal intervertebral disc microenvironment on microglial cells and the potential role of sphingosine-1-phosphate, a pro-inflammatory sphingolipid, in their crosstalk. Human degenerated intervertebral discs (Pfirrmann grade IV) were obtained at surgery for spondylolisthesis. Normal intervertebral discs were collected from cadaveric normal lumbar spines. Normal and degenerated-intervertebral discs were kept in culture to obtain media conditioning. Then, microglial cells were cocultured with conditioned media and viability, proliferation, migration, chemotaxis, and inflammatory gene expression were evaluated. The results demonstrate that conditioned media from degenerated intervertebral discs activate microglial cells, increasing chemotaxis, migration, and pro-inflammatory mediators release to a great extent than normal discs. In addition, we show that the administration of sphingosine-1-phosphate to normal intervertebral disc/microglia coculture mimicked degenerative effects. Interestingly, sphingosine-1-phosphate content in conditioned media from degenerated discs was significantly higher than that from normal ones. In addition, FTY720, a functional antagonist of sphingosine-1-phosphate, potently inhibited the effect of degenerated intervertebral discs on microglial inflammatory factor transcription and migration. Our data report, for the first time, that sphingosine-1-phosphate is involved as signal in the microenvironment of human degenerated intervertebral discs. Sphingosine-1-phosphate signaling modulation by FTY720 may induce beneficial effects in counteracting microglial activation during intervertebral disc degeneration., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)
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- 2021
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23. Decreased serum level of sphingosine-1-phosphate: a novel predictor of clinical severity in COVID-19.
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Marfia G, Navone S, Guarnaccia L, Campanella R, Mondoni M, Locatelli M, Barassi A, Fontana L, Palumbo F, Garzia E, Ciniglio Appiani G, Chiumello D, Miozzo M, Centanni S, and Riboni L
- Subjects
- Aged, Biomarkers blood, COVID-19 diagnosis, COVID-19 pathology, Case-Control Studies, Female, Humans, Male, Middle Aged, Prognosis, Prospective Studies, SARS-CoV-2 isolation & purification, Severity of Illness Index, Sphingosine blood, COVID-19 blood, Lysophospholipids blood, Sphingosine analogs & derivatives
- Abstract
The severity of coronavirus disease 2019 (COVID-19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine-1-phosphate (S1P) along with severity markers, in COVID-19 patients. One hundred eleven COVID-19 patients and forty-seven healthy subjects were included. The severity of COVID-19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil-to-lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C-reactive protein (CRP), and D-dimer. Serum S1P level was inversely associated with COVID-19 severity, being significantly correlated with CRP, LDH, ferritin, and D-dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient's outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID-19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID-19., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2021
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24. Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department.
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Campanella R, Guarnaccia L, Caroli M, Zarino B, Carrabba G, La Verde N, Gaudino C, Rampini A, Luzzi S, Riboni L, Locatelli M, Navone SE, and Marfia G
- Subjects
- Humans, Laboratories, Precision Medicine, Proteomics, Brain Neoplasms surgery, Neurosurgery
- Abstract
Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the "one-size-fits-all" approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory., Competing Interests: Declaration of Competing Interest The authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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25. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks.
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Riboni L, Abdel Hadi L, Navone SE, Guarnaccia L, Campanella R, and Marfia G
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- Animals, Biological Transport, Humans, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Sphingosine metabolism, Lysophospholipids metabolism, Neoplasms metabolism, Signal Transduction, Sphingosine analogs & derivatives, Tumor Microenvironment
- Abstract
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment.
- Published
- 2020
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26. Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology.
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Campanella R, Guarnaccia L, Cordiglieri C, Trombetta E, Caroli M, Carrabba G, La Verde N, Rampini P, Gaudino C, Costa A, Luzzi S, Mantovani G, Locatelli M, Riboni L, Navone SE, and Marfia G
- Subjects
- Adenosine Diphosphate pharmacology, Adult, Aged, Blood Platelets drug effects, Blood Platelets pathology, Brain Neoplasms pathology, Cells, Cultured, Endothelial Cells metabolism, Female, Glioblastoma pathology, Humans, Male, Middle Aged, Peptide Fragments pharmacology, Phosphotransferases (Alcohol Group Acceptor) metabolism, Platelet Membrane Glycoproteins metabolism, Prognosis, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Biomarkers, Tumor metabolism, Blood Platelets metabolism, Brain Neoplasms metabolism, Glioblastoma metabolism, Neovascularization, Pathologic metabolism, Sphingosine-1-Phosphate Receptors metabolism
- Abstract
: Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers., Competing Interests: The authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2020
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27. The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity.
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Pesenti C, Navone SE, Guarnaccia L, Terrasi A, Costanza J, Silipigni R, Guarneri S, Fusco N, Fontana L, Locatelli M, Rampini P, Campanella R, Tabano S, Miozzo M, and Marfia G
- Abstract
Glioblastoma (GBM) is the most malignant human brain tumour, characterized by rapid progression, invasion, intense angiogenesis, high genomic instability, and resistance to therapies. Despite countless experimental researches for new therapeutic strategies and promising clinical trials, the prognosis remains extremely poor, with a mean survival of less than 14 months. GBM aggressive behaviour is due to a subpopulation of tumourigenic stem-like cells, GBM stem cells (GSCs), which hierarchically drive onset, proliferation, and tumour recurrence. The morbidity and mortality of this disease strongly encourage exploring genetic characteristics of GSCs. Here, using array-CGH platform, we investigated genetic and genomic aberration profiles of GBM parent tumour ( n = 10) and their primarily derived GSCs. Statistical analysis was performed by using R software and complex heatmap and corrplot packages. Pearson correlation and K -means algorithm were exploited to compare genetic alterations and to group similar genetic profiles in matched pairs of GBM and derived GSCs. We identified, in both GBM and matched GSCs, recurrent copy number alterations, as chromosome 7 polysomy, chromosome 10 monosomy, and chromosome 9p21deletions, which are typical features of primary GBM, essential for gliomagenesis. These observations suggest a condition of strong genomic instability both in GBM as GSCs. Our findings showed the robust similarity between GBM mass and GSCs (Pearson corr.≥0.65) but also highlighted a marked variability among different patients. Indeed, the heatmap reporting Gain/Loss State for 21022 coding/noncoding genes demonstrated high interpatient divergence. Furthermore, K -means algorithm identified an impairment of pathways related to the development and progression of cancer, such as angiogenesis, as well as pathways related to the immune system regulation, such as T cell activation. Our data confirmed the preservation of the genomic landscape from tumour tissue to GSCs, supporting the relevance of this cellular model to test in vitro new target therapies for GBM.
- Published
- 2019
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28. Correlation of Preoperative Von Willebrand Factor with Magnetic Resonance Imaging Perfusion and Permeability Parameters as Predictors of Prognosis in Glioblastoma.
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Navone SE, Doniselli FM, Summers P, Guarnaccia L, Rampini P, Locatelli M, Campanella R, Marfia G, and Costa A
- Subjects
- Aged, Biomarkers blood, Blood Volume, Brain diagnostic imaging, Cerebrovascular Circulation, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Brain Neoplasms diagnosis, Glioblastoma diagnosis, Magnetic Resonance Angiography, von Willebrand Factor metabolism
- Abstract
Background: Angiogenesis has been shown to be strictly related to tumor malignancy. Glioblastoma (GBM) is highly vascularized and von Willebrand Factor (VWF) plays a potent proangiogenic role. Dynamic contrast-enhanced and dynamic susceptibility contrast magnetic resonance imaging (MRI) represent a widely accepted method to assess GBM microvasculature. Our aim was to investigate the correlation between plasma VWF:Ag, permeability, and perfusion MRI parameters and examine their potential in predicting GBM patient prognosis., Methods: We retrospectively analyzed preoperative dynamic contrast-enhanced, dynamic susceptibility contrast MRI, and VWF:Ag level of 26 patients with GBM. We assessed the maximum values of relative cerebral blood flow and volume, volume transfer constant K
trans , plasma volume (Vp ) and reflux rate constant between fractional volume of the extravascular space and blood plasma (Kep ). Nonparametric Mann-Whitney test and Kaplan-Meier survival analyses were conducted and a P value < 0.05 was considered statistically significant., Results: The median VWF:Ag value was 248 IU/dL and the median follow-up duration was about 13 months. We divided patients according to low-VWF:Ag and high-VWF:Ag and we found significant differences in the median follow-up duration (19 months vs. 10 months; P = 0.04) and in Ktrans (0.31/minute vs. 0.53/minute; P = 0.02), and Kep (1.79/minute vs. 3.89/minute; P = 0.005) values. The cumulative 1-year survival was significantly shorter in patients with high-VWF:Ag and high-Kep compared with patients with low-VWF:Ag and low-Kep (37.5% vs. 68%; P = 0.05)., Conclusions: These findings, in a small group of patients, suggest a role for VWF:Ag, similar to Ktrans , and Kep as a prognostic indicator of postoperative survival of patients with GBM., (Copyright © 2018. Published by Elsevier Inc.)- Published
- 2019
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29. Significance and Prognostic Value of The Coagulation Profile in Patients with Glioblastoma: Implications for Personalized Therapy.
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Navone SE, Guarnaccia L, Locatelli M, Rampini P, Caroli M, La Verde N, Gaudino C, Bettinardi N, Riboni L, Marfia G, and Campanella R
- Subjects
- Aged, Female, Fibrin Fibrinogen Degradation Products metabolism, Fibrinogen metabolism, Hemoglobins metabolism, Humans, Kaplan-Meier Estimate, Leukocyte Count, Male, Meningeal Neoplasms blood, Meningeal Neoplasms diagnosis, Meningioma blood, Meningioma diagnosis, Middle Aged, Prognosis, von Willebrand Factor metabolism, Brain Neoplasms blood, Brain Neoplasms diagnosis, Glioblastoma blood, Glioblastoma diagnosis, Partial Thromboplastin Time methods
- Abstract
Background: Coagulation is an important aspect of the vascular microenvironment in which brain tumors evolve. Patients with tumor often show aberrant coagulation and fibrinolysis activation. In particular, glioblastoma (GBM), the most aggressive primary brain tumor, is associated with a state of hypercoagulability, and venous thromboembolism is a common complication of this cancer and its treatment. Our study aims to investigate the clinical and prognostic significance of routine laboratory tests to assess the coagulative state of patients with brain tumors, to identify potential new prognostic factors and targets for personalized therapy., Methods: Blood samples were collected from patients with GBM (n = 58) and patients with meningioma (MNG, n = 22), before any treatment. The parameters analyzed were prothrombin time (PT), activated partial thromboplastin time (aPTT), D dimer (DD), fibrinogen, von Willebrand factor (VWF), leukocyte count, and hemoglobin levels., Results: Plasma levels of PT and aPTT were significantly reduced in GBMs compared with MNGs (P < 0.05), whereas DD, VWF:Ag levels, and leukocyte count were significantly higher in GBMs than in MNGs (P < 0.01). Furthermore, we observed that patients with GBM with reduced PT and aPTT and high levels of DD and VWF, defined as hypercoagulable patients, showed reduced overall survival (P < 0.05) compared with nonhypercoagulable patients., Conclusions: Our data support the assumption that patients with GBM show a plasma hypercoagulable profile and that coagulation profile is related to adverse outcome in patients with GBM. If confirmed, hypercoagulability could play an important role as a prognostic factor of the disease and in the decision of an antithrombotic prophylaxis., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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30. Aspirin Affects Tumor Angiogenesis and Sensitizes Human Glioblastoma Endothelial Cells to Temozolomide, Bevacizumab, and Sunitinib, Impairing Vascular Endothelial Growth Factor-Related Signaling.
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Navone SE, Guarnaccia L, Cordiglieri C, Crisà FM, Caroli M, Locatelli M, Schisano L, Rampini P, Miozzo M, La Verde N, Riboni L, Campanella R, and Marfia G
- Subjects
- Angiogenesis Inhibitors pharmacology, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Immunological pharmacology, Blotting, Western, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Survival drug effects, Drug Synergism, Endothelial Cells metabolism, Glioblastoma genetics, Glioblastoma metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit drug effects, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mitogen-Activated Protein Kinase Kinases drug effects, Mitogen-Activated Protein Kinase Kinases genetics, Mitogen-Activated Protein Kinase Kinases metabolism, Proto-Oncogene Proteins c-akt drug effects, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA, Messenger drug effects, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Signal Transduction, Vascular Endothelial Growth Factor A drug effects, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 drug effects, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 drug effects, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, bcl-2-Associated X Protein drug effects, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, ras Proteins drug effects, ras Proteins genetics, ras Proteins metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents pharmacology, Aspirin pharmacology, Bevacizumab pharmacology, Brain Neoplasms blood supply, Endothelial Cells drug effects, Glioblastoma blood supply, Sunitinib pharmacology, Temozolomide pharmacology
- Abstract
Background: Glioblastoma (GBM) is the most common and fatal human brain tumor, with the worst prognosis. The aberrant microenvironment, enhanced by the activation of proangiogenic mediators such as hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and their downstream effectors, sustain GBM malignancy. Proangiogenic signaling represents an attractive chemotherapeutic target. Recent evidence suggests a therapeutic benefit from aspirin (acetylsalicylic acid, or ASA) intake in reducing risk and cancer progression., Methods: In the present study, human primary GBM-endothelial cells (ECs) were used to ascertain whether ASA could inhibit angiogenesis and improve cell sensitivity to drugs. The impact of ASA was observed by measuring cell viability, tube-like structure formation, migration, VEGF production, and proliferative, proangiogenic, and apoptotic modulators expression, such as HIF-1α/VEGF/vascular endothelial growth factor receptor/(VEGFR)-1/VEGFR-2, Ras/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/AKT signaling axis, and Bcl-2-associated X protein/B-cell lymphoma 2 (BCL-2) ratio. Furthermore, we evaluated the effect of ASA alone or in combination with temozolomide (TMZ), bevacizumab (BEV), and sunitinib (SUN)., Results: Our data reported that ASA affected GBM-EC viability, tube-like structure formation, cell migration, and VEGF releasing in a dose-dependent manner and that combined treatments with TMZ, BEV, and SUN synergized to counteract proangiogenic cell ability. mRNA expression analysis displayed a marked effect of ASA in reducing VEGF, VEGFR-1, HIF-1α, RAS, mitogen-activated protein kinase kinase, AKT, and BCL-2, as well a combined anticancer effect of ASA together with TMZ, BEV, and SUN. Levels of HIF-1α, VEGFR-2, Bcl-2-associated X protein, and BCL-2 protein expression confirmed a positive trend., Conclusions: ASA and antiangiogenic therapies showed synergetic anticancer efficacy in human primary GBM-ECs. Thus, the combination of conventional chemotherapy with ASA may offer a new strategy to counteract tumor malignancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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31. A bidirectional crosstalk between glioblastoma and brain endothelial cells potentiates the angiogenic and proliferative signaling of sphingosine-1-phosphate in the glioblastoma microenvironment.
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Abdel Hadi L, Anelli V, Guarnaccia L, Navone S, Beretta M, Moccia F, Tringali C, Urechie V, Campanella R, Marfia G, and Riboni L
- Subjects
- Animals, Cell Line, Tumor, Cell Membrane drug effects, Cell Membrane metabolism, Cell Movement drug effects, Cell Proliferation drug effects, Coculture Techniques, Endothelial Cells drug effects, Endothelial Cells pathology, Glioblastoma metabolism, Humans, Neovascularization, Pathologic pathology, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) metabolism, Protein Kinase Inhibitors pharmacology, Rats, Receptors, Lysosphingolipid metabolism, Sphingosine metabolism, Brain pathology, Endothelial Cells metabolism, Glioblastoma pathology, Lysophospholipids metabolism, Neovascularization, Pathologic metabolism, Signal Transduction drug effects, Sphingosine analogs & derivatives, Tumor Microenvironment drug effects
- Abstract
Glioblastoma is one of the most malignant, angiogenic, and incurable tumors in humans. The aberrant communication between glioblastoma cells and tumor microenvironment represents one of the major factors regulating glioblastoma malignancy and angiogenic properties. Emerging evidence implicates sphingosine-1-phosphate signaling in the pathobiology of glioblastoma and angiogenesis, but its role in glioblastoma-endothelial crosstalk remains largely unknown. In this study, we sought to determine whether the crosstalk between glioblastoma cells and brain endothelial cells regulates sphingosine-1-phosphate signaling in the tumor microenvironment. Using human glioblastoma and brain endothelial cell lines, as well as primary brain endothelial cells derived from human glioblastoma, we report that glioblastoma-co-culture promotes the expression, activity, and plasma membrane enrichment of sphingosine kinase 2 in brain endothelial cells, leading to increased cellular level of sphingosine-1-phosphate, and significant potentiation of its secretion. In turn, extracellular sphingosine-1-phosphate stimulates glioblastoma cell proliferation, and brain endothelial cells migration and angiogenesis. We also show that, after co-culture, glioblastoma cells exhibit enhanced expression of S1P
1 and S1P3 , the sphingosine-1-phosphate receptors that are of paramount importance for cell growth and invasivity. Collectively, our results envision glioblastoma-endothelial crosstalk as a multi-compartmental strategy to enforce pro-tumoral sphingosine-1-phosphate signaling in the glioblastoma microenvironment., (Copyright © 2018. Published by Elsevier B.V.)- Published
- 2018
- Full Text
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32. Spontaneous intracerebral hemorrhage as presentation of atypical central neurocytoma: the role of angiogenesis through the characterization of tumor endothelial cells.
- Author
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Marfia G, Pirola E, Navone SE, Beretta M, Guarnaccia L, Trombetta E, Franzini A, Rampini P, and Campanella R
- Subjects
- Adult, Brain Neoplasms pathology, Cerebral Hemorrhage pathology, Humans, Male, Neurocytoma pathology, Brain Neoplasms complications, Cerebral Hemorrhage etiology, Endothelial Cells pathology, Neovascularization, Pathologic pathology, Neurocytoma complications
- Abstract
A 36-year-old white man presented with sudden-onset headache and rapid deterioration of consciousness. Computer tomography revealed a right capsular intra-parenchimal hemorrhage with an intraventricular component; therefore, emergency surgery was performed. Once the hematoma was evacuated, the cause of the hemorrhage was identified as a tumor mass and it was resected. Histopathological and immunohistochemical examinations of the surgical specimen disclosed a diagnosis of atypical central neurocytoma. By using a protocol recently set up in our laboratory, we succeeded in isolating and propagating, for the first time, human endothelial cells from central neurocytoma (CN-ECs). Different analyses revealed that isolated CN-ECs consist of a pure endothelial cell population, with the expression of endothelial markers (CD31, CD309/VEGFR2, CD105, eNOS) and with angiogenic properties, such as the uptake of LDL. Moreover, CN-ECs spontaneously organize in a vascular-like structure. The goal of this case report is to stress the need for further studies focused on understanding the causes of the onset of an intra-parenchimal hemorrhage in the presence of an atypical central neurocytoma in order to tailor treatments to each single patient and achieve the best clinical outcome.
- Published
- 2018
- Full Text
- View/download PDF
33. Angiogenesis in human brain tumors: screening of drug response through a patient-specific cell platform for personalized therapy.
- Author
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Guarnaccia L, Navone SE, Trombetta E, Cordiglieri C, Cherubini A, Crisà FM, Rampini P, Miozzo M, Fontana L, Caroli M, Locatelli M, Riboni L, Campanella R, and Marfia G
- Subjects
- Aged, Aged, 80 and over, Brain Neoplasms pathology, Endothelial Cells drug effects, Endothelial Cells pathology, Glioblastoma pathology, Humans, Middle Aged, Neovascularization, Pathologic pathology, Precision Medicine methods, Tumor Cells, Cultured, Angiogenesis Inhibitors pharmacology, Brain Neoplasms blood supply, Brain Neoplasms drug therapy, Drug Screening Assays, Antitumor methods, Glioblastoma blood supply, Glioblastoma drug therapy, Neovascularization, Pathologic drug therapy
- Abstract
Gliomas are the most common brain tumors, with diverse biological behaviour. Glioblastoma (GBM), the most aggressive and with the worst prognosis, is characterized by an intense and aberrant angiogenesis, which distinguishes it from low-grade gliomas (LGGs) and benign expansive lesions, as meningiomas (MNGs). With increasing evidence for the importance of vascularization in tumor biology, we focused on the isolation and characterization of endothelial cells (ECs) from primary GBMs, LGGs and MNGs. Gene expression analysis by Real-Time PCR, immunofluorescence and flow cytometry analysis, tube-like structures formation and vascular permeability assays were performed. Our results showed a higher efficiency of ECs to form a complex vascular architecture, as well as a greater impairment of a brain blood barrier model, and an overexpression of pro-angiogenic mediators in GBM than in LGG and MNG. Furthermore, administration of temozolomide, bevacizumab, and sunitinib triggered a different proliferative, apoptotic and angiogenic response, in a dose and time-dependent manner. An increased resistance to temozolomide was observed in T98G cells co-cultured in GBM-EC conditioned media. Therefore, we developed a novel platform to reproduce tumor vascularization as "disease in a dish", which allows us to perform screening of sensitivity/resistance to drugs, in order to optimize targeted approaches to GBM therapy.
- Published
- 2018
- Full Text
- View/download PDF
34. Inflammatory mediators and signalling pathways controlling intervertebral disc degeneration.
- Author
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Navone SE, Marfia G, Giannoni A, Beretta M, Guarnaccia L, Gualtierotti R, Nicoli D, Rampini P, and Campanella R
- Subjects
- Animals, Humans, Inflammation Mediators immunology, Intervertebral Disc Degeneration immunology, Intervertebral Disc Degeneration pathology, Inflammation Mediators metabolism, Intervertebral Disc Degeneration physiopathology, Signal Transduction physiology
- Abstract
Intervertebral disc (IVD) degeneration (IDD) is one of the major causes of back pain, a condition that represents a serious socio-economic burden. Deeper knowledge of the complex and fine relationship between IVD degeneration, tissue inflammation and pain, appears to be critical to improve the current therapies, which have so far proven themselves ineffective. Upon degeneration, IVD tissues become inflamed, and this inflammatory microenvironment is associated with a cascade of degenerative events that may eventually cause discogenic pain. In particular, several studies have highlighted the major role of a number of proinflammatory mediators not only in the onset of the inflammatory condition, but also in the development of IDD in general. In this review, we will present the main pathological events that occur during disc degeneration, focusing on the relationship between the abnormal inflammatory milieu of the degenerating IVD, IDD and the generation of pain. Finally, we will present the current therapies for the treatment of IDD and low back pain, and the perspectives of future, more effective therapies.
- Published
- 2017
- Full Text
- View/download PDF
35. Modulation of Neuroinflammation in the Central Nervous System: Role of Chemokines and Sphingolipids.
- Author
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Gualtierotti R, Guarnaccia L, Beretta M, Navone SE, Campanella R, Riboni L, Rampini P, and Marfia G
- Subjects
- Animals, Humans, Neuroimmunomodulation immunology, Central Nervous System immunology, Central Nervous System physiopathology, Chemokines immunology, Inflammation immunology, Sphingolipids immunology
- Abstract
Neuroinflammation is a process involved in the pathogenesis of different disorders, both autoimmune, such as neuropsychiatric systemic lupus erythematosus, and degenerative, such as Alzheimer's and Parkinson's disease. In the central nervous system, the local milieu is tightly regulated by different mediators, among which are chemoattractant cytokines, also known as chemokines. These small molecules are able to modulate trafficking of immune cells in the course of nervous system development or in response to tissue damage, and different patterns of chemokine molecule and receptor expression have been described in several neuroinflammatory disorders. In recent years, a number of studies have highlighted a pivotal role of sphingolipids in regulating neuroinflammation. Sphingolipids have different functions, among which are the control of leukocyte egress from lymphonodes into inflamed tissues, the expression of various mediators of inflammation and a direct effect on the cells of the central nervous system as regulators of neuroinflammation. In the future, a better knowledge of these two groups of mediators could provide insight into the pathogenesis of neuroinflammatory disorders and could help develop novel diagnostic tools and therapeutic strategies.
- Published
- 2017
- Full Text
- View/download PDF
36. Silibinin Regulates Lipid Metabolism and Differentiation in Functional Human Adipocytes.
- Author
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Barbagallo I, Vanella L, Cambria MT, Tibullo D, Godos J, Guarnaccia L, Zappalà A, Galvano F, and Li Volti G
- Abstract
Silibinin, a natural plant flavonolignan is the main active constituent found in milk thistle (Silybum marianum). It is known to have hepatoprotective, anti-neoplastic effect, and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM) treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α, and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS, and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodeling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα, and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.
- Published
- 2016
- Full Text
- View/download PDF
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