Search

Your search keyword '"Svelto M"' showing total 478 results
Start Over Author "Svelto M"
478 results on '"Svelto M"'

5. AQP4-dependent glioma cell features affect the phenotype of surrounding cells via extracellular vesicles

Author

Simone, L, Pisani, F, Binda, E, Frigeri, A, Vescovi, A, Svelto, M, Nicchia, G, Simone L., Pisani F., Binda E., Frigeri A., Vescovi A. L., Svelto M., Nicchia G. P., Simone, L, Pisani, F, Binda, E, Frigeri, A, Vescovi, A, Svelto, M, Nicchia, G, Simone L., Pisani F., Binda E., Frigeri A., Vescovi A. L., Svelto M., and Nicchia G. P.

Abstract

Background: Extracellular vesicles (EVs) are membrane-enclosed particles released systemically by all cells, including tumours. Tumour EVs have been shown to manipulate their local environments as well as distal targets to sustain the tumour in a variety of tumours, including glioblastoma (GBM). We have previously demonstrated the dual role of the glial water channel aquaporin-4 (AQP4) protein in glioma progression or suppression depending on its aggregation state. However, its possible role in communication mechanisms in the microenvironment of malignant gliomas remains to be unveiled. Results: Here we show that in GBM cells AQP4 is released via EVs that are able to affect the GBM microenvironment. To explore this role, EVs derived from invasive GBM cells expressing AQP4-tetramers or apoptotic GBM cells expressing orthogonal arrays of particles (AQP4-OAPs) were isolated, using a differential ultracentrifugation method, and were added to pre-seeded GBM cells. Confocal microscopy analysis was used to visualize the interaction and uptake of AQP4-containing EVs by recipient cells. Chemoinvasion and Caspase3/7 activation assay, performed on recipient cells after EVs uptake, revealed that EVs produced by AQP4-tetramers expressing cells were able to drive surrounding tumour cells toward the migratory phenotype, whereas EVs produced by AQP4-OAPs expressing cells drive them toward the apoptosis pathway. Conclusion: This study demonstrates that the different GBM cell phenotypes can be transferred by AQP4-containing EVs able to influence tumour cell fate toward invasiveness or apoptosis. This study opens a new perspective on the role of AQP4 in the brain tumour microenvironment associated with the EV-dependent communication mechanism.

Published
2022

9. AQP4 aggregation state is a determinant for glioma cell fate

Author

Simone, L, Pisani, F, Mola, M, De Bellis, M, Merla, G, Micale, L, Frigeri, A, Vescovi, A, Svelto, M, Nicchia, G, Simone L., Pisani F., Mola M. G., De Bellis M., Merla G., Micale L., Frigeri A., Vescovi A. L., Svelto M., Nicchia G. P., Simone, L, Pisani, F, Mola, M, De Bellis, M, Merla, G, Micale, L, Frigeri, A, Vescovi, A, Svelto, M, Nicchia, G, Simone L., Pisani F., Mola M. G., De Bellis M., Merla G., Micale L., Frigeri A., Vescovi A. L., Svelto M., and Nicchia G. P.

Abstract

The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton. Significance: This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.

Published
2019

10. Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats

Author

Zalfa, C, Rota Nodari, L, Vacchi, E, Gelati, M, Profico, D, Boido, M, Binda, E, De Filippis, L, Copetti, M, Garlatti, V, Daniele, P, Rosati, J, De Luca, A, Pinos, F, Cajola, L, Visioli, A, Mazzini, L, Vercelli, A, Svelto, M, Vescovi, A, Ferrari, D, Zalfa C., Rota Nodari L., Vacchi E., Gelati M., Profico D., Boido M., Binda E., De Filippis L., Copetti M., Garlatti V., Daniele P., Rosati J., De Luca A., Pinos F., Cajola L., Visioli A., Mazzini L., Vercelli A., Svelto M., Vescovi A. L., Ferrari D., Zalfa, C, Rota Nodari, L, Vacchi, E, Gelati, M, Profico, D, Boido, M, Binda, E, De Filippis, L, Copetti, M, Garlatti, V, Daniele, P, Rosati, J, De Luca, A, Pinos, F, Cajola, L, Visioli, A, Mazzini, L, Vercelli, A, Svelto, M, Vescovi, A, Ferrari, D, Zalfa C., Rota Nodari L., Vacchi E., Gelati M., Profico D., Boido M., Binda E., De Filippis L., Copetti M., Garlatti V., Daniele P., Rosati J., De Luca A., Pinos F., Cajola L., Visioli A., Mazzini L., Vercelli A., Svelto M., Vescovi A. L., and Ferrari D.

Abstract

Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of

Published
2019

13. Lovastatin-induced cholesterol depletion affects both apical sorting and endocytosis of aquaporin-2 in renal cells

Author

Procino, G., Barbieri, C., Carmosino, M., Rizzo, F., Valenti, G., and Svelto, M.

Subjects
Biological sciences
Abstract

Vasopressin causes the redistribution of the water channel aquaporin-2 (AQP2) from cytoplasmic storage vesicles to the apical plasma membrane of collecting duct principal cells, leading to urine concentration. The molecular mechanisms regulating the selective apical sorting of AQP2 are only partially uncovered. In this work, we investigate whether AQP2 sorting/trafficking is regulated by its association with membrane rafts. In both MCD4 cells and rat kidney, AQP2 preferentially associated with Lubrol WX-insoluble membranes regardless of its presence in the storage compartment or at the apical membrane. Block-andrelease experiments indicate that 1) AQP2 associates with detergent-resistant membranes early in the biosynthetic pathway; 2) strong cholesterol depletion delays the exit of AQP2 from the trans-Golgi network. Interestingly, mild cholesterol depletion promoted a dramatic accumulation of AQP2 at the apical plasma membrane in MCD4 cells in the absence of forskolin stimulation. An internalization assay showed that AQP2 endocytosis was clearly reduced under this experimental condition. Taken together, these data suggest that association with membrane rafts may regulate both AQP2 apical sorting and endocytosis. membrane rafts doi: 10.1152/ajprenal.00359.2009

Published
2010

14. MiT/TFE factors control ER‐phagy via transcriptional regulation of FAM134B

Author

Cinque, L., Leonibus, C. De., Iavazzo, M., Krahmer, N., Intartaglia, D., Salierno, F.G., Cegli, R. De, Malta, C. Di, Svelto, M., Lanzara, C., Maddaluno, M., Wanderlingh, L.G., Huebner, A.K., Cesana, M., Bonn, F., Polishchuk, E., Hübner, C.A., Conte, I., Dikic, I., Mann, M., Ballabio, A., Sacco, F., Grumati, P., Settembre, C., and Publica

Abstract

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER‐phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER‐phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER‐phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3-master regulators of lysosomal biogenesis and autophagy-control ER‐phagy by inducing the expression of the ER‐phagy receptor FAM134B. The TFEB/TFE3‐FAM134B axis promotes ER‐phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK‐dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K‐PKB/Akt‐mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER‐phagy to respond to both metabolic and developmental cues.

Published
2020

31. p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

Author

Carugo, A., Minelli, R., Sapio, L., Soeung, M., Carbone, F., Robinson, F. S., Tepper, J., Chen, Z., Lovisa, S., Svelto, M., Amin, S., Srinivasan, S., Del Poggetto, E., Loponte, S., Puca, F., Dey, P., Malouf, G. G., Su, X., Li, L., Lopez-Terrada, D., Rakheja, D., Lazar, A. J., Netto, G. J., Rao, P., Sgambato, A., Maitra, A., Tripathi, D. N., Walker, C. L., Karam, J. A., Heffernan, T. P., Viale, A., Roberts, C. W. M., Msaouel, P., Tannir, N. M., Draetta, G. F., Genovese, G., Sgambato A. (ORCID:0000-0002-9487-4563), Genovese G., Carugo, A., Minelli, R., Sapio, L., Soeung, M., Carbone, F., Robinson, F. S., Tepper, J., Chen, Z., Lovisa, S., Svelto, M., Amin, S., Srinivasan, S., Del Poggetto, E., Loponte, S., Puca, F., Dey, P., Malouf, G. G., Su, X., Li, L., Lopez-Terrada, D., Rakheja, D., Lazar, A. J., Netto, G. J., Rao, P., Sgambato, A., Maitra, A., Tripathi, D. N., Walker, C. L., Karam, J. A., Heffernan, T. P., Viale, A., Roberts, C. W. M., Msaouel, P., Tannir, N. M., Draetta, G. F., Genovese, G., Sgambato A. (ORCID:0000-0002-9487-4563), and Genovese G.

Abstract

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

Published
2019

38. Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS

Author

D'Erchia, A. M., Gallo, A., Manzari, C., Raho, S., Horner, D. S., Chiara, M., Valletti, A., Aiello, I., Mastropasqua, F., Ciaccia, L., Locatelli, Franco, Pisani, F., Nicchia, G. P., Svelto, M., Pesole, G., Picardi, E., Locatelli F. (ORCID:0000-0002-7976-3654), D'Erchia, A. M., Gallo, A., Manzari, C., Raho, S., Horner, D. S., Chiara, M., Valletti, A., Aiello, I., Mastropasqua, F., Ciaccia, L., Locatelli, Franco, Pisani, F., Nicchia, G. P., Svelto, M., Pesole, G., Picardi, E., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post-mortem ALS human donors affected by the sporadic form of the disease (which comprises ∼90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing.

Published
2017

39. Kidney Stone Risk during Microgravity and Long-Term Bed Rest: Role of Hypercalciuria and Aquaporins

Author

Tamma G, Di Mise A, Ranieri M, Svelto M, Bilancio G, Cirillo M, De Santo NG, Valenti G, Tamma, G, Di Mise, A, Ranieri, M, Svelto, M, Bilancio, G, Cirillo, M, De Santo, Ng, and Valenti, G

Abstract

Background: Exposure to microgravity results in alterations of renal function, uid redistribution and bone loss which contributes to the potential risk of renal stone formation. Hypercalciuria is recognized as a condition predisposing to calcium nephrolitiasis and long-term space ights cause bone loss coupled to a rise of urinary calcium excretion. Methods: AQP2 excretion was measured by ELISA in urines collected from healthy volunteers participating at the studies. Results: We recently demonstrated that high calcium delivery to the collecting duct reduces local Aquaporin 2 (AQP2) mediated water reabsorption under vasopressin action, thus limiting the maximal urinary concentration and reducing calcium saturation. To analyze alteration of renal water handling during microgravity, we evaluated two ground-based analog of space ight, thermoneutral water immersion and bed rest. AQP2 excretion and diuresis were measured in two separated studies mimicking acute adaptation (6 hours water immersion) or chronic adaptation (35 days bed rest) to microgravity. Water immersion resulted in a signi cant increase in urinary output apparently not related to AQP2 alteration and manly due to reduced vasopressin secretion. On the other hand 35 days bed rest resulted in an increase in urinary calcium, which coincided with a signi cant decrease in AQP2 excretion (645±7.4 fmol/ml to 569±10.3 fmol/ml), which is expected to result in urine dilution reducing the risk of calcium saturation. Conclusions: Our data indicate that calciuria and water balance have to be strictly controlled during microgravity and long-term bed rest as key elements for the risk of kidney stone formation.

Published
2013

40. SOCS3 and IRS-1 Gene Expression Differs Between Genotype 1 and Genotype 2 HCV-Infected HEPG2 Cells

Author

PERSICO, LICER ENRICO ANGELO, RUSSO, RAFFAELE, CAPASSO, MARTA, TIRIBELLI, CLAUDIO, Persico, E, Svelto, M, Spano, D, Andolfo, I, La Mura, V, Torella, R, Iolascon, A., Persico, LICER ENRICO ANGELO, Russo, Raffaele, Persico, E, Svelto, M, Spano, D, Andolfo, I, La Mura, V, Capasso, Marta, Tiribelli, Claudio, Torella, R, and Iolascon, A.

Subjects
Gene Expression Regulation* Genotype Hep G2 Cells Hepacivirus/physiology* Hepatitis C/genetics* Hepatitis C/metabolism Humans Insulin Receptor Substrate Proteins/genetics* Insulin Receptor Substrate Proteins/metabolism* Proto-Oncogene Proteins c-akt/metabolism Suppressor of Cytokine Signaling Proteins/genetics* Suppressor of Cytokine Signaling Proteins/metabolism* Virus Replication
Abstract

BACKGROUND: The poor response to antiviral treatment of hepatitis C virus (HCV)-infected patients with genotype 1b has been associated with a higher prevalence of metabolic syndrome. However, the molecular link between these clinical entities is not clear. The goal of this study was to clarify the role of genotype 1b and 2 in the genetic expression of suppressor of cytokine signaling 3 (SOCS3) and insulin receptor substrate 1 (IRS-1). METHODS: We infected human hepatocellular carcinoma cell line (HepG2) cells with human HCV genotype 1b or 2 and measured the gene and protein expression of SOCS3 at various times. We also evaluated impairment in the insulin pathway by analysis of IRS-1 and phospho-AKT. For the control, we used HepG2 cell cultures treated with non-infectious serum. We also demonstrated the occurrence of HCV infection by the detection of both positive and negative strands in the cells and culture medium. To test infection of the HepG2 cells, we performed quantitative real-time polymerase chain reaction (qRT-PCR) of viral load at different time points. We analyzed the viral genotype in the pellet and supernatant. RESULTS: At each time point, we found positive and negative strands in the infected cells, while in the medium we found positive, but no negative strands. We also detected the presence of the correct genotype in the medium. Two weeks following infection when the viral load was higher, we tested genotype 1b and 2 infected cells. SOCS3 gene expression was significantly higher in genotype 1b-infected cells (median 2.56; mean 2.82+/-0.59) compared with genotype 2 (median 1.34; mean 1.46+/-0.31) (p=0.04) and control cells (median 1.09; mean 1.02+/-0.11, p=0.02). There was no difference between cells exposed to genotype 2 and control cells. Conversely, IRS-1 was significantly lower in genotype 1b-infected cells (median 15.97; mean 15.45+/-0.67) compared with genotype 2-infected cells (median 16.45; mean 16.44+/-0.01, p=0.04). Statistically significant differences were seen when comparing the pAKT/AKT ratio in genotype 1b-infected cells (0.19+/-0.034) and not genotype 1b-infected (genotype 2-infected and non-infected) cells (0.253+/-0.004, p=0.03). This inverse regulation is compatible with interactions between the molecular expression of SOCS3, IRS-1 and phospho-AKT mediated by the genotype 1b virus. CONCLUSIONS: Up-regulation of the SOCS3 gene might be one of the mechanisms governing non-response to therapy and expression of insulin resistance mediated via a direct mechanism at this level of genotype 1b HCV.

Published
2009

49. New Insights into the CD133 (Prominin-1) Expression in Mouse and Human Colon Cancer Cells

Author

Sgambato, Alessandro, Corbi, M, Svelto, M, Caredda, E, and Cittadini, A.

Subjects
Mice, colon cancer, stem cells, Settore MED/04 - PATOLOGIA GENERALE, Colonic Neoplasms, Neoplastic Stem Cells, Animals, Humans, Colorectal Neoplasms, Prognosis
Abstract

Following its discovery as a cancer stem cell marker, CD133 has been widely studied for its role in colorectal tumorigenesis. Indeed, colon cancer remains one of the major causes of cancer-related disease and death worldwide, and there is a strong need for an improvement of current diagnostic, prognostic, and therapeutic strategies. Thus, efforts have been devoted to try to understand whether CD133 might play a role in human colorectal tumorigenesis and might contribute to a better management of colon cancer patients. This chapter reviews the current knowledge on CD133 expression in normal and cancer colon tissues, both in humans and mice, discussing apparently conflicting data reported in the two species. Moreover, a great attention is devoted to the available information regarding the functional role of CD133 in colon cancer cells. Finally, the proposed clinical applications of CD133, as a prognostic and/or predictive marker as well as a target for novel antineoplastic strategies in colorectal cancer, are discussed. Overall, the available data support a potential important role of CD133 as cancer stem cell marker in colon cancer cells and warrant future studies to verify its potential use in the routine clinical management of colon cancer patients.

Published
2012

50. Aquaporin-8-facilitated mitochondrial ammonia transport

Author

Soria LR, Fanelli E, Altamura N, Svelto M, Marinelli RA, Calamita G. Altamura N, and Calamita G.

Subjects
Biophysics, Aquaporin, Mitochondria, Liver, Saccharomyces cerevisiae, Mitochondrion, Aquaporins, Biochemistry, Mitochondrial membrane transport protein, Ammonia, Yeast expression system, Inner mitochondrial membrane, Inner membrane, Animals, Molecular Biology, Mitochondrial transport, biology, Formamides, Brain, Water, Aqua-ammoniaporin, Biological Transport, Cell Biology, Mitochondrial carrier, Recombinant Proteins, Mitochondria, Rats, Liver, biology.protein, ATP–ADP translocase, Ammonia transport
Abstract

Aquaporin-8 (AQP8) is a membrane channel permeable to water and ammonia. As AQP8 is expressed in the inner mitochondrial membrane of several mammalian tissues, we studied the effect of the AQP8 expression on the mitochondrial transport of ammonia. Recombinant rat AQP8 was expressed in the yeast Saccharomyces cerevisiae. The presence of AQP8 in the inner membrane of yeast mitochondria was demonstrated by subcellular fractionation and immunoblotting analysis. The ammonia transport was determined in isolated mitochondria by stopped flow light scattering using formamide as ammonia analog. We found that the presence of AQP8 increased by threefold mitochondrial formamide transport. AQP8-facilitated mitochondrial formamide transport in rat native tissue was confirmed in liver (a mitochondrial AQP8-expressing tissue) vs. brain (a mitochondrial AQP8 non-expressing tissue). Comparative studies indicated that the AQP8-mediated mitochondrial movement of formamide was markedly higher than that of water. Together, our data suggest that ammonia diffusional transport is a major function for mitochondrial AQP8.

Published
2010
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results