44 results on '"Carelli, Stephana"'
Search Results
2. Mechanical Activation of Adipose Tissue and Derived Mesenchymal Stem Cells: Novel Anti-Inflammatory Properties.
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Carelli, Stephana, Colli, Mattia, Vinci, Valeriano, Caviggioli, Fabio, Klinger, Marco, and Gorio, Alfredo
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ADIPOSE tissues , *MESENCHYMAL stem cells , *ANTI-inflammatory agents , *TUMOR necrosis factors , *CYTOKINES - Abstract
The adipose tissue is a source of inflammatory proteins, such as TNF, IL-6, and CXCL8. Most of their production occurs in macrophages that act as scavengers of dying adipocytes. The application of an orbital mechanical force for 6-10 min at 97 g to the adipose tissue, lipoaspirated and treated according to Coleman procedures, abolishes the expression of TNF-α and stimulates the expression of the anti-inflammatory protein TNF-stimulated gene-6 (TSG-6). This protein had protective and anti-inflammatory effects when applied to animal models of rheumatic diseases. We examined biopsy, lipoaspirate, and mechanically activated fat and observed that in addition to the increased TSG-6, Sox2, Nanog, and Oct4 were also strongly augmented by mechanical activation, suggesting an effect on stromal cell stemness. Human adipose tissue-derived mesenchymal stem cells (hADSCs), produced from activated fat, grow and differentiate normally with proper cell surface markers and chromosomal integrity, but their anti-inflammatory action is far superior compared to those mesenchymal stem cells (MSCs) obtained from lipoaspirate. The expression and release of inflammatory cytokines from THP-1 cells was totally abolished in mechanically activated adipose tissue-derived hADSCs. In conclusion, we report that the orbital shaking of adipose tissue enhances its anti-inflammatory properties, and derived MSCs maintain such enhanced activity. [ABSTRACT FROM AUTHOR]
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- 2018
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3. Recovery from experimental parkinsonism by intrastriatal application of erythropoietin or EPO-releasing neural precursors.
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Carelli, Stephana, Giallongo, Toniella, Viaggi, Cristina, Latorre, Elisa, Gombalova, Zuzana, Raspa, Andrea, Mazza, Massimiliano, Vaglini, Francesca, Di Giulio, Anna Maria, and Gorio, Alfredo
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PARKINSONIAN disorders , *ERYTHROPOIETIN , *NEUROPROTECTIVE agents , *REGENERATIVE medicine , *STEM cell treatment , *THERAPEUTICS - Abstract
An extensive literature has shown a powerful neuroprotective action of Erythropoietin (EPO) both in vivo and in vitro. This study shows that EPO, whether ectopically administered or released by neural precursors, does reverse MPTP-induced parkinsonism in mice. Unilateral stereotaxic injection of 2.5 × 10 5 erythropoietin-releasing neural precursor cells (Er-NPCs) rescued degenerating striatal dopaminergic neurons and promoted behavioral recovery as shown by three independent behavioral tests. These effects were replicated through direct intrastriatal administration of recombinant human EPO. At the end of the observational period, most of the transplanted Er-NPCs were vital and migrated via the striatum to reach Substantia Nigra. The restorative effects appear to be mediated by EPO since co-injection of anti-EPO or anti-EPOR antibodies antagonized the positive outcomes. Furthermore, this report supports the neuroprotective action of EPO, which may also be achieved via administration of EPO-releasing cells such as Er-NPCs. [ABSTRACT FROM AUTHOR]
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- 2017
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4. The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial-Mesenchymal Transition in Breast Cancer.
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Latorre, Elisa, Carelli, Stephana, Raimondi, Ivan, D'Agostino, Vito, Castiglioni, Ilaria, Zucal, Chiara, Moro, Giacomina, Luciani, Andrea, Ghilardi, Giorgio, Monti, Eleonora, Inga, Alberto, Di Giulio, Anna Maria, Gorio, Alfredo, and Provenzani, Alessandro
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EPITHELIAL cells , *CELL migration , *MORPHOGENESIS , *NEOPLASTIC cell transformation , *METASTASIS , *CANCER stem cells , *GENE expression - Abstract
Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMTin various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDAMB- 231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ER+ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes. Cancer Res; 76(9); 2626-36. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Enhanced brain release of erythropoietin, cytokines and NO during carotid clamping.
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Carelli, Stephana, Ghilardi, Giorgio, Bianciardi, Paola, Latorre, Elisa, Rubino, Federico, Bissi, Marina, Di Giulio, Anna, Samaja, Michele, Gorio, Alfredo, and Di Giulio, Anna Maria
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CAROTID endarterectomy , *ERYTHROPOIETIN , *CYTOKINES , *PHYSIOLOGICAL effects of nitric oxide , *CEREBRAL ischemia , *ANTIOXIDANTS , *ANIMAL experimentation , *ANIMALS , *BRAIN , *MICE , *NITRIC oxide , *TUMOR necrosis factors ,BRAIN metabolism - Abstract
Although effective and safe, carotid endarterectomy (CEA) implies a reduced blood flow to the brain and likely an ischemia/reperfusion event. The high rate of uneventful outcomes associated with CEA suggests the activation of brain endogenous protection mechanisms aimed at limiting the possible ischemia/reperfusion damage. This study aims at assessing whether CEA triggers protective mechanisms such as brain release of erythropoietin and nitric oxide. CEA was performed in 12 patients; blood samples were withdrawn simultaneously from the surgically exposed ipsilateral jugular and leg veins before, during (2 and 40 min) and after clamp removal (2 min). Plasma antioxidant capacity, carbonylated proteins, erythropoietin, nitrates and nitrites (NOx) were determined. No changes in intraoperative EEG, peripheral and transcranial blood oxygen saturation were detectable, and no patients showed any neurologic sign after the intervention. Antioxidant capacity and protein carbonylation in plasma were unaffected. Differently, erythropoietin, VEGF, TNF-α and NOx increased during clamping in the jugular blood (2 and 40 min), while no changes were observed in the peripheral circulation. These results show that blood erythropoietin, VEGF, TNF-α, and NOx increased in the brain during uncomplicated CEA. This may represent an endogenous self-activated neuroprotective mechanism aimed at the prevention of ischemia/reperfusion damage. [ABSTRACT FROM AUTHOR]
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- 2016
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6. Survivin Expression in Tuberous Sclerosis Complex Cells.
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Carelli, Stephana, Lesma, Elena, Paratore, Simona, Grande, Vera, Zadra, Giorgia, Bosari, Silvano, Di Giulio, Anna Maria, and Gorio, Alfredo
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TUBEROUS sclerosis , *CENTRAL nervous system , *KIDNEYS , *LIVER , *SMOOTH muscle , *LYMPHANGIOMYOMATOSIS , *INTELLECTUAL disabilities - Abstract
Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene disorder with mutations of TSC1/TSC2 genes. This leads to the development of hamartomas that most frequently affect central nervous system, kidney, and skin. Angiomyolipomas are abdominal masses made up of muscle vessels and adipose tissues that grow mostly in proximity to kidneys and liver. Bleeding and kidney failure are the major justification for surgery. This study shows that angiomyolipoma-derived human smooth muscle TSC2-/- cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin expression is also triggered whenever culture conditions perturb normal TSC2-/- cell function, such as the omission of EGF from the growth medium, the supplementation of anti-EGFR, blockade of PI3K and ERK, or inhibition of mTOR. Interestingly, single or simultaneous inhibition of PI3K by LY294002 and ERK by PD98059 does not prevent IGF-1-mediated survivin expression. Apoptogenic Smac/DIABLO, which is constitutively expressed by TSC2-/- K cells, is down-regulated by IGF-1 even in the presence of LY294002 and PD98059. These cells release IGF-1 by means of a negative feedback-regulated mechanism that is overrun when they are exposed to antibodies to IGF-1 R, which increases the released amount by more than 400%. The autocrine release of IGF-1 may therefore be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Future experimental therapies for ISO and LAM may result from the targeted inhibition of survivin, which may enhance sensitivity to TSC2 therapy. [ABSTRACT FROM AUTHOR]
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- 2007
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7. Up-regulation of focal adhesion kinase in non-small cell lung cancer
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Carelli, Stephana, Zadra, Giorgia, Vaira, Valentina, Falleni, Monica, Bottiglieri, Luca, Nosotti, Mario, Di Giulio, Anna Maria, Gorio, Alfredo, and Bosari, Silvano
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FOCAL adhesion kinase , *CYTOSKELETAL proteins , *PROTEIN-tyrosine kinases , *LUNG cancer - Abstract
Summary: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase linked to the integrin and growth factor receptor-signalling pathways that regulates a number of the biological processes involved in neoplastic transformation, invasion and metastases, such as cell adhesion, migration and apoptosis. Its up-regulation might play a role in the tumourigenesis of invasive tumours, but its involvement in human lung cancer tissues has not yet been determined. We immunohistochemically compared FAK expression and localisation in 60 formalin-fixed and paraffin-embedded non-small cell lung cancer (NSCLC) tissues with that in the surrounding non-neoplastic tissue and in a further five microscopically normal lungs. FAK mRNA levels were quantitatively determined by real-time RT-PCR in frozen tissue specimens of all of the tumours and 21 matched non-neoplastic lung parenchymas, and protein expression in 16 homogenates of the matched neoplastic/non-neoplastic specimens was evaluated by Western blotting. The three different techniques showed that FAK is weakly expressed in non-neoplastic lung parenchyma and up-regulated in NSCLCs. Moreover, Western blotting and real-time RT-PCR indicated a statistically significant correlation between FAK up-regulation and higher disease stages (I+II versus III+IV, p =0.019 and 0.028, respectively). Our results provide evidence that FAK is up-regulated in NSCLCs, and suggest its potential involvement in lung cancer progression. [Copyright &y& Elsevier]
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- 2006
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8. Cysteine and glutathione secretion in response to protein disulfide bond formation in the ER.
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Carelli, Stephana and Ceriotti, Aldo
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ENDOPLASMIC reticulum , *OXIDATION-reduction reaction , *THIOLS , *SECRETION , *PHYSIOLOGY - Abstract
Presents research which asserts that the secretion of thiols in the endoplasmic reticulum (ER) might link disulfide bond formation to intra- and intercellular redox signaling. Protein folding in ER; Oxidizing conditions required; Stimulation of thiol secretion; Prevention of secretion; Role of endogenously generated cysteine and glutathione.
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- 1997
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9. A specific combination of zeaxanthin, spermidine and rutin prevents apoptosis in human dermal papilla cells.
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Carelli, Stephana, Hebda, Danuta M., Traversa, Maria V., Messaggio, Fanuel, Giuliani, Giammaria, Marzani, Barbara, Benedusi, Anna, Di Giulio, Anna M., and Gorio, Alfredo
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ZEAXANTHIN , *SPERMIDINE , *RUTIN , *HAIR follicles ,APOPTOSIS prevention - Abstract
Hair follicle ( HF) regression is characterized by the activation of apoptosis in HF cells. Dermal papilla cells play a leading role in the regulation of HF development and cycling. Human follicular dermal papilla cells ( HFDPC) were used to investigate the protective activities of rutin, sperimidine and zeaxanthine. HFDP cell incubation with staurosporine caused apoptosis, which was completely inhibited by exposure to rutin (2.2 μ m), spermidine (1 μ m) and zeaxanthin (80 μ m). These agents were much less effective when applied as single compounds. Moreover, treatment preserved the expression of anti-apoptotic molecules such as Bcl-2, MAP-kinases and their phosphorylated forms. In conclusion, the investigated agents may represent an effective treatment for the prevention of apoptosis, one of the leading events involved in hair bulb regression. [ABSTRACT FROM AUTHOR]
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- 2012
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10. Neuroprotection, Recovery of Function and Endogenous Neurogenesis in Traumatic Spinal Cord Injury Following Transplantation of Activated Adipose Tissue.
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Carelli, Stephana, Giallongo, Toniella, Rey, Federica, Colli, Mattia, Tosi, Delfina, Bulfamante, Gaetano, Di Giulio, Anna Maria, and Gorio, Alfredo
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ADIPOSE tissue transplantation , *SPINAL cord injuries , *DEVELOPMENTAL neurobiology , *STROMAL cells , *SPINAL cord - Abstract
Spinal cord injury (SCI) is a devastating disease, which leads to paralysis and is associated to substantially high costs for the individual and society. At present, no effective therapies are available. Here, the use of mechanically-activated lipoaspirate adipose tissue (MALS) in a murine experimental model of SCI is presented. Our results show that, following acute intraspinal MALS transplantation, there is an engraftment at injury site with the acute powerful inhibition of the posttraumatic inflammatory response, followed by a significant progressive improvement in recovery of function. This is accompanied by spinal cord tissue preservation at the lesion site with the promotion of endogenous neurogenesis as indicated by the significant increase of Nestin-positive cells in perilesional areas. Cells originated from MALS infiltrate profoundly the recipient cord, while the extra-dural fat transplant is gradually impoverished in stromal cells. Altogether, these novel results suggest the potential of MALS application in the promotion of recovery in SCI. [ABSTRACT FROM AUTHOR]
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- 2019
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11. Counteracting neuroinflammation in experimental Parkinson's disease favors recovery of function: effects of Er-NPCs administration.
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Carelli, Stephana, Giallongo, Toniella, Gombalova, Zuzana, Rey, Federica, Gorio, Maria Carlotta F., Mazza, Massimiliano, and Di Giulio, Anna Maria
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PARKINSON'S disease , *ERYTHROPOIETIN , *NEURAL stem cell transplantation , *STEM cells , *REGENERATIVE medicine - Abstract
Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, presenting with midbrain dopaminergic neurons degeneration. A number of studies suggest that microglial activation may have a role in PD. It has emerged that inflammation-derived oxidative stress and cytokine-dependent toxicity may contribute to nigrostriatal pathway degeneration and exacerbate the progression of the disease in patients with idiopathic PD. Cell therapies have long been considered a feasible regenerative approach to compensate for the loss of specific cell populations such as the one that occurs in PD. We recently demonstrated that erythropoietin-releasing neural precursors cells (Er-NPCs) administered to MPTP-intoxicated animals survive after transplantation in the recipient's damaged brain, differentiate, and rescue degenerating striatal dopaminergic neurons. Here, we aimed to investigate the potential anti-inflammatory actions of Er-NPCs infused in an MPTP experimental model of PD.Methods: The degeneration of dopaminergic neurons was caused by MPTP administration in C57BL/6 male mice. 2.5 × 105 GFP-labeled Er-NPCs were administered by stereotaxic injection unilaterally in the left striatum. Functional recovery was assessed by two independent behavioral tests. Neuroinflammation was investigated measuring the mRNAs levels of pro-inflammatory and anti-inflammatory cytokines, and immunohistochemistry studies were performed to evaluate markers of inflammation and the potential rescue of tyrosine hydroxylase (TH) projections in the striatum of recipient mice.Results: Er-NPC administration promoted a rapid anti-inflammatory effect that was already evident 24 h after transplant with a decrease of pro-inflammatory and increase of anti-inflammatory cytokines mRNA expression levels. This effect was maintained until the end of the observational period, 2 weeks post-transplant. Here, we show that Er-NPCs transplant reduces macrophage infiltration, directly counteracting the M1-like pro-inflammatory response of murine-activated microglia, which corresponds to the decrease of CD68 and CD86 markers, and induces M2-like pro-regeneration traits, as indicated by the increase of CD206 and IL-10 expression. Moreover, we also show that this activity is mediated by Er-NPCs-derived erythropoietin (EPO) since the co-injection of cells with anti-EPO antibodies neutralizes the anti-inflammatory effect of the Er-NPCs treatment.Conclusion: This study shows the anti-inflammatory actions exerted by Er-NPCs, and we suggest that these cells may represent good candidates for cellular therapy to counteract neuroinflammation in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]- Published
- 2018
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12. Activated Human Adipose Tissue Transplantation Promotes Sensorimotor Recovery after Acute Spinal Cord Contusion in Rats.
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Bonnet, Maxime, Ertlen, Céline, Seblani, Mostafa, Brezun, Jean-Michel, Coyle, Thelma, Cereda, Cristina, Zuccotti, Gianvincenzo, Colli, Mattia, Desouches, Christophe, Decherchi, Patrick, Carelli, Stephana, and Marqueste, Tanguy
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ADIPOSE tissue transplantation , *SPINAL cord , *SPRAGUE Dawley rats , *ADIPOSE tissues , *SENSORIMOTOR cortex , *SPINAL cord injuries , *RATS - Abstract
Traumatic spinal cord injuries (SCIs) often result in sensory, motor, and vegetative function loss below the injury site. Although preclinical results have been promising, significant solutions for SCI patients have not been achieved through translating repair strategies to clinical trials. In this study, we investigated the effective potential of mechanically activated lipoaspirated adipose tissue when transplanted into the epicenter of a thoracic spinal contusion. Male Sprague Dawley rats were divided into three experimental groups: SHAM (uninjured and untreated), NaCl (spinal cord contusion with NaCl application), and AF (spinal cord contusion with transplanted activated human fat). Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured to assess endogenous inflammation levels 14 days after injury. Sensorimotor recovery was monitored weekly for 12 weeks, and gait and electrophysiological analyses were performed at the end of this observational period. The results indicated that AF reduced endogenous inflammation post-SCI and there was a significant improvement in sensorimotor recovery. Moreover, activated adipose tissue also reinstated the segmental sensorimotor loop and the communication between supra- and sub-lesional spinal cord regions. This investigation highlights the efficacy of activated adipose tissue grafting in acute SCI, suggesting it is a promising therapeutic approach for spinal cord repair after traumatic contusion in humans. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications.
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Pandini, Cecilia, Rey, Federica, Cereda, Cristina, Carelli, Stephana, and Gandellini, Paolo
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NEURAL stem cells , *NEUROLOGICAL disorders , *LINCRNA , *PEDIATRIC neurology , *NEURAL development , *CENTRAL nervous system - Abstract
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and when a pathological condition is present. We describe the role of lncRNAs in neural development, highlighting their significance in processes such as neural stem cell proliferation, differentiation, and synaptogenesis. Dysregulation of specific lncRNAs is associated with multiple pediatric neurological diseases, such as neurodevelopmental or neurodegenerative disorders and brain tumors. The collected evidence indicates that there is a need for further research to uncover the full spectrum of lncRNA involvement in pediatric neurological diseases and brain tumors. While challenges exist, ongoing advancements in technology and our understanding of lncRNA biology offer hope for future breakthroughs in the field of pediatric neurology, leveraging lncRNAs as potential therapeutic targets and biomarkers. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Long non-coding RNAs in metabolic diseases: from bench to bedside.
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Rey, Federica, Zuccotti, Gian Vincenzo, and Carelli, Stephana
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LINCRNA , *METABOLIC disorders - Abstract
Long non-coding RNAs (lncRNAs) are being widely studied for their implications in physiological and diseases contexts but their functions and therapeutic potentials in metabolic diseases are far from clarified. Here, we report a summary of current advances in lncRNAs identification, functions, role as biomarkers and therapeutic prospects in metabolic diseases. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Subcutaneous Adipose Tissue Transcriptome Highlights Specific Expression Profiles in Severe Pediatric Obesity: A Pilot Study.
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Berardo, Clarissa, Calcaterra, Valeria, Mauri, Alessia, Carelli, Stephana, Messa, Letizia, Destro, Francesca, Rey, Federica, Cordaro, Erika, Pelizzo, Gloria, Zuccotti, Gianvincenzo, and Cereda, Cristina
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ADIPOSE tissues , *CHILDHOOD obesity , *GENE expression , *OVERWEIGHT children , *GENETIC transcription regulation , *LIPID metabolism , *TRANSCRIPTOMES - Abstract
The prevalence of pediatric obesity is rising rapidly worldwide, and "omic" approaches are helpful in investigating the molecular pathophysiology of obesity. This work aims to identify transcriptional differences in the subcutaneous adipose tissue (scAT) of children with overweight (OW), obesity (OB), or severe obesity (SV) compared with those of normal weight (NW). Periumbilical scAT biopsies were collected from 20 male children aged 1–12 years. The children were stratified into the following four groups according to their BMI z-scores: SV, OB, OW, and NW. scAT RNA-Seq analyses were performed, and a differential expression analysis was conducted using the DESeq2 R package. A pathways analysis was performed to gain biological insights into gene expression. Our data highlight the significant deregulation in both coding and non-coding transcripts in the SV group when compared with the NW, OW, and OB groups. A KEGG pathway analysis showed that coding transcripts were mainly involved in lipid metabolism. A GSEA analysis revealed the upregulation of lipid degradation and metabolism in SV vs. OB and SV vs. OW. Bioenergetic processes and the catabolism of branched-chain amino acids were upregulated in SV compared with OB, OW, and NW. In conclusion, we report for the first time that a significant transcriptional deregulation occurs in the periumbilical scAT of children with severe obesity compared with those of normal weight or those with overweight or mild obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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16. Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation.
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Rey, Federica, Messa, Letizia, Maghraby, Erika, Casili, Giovanna, Ottolenghi, Sara, Barzaghini, Bianca, Raimondi, Manuela Teresa, Cereda, Cristina, Cuzzocrea, Salvatore, Zuccotti, Gianvincenzo, Esposito, Emanuela, Paterniti, Irene, and Carelli, Stephana
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NEURODEGENERATION , *AMYOTROPHIC lateral sclerosis , *ALZHEIMER'S disease , *PARKINSON'S disease , *OXYGEN , *CELLULAR signal transduction , *REACTIVE oxygen species - Abstract
Significance: Oxygen (O2) sensing is the fundamental process through which organisms respond to changes in O2 levels. Complex networks exist allowing the maintenance of O2 levels through the perception, capture, binding, transport, and delivery of molecular O2. The brain extreme sensitivity to O2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how O2 sensing plays a role in the above indicated neurodegenerations. Specifically, O2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future Directions: Future studies should focus on the precise characterization of O2 level disruption and O2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160–182. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Patients' Stem Cells Differentiation in a 3D Environment as a Promising Experimental Tool for the Study of Amyotrophic Lateral Sclerosis.
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Scarian, Eveljn, Bordoni, Matteo, Fantini, Valentina, Jacchetti, Emanuela, Raimondi, Manuela Teresa, Diamanti, Luca, Carelli, Stephana, Cereda, Cristina, and Pansarasa, Orietta
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BIOPRINTING , *STEM cells , *AMYOTROPHIC lateral sclerosis , *CELL differentiation , *MOTOR neurons , *NEURAL stem cells , *MONONUCLEAR leukocytes , *MOTOR neuron diseases - Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease (NDD) that affects motor neurons, causing weakness, muscle atrophy and spasticity. Unfortunately, there are only symptomatic treatments available. Two important innovations in recent years are three-dimensional (3D) bioprinting and induced pluripotent stem cells (iPSCs). The aim of this work was to demonstrate the robustness of 3D cultures for the differentiation of stem cells for the study of ALS. We reprogrammed healthy and sALS peripheral blood mononuclear cells (PBMCs) in iPSCs and differentiated them in neural stem cells (NSCs) in 2D. NSCs were printed in 3D hydrogel-based constructs and subsequently differentiated first in motor neuron progenitors and finally in motor neurons. Every step of differentiation was tested for cell viability and characterized by confocal microscopy and RT-qPCR. Finally, we tested the electrophysiological characteristics of included NSC34. We found that NSCs maintained good viability during the 3D differentiation. Our results suggest that the hydrogel does not interfere with the correct differentiation process or with the electrophysiological features of the included cells. Such evidence confirmed that 3D bioprinting can be considered a good model for the study of ALS pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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18. Lysosomes Dysfunction Causes Mitophagy Impairment in PBMCs of Sporadic ALS Patients.
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Bordoni, Matteo, Pansarasa, Orietta, Scarian, Eveljn, Cristofani, Riccardo, Leone, Roberta, Fantini, Valentina, Garofalo, Maria, Diamanti, Luca, Bernuzzi, Stefano, Gagliardi, Stella, Carelli, Stephana, Poletti, Angelo, and Cereda, Cristina
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AMYOTROPHIC lateral sclerosis , *MONONUCLEAR leukocytes , *LYSOSOMES , *SMALL molecules - Abstract
Mitochondria alterations are present in tissues derived from patients and animal models, but no data are available for peripheral blood mononuclear cells (PBMCs) of ALS patients. This work aims to investigate mitophagy in PBMCs of sporadic (sALS) patients and how this pathway can be tuned by using small molecules. We found the presence of morphologically atypical mitochondria by TEM and morphological abnormalities by MitoTracker™. We found a decreased number of healthy mitochondria in sALS PBMCs and an impairment of mitophagy with western blot and immunofluorescence. After rapamycin treatment, we found a higher increase in the LC3 marker in sALS PBMCs, while after NH4Cl treatment, we found a lower increase in the LC3 marker. Finally, mTOR-independent autophagy induction with trehalose resulted in a significant decrease in the lysosomes level sALS PBMCs. Our data suggest that the presence of morphologically altered mitochondria and an inefficient turnover of damaged mitochondria in PBMCs of sALS patients rely on the impairment of the mitophagy pathway. We also found that the induction of the mTOR-independent autophagy pathway leads to a decrease in lysosomes level, suggesting a more sensitivity of sALS PBMCs to trehalose. Such evidence suggests that trehalose could represent an effective treatment for ALS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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19. α‐Synuclein antisense transcript SNCA‐AS1 regulates synapses‐ and aging‐related genes suggesting its implication in Parkinson's disease.
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Rey, Federica, Pandini, Cecilia, Messa, Letizia, Launi, Rossella, Barzaghini, Bianca, Zangaglia, Roberta, Raimondi, Manuela Teresa, Gagliardi, Stella, Cereda, Cristina, Zuccotti, Gian Vincenzo, and Carelli, Stephana
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PARKINSON'S disease , *PHYSIOLOGY , *CELLULAR aging , *CELL physiology , *NEUROPLASTICITY - Abstract
SNCA protein product, α‐synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson's disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA‐AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA‐AS1 upregulates both SNCA and α‐synuclein and, through RNA‐sequencing analysis, we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites' extension and synapses' biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA‐AS1 expression leads to the opposite effect. As part of this signature is co‐regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA‐AS1 or SNCA's overexpression, observing a relevant role for SNCA‐AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging‐related processes, suggesting that SNCA‐AS1 could be a key player in cellular senescence, with implications for aging‐related diseases. Indeed, the upregulation of SNCA‐AS1 leads to alterations in numerous PD‐specific genes, with an impact highly comparable to that of SNCA's upregulation. Our results show that SNCA‐AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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20. MINCR: A long non-coding RNA shared between cancer and neurodegeneration.
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Pandini, Cecilia, Garofalo, Maria, Rey, Federica, Garau, Jessica, Zucca, Susanna, Sproviero, Daisy, Bordoni, Matteo, Berzero, Giulia, Davin, Annalisa, Poloni, Tino Emanuele, Pansarasa, Orietta, Carelli, Stephana, Gagliardi, Stella, and Cereda, Cristina
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LINCRNA , *NEURODEGENERATION , *RNA metabolism , *GENETIC overexpression , *GENE expression , *RNA sequencing - Abstract
The multitasking nature of lncRNAs allows them to play a central role in both physiological and pathological conditions. Often the same lncRNA can participate in different diseases. Specifically, the MYC-induced Long non-Coding RNA MINCR is upregulated in various cancer types, while downregulated in Amyotrophic Lateral Sclerosis patients. Therefore, this work aims to investigate MINCR potential mechanisms of action and its implications in cancer and neurodegeneration in relation to its expression levels in SH-SY5Y cells through RNA-sequencing approach. Our results show that MINCR overexpression causes massive alterations in cancer-related genes, leading to disruption in many fundamental processes, such as cell cycle and growth factor signaling. On the contrary, MINCR downregulation influences a small number of genes involved in different neurodegenerative disorders, mostly concerning RNA metabolism and inflammation. Thus, understanding the cause and functional consequences of MINCR deregulation gives important insights on potential pathogenetic mechanisms both in cancer and in neurodegeneration. • lncRNAs can exert different mechanisms depending on their expression level. • MINCR is conversely expressed in tumor and in neurodegenerative disease patients, being up- and downregulated, respectively. • MINCR overexpression causes alteration in cancer-related gene expression. • MINCR downregulation influences genes involved in different neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Transcriptional characterization of subcutaneous adipose tissue in obesity affected women highlights metabolic dysfunction and implications for lncRNAs.
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Rey, Federica, Messa, Letizia, Pandini, Cecilia, Barzaghini, Bianca, Micheletto, Giancarlo, Raimondi, Manuela Teresa, Bertoli, Simona, Cereda, Cristina, Zuccotti, Gian Vincenzo, Cancello, Raffaella, and Carelli, Stephana
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OBESITY in women , *METABOLIC disorders , *ADIPOSE tissues , *LINCRNA , *GENETIC transcription regulation , *CELL differentiation - Abstract
Obesity is a complex disease with multifactorial causes, and its prevalence is becoming a serious health crisis. For this reason, there is a crucial need to identify novel targets and players. With this aim in mind, we analyzed via RNA-sequencing the subcutaneous adipose tissue of normal weight and obesity-affected women, highlighting the differential expression in the two tissues. We specifically focused on long non-coding RNAs, as 6 of these emerged as dysregulated in the diseased-tissue (COL4A2-AS2, RPS21-AS, PELATON, ITGB2-AS1, ACER2-AS and CTEPHA1). For each of them, we performed both a thorough in silico dissection and in vitro validation, to predict their function during adipogenesis. We report the lncRNAs expression during adipose derived stem cells differentiation to adipocytes as model of adipogenesis and their potential modulation by adipogenesis-related transcription factors (C/EBPs and PPARγ). Moreover, inhibiting CTEPHA1 expression we investigated its impact on adipogenesis-related transcription factors, showing its significative dysregulation of C/EBPα expression. Lastly, we dissected the subcellular localization, pathway involvement and disease-correlation for coding differentially expressed genes. Together, these findings highlight a transcriptional deregulation at the basis of obesity, impacted by both coding and long non-coding RNAs. • There is a crucial need to identify novel targets and players in obesity. • RNA-seq allows the analysis of subcutaneous adipose tissue dysfunctions in obesity. • Long non-coding RNAs are novel players emerging as regulators in the disease. • Differential RNA expression analysis could provide new targets altered in obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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22. Role of long non‐coding RNAs in adipogenesis: State of the art and implications in obesity and obesity‐associated diseases.
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Rey, Federica, Urrata, Valentina, Gilardini, Luisa, Bertoli, Simona, Calcaterra, Valeria, Zuccotti, Gian Vincenzo, Cancello, Raffaella, and Carelli, Stephana
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LINCRNA , *OBESITY , *ADIPOGENESIS , *SLEEP apnea syndromes , *HYPERTENSION - Abstract
Summary: Obesity is an evolutionary, chronic, and relapsing disease that consists of a pathological accumulation of adipose tissue able to increase morbidity for high blood pressure, type 2 diabetes, metabolic syndrome, and obstructive sleep apnea in adults, children, and adolescents. Despite intense research over the last 20 years, obesity remains today a disease with a complex and multifactorial etiology. Recently, long non‐coding RNAs (lncRNAs) are emerging as interesting new regulators as different lncRNAs have been found to play a role in early and late phases of adipogenesis and to be implicated in obesity‐associated complications onset. In this review, we discuss the most recent advances on the role of lncRNAs in adipocyte biology and in obesity‐associated complications. Indeed, more and more researchers are focusing on investigating the underlying roles that these molecular modulators could play. Even if a significant number of evidence is correlation‐based, with lncRNAs being differentially expressed in a specific disease, recent works are now focused on deeply analyzing how lncRNAs can effectively modulate the disease pathogenesis onset and progression. LncRNAs possibly represent new molecular markers useful in the future for both the early diagnosis and a prompt clinical management of patients with obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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23. Majority of cerebrospinal fluid‐contacting neurons in the spinal cord of C57Bl/6N mice is present in ectopic position unlike in other studied experimental mice strains and mammalian species.
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Tonelli Gombalová, Zuzana, Košuth, Ján, Alexovič Matiašová, Anna, Zrubáková, Jarmila, Žežula, Ivan, Giallongo, Toniella, Di Giulio, Anna Maria, Carelli, Stephana, Tomašková, Lenka, Daxnerová, Zuzana, and Ševc, Juraj
- Abstract
Cerebrospinal fluid contacting neurons (CSF‐cNs) represent a specific class of neurons located in close vicinity of brain ventricles and central canal. In contrast with knowledge gained from other vertebrate species, we found that vast majority of CSF‐cNs in the spinal cord of C57Bl/6N mice is located in ectopic distal ventral position. However, we found that small number of ectopic CSF‐cNs is present also in spinal cord of other investigated experimental mice strains (C57Bl/6J, Balb/C) and mammalian species (Wistar rats, New Zealand White rabbits). Similarly, as the proximal populations, ectopic CSF‐cNs retain PKD2L1‐immunoreactivity and synaptic contacts with other neurons. On the other side, they show rather multipolar morphology lacking thick dendrite contacting central canal lumen. Ectopic CSF‐cNs in the spinal cord of C57Bl/6N mice emerge during whole period devoted to production of CSF‐cNs and reach their ventral destinations during first postnatal weeks. In order to identify major gene, whose impairment could trigger translocation of CSF‐cNs outside the central canal area, we took advantage of close consanguinity of C57Bl/6J substrain with normal CSF‐cN distribution and C57Bl/6N substrain with majority of CSF‐cNs in ectopic position. Employing in silico analyses, we ranked polymorphisms in C57Bl/6N substrain and selected genes Crb1, Cyfip2, Adamts12, Plk1, and Herpud2 as the most probable candidates, whose product dysfunction might be responsible for the ectopic distribution of CSF‐cNs. Furthermore, segregation analysis of F2 progeny of parental C57Bl/6N and Balb/C mice revealed that polymorphic loci of Crb1 and Cyfip2 underlie the ectopic position of CSF‐cNs in the spinal cord of C57Bl/6N mice. [ABSTRACT FROM AUTHOR]
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- 2020
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24. Adipose-Derived Stem Cells from Fat Tissue of Breast Cancer Microenvironment Present Altered Adipogenic Differentiation Capabilities.
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Rey, Federica, Lesma, Elena, Massihnia, Daniela, Ciusani, Emilio, Nava, Sara, Vasco, Chiara, Al Haj, Ghina, Ghilardi, Giorgio, Opocher, Enrico, Gorio, Alfredo, Carelli, Stephana, and Di Giulio, Anna Maria
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STEM cells , *FAT cells , *ADIPOSE tissues , *BREAST cancer , *MESENCHYMAL stem cells , *STROMAL cells , *ENDOCHONDRAL ossification - Abstract
Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into multiple cell types, including adipocytes, osteoblasts, and chondrocytes. The role of adipose-derived stem cells (ADSCs) in cancers is significantly relevant. They seem to be involved in the promotion of tumour development and progression and relapse processes. For this reason, investigating the effects of breast cancer microenvironment on ADSCs is of high importance in order to understand the relationship between tumour cells and the surrounding stromal cells. With the current study, we aimed to investigate the specific characteristics of human ADSCs isolated from the adipose tissue of breast tumour patients. We compared ADSCs obtained from periumbilical fat (PF) of controls with ADSCs obtained from adipose tissue of breast cancer- (BC-) bearing patients. We analysed the surface antigens and the adipogenic differentiation ability of both ADSC populations. C/EBPδ expression was increased in PF and BC ADSCs induced to differentiate compared to the control while PPARγ and FABP4 expressions were enhanced only in PF ADSCs. Conversely, adiponectin expression was reduced in PF-differentiated ADSCs while it was slightly increased in differentiated BC ADSCs. By means of Oil Red O staining, we further observed an impaired differentiation capability of BC ADSCs. To investigate this aspect more in depth, we evaluated the effect of selective PPARγ activation and nutritional supplementation on the differentiation efficiency of BC ADSCs, noting that it was only with a strong differentiation stimuli that the process took place. Furthermore, we observed no response in BC ADSCs to the PPARγ inhibitor T0070907, showing an impaired activation of this receptor in adipose cells surrounding the breast cancer microenvironment. In conclusion, our study shows an impaired adipogenic differentiation capability in BC ADSCs. This suggests that the tumour microenvironment plays a key role in the modulation of the adipose microenvironment located in the surrounding tissue. [ABSTRACT FROM AUTHOR]
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- 2019
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25. Ferritin nanoconjugates guide trastuzumab brain delivery to promote an antitumor response in murine HER2 + breast cancer brain metastasis.
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Sevieri, Marta, Mazzucchelli, Serena, Barbieri, Linda, Garbujo, Stefania, Carelli, Stephana, Bonizzi, Arianna, Rey, Federica, Recordati, Camilla, Recchia, Matteo, Allevi, Raffaele, Sitia, Leopoldo, Morasso, Carlo, Zerbi, Pietro, Prosperi, Davide, Corsi, Fabio, and Truffi, Marta
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HEART , *FERRITIN , *BREAST , *TRANSFERRIN receptors , *TRANSFERRIN , *TRASTUZUMAB , *BRAIN metastasis , *CENTRAL nervous system , *INTRAPERITONEAL injections - Abstract
Brain metastasis (BM) represents a clinical challenge for patients with advanced HER2 + breast cancer (BC). The monoclonal anti-HER2 antibody trastuzumab (TZ) improves survival of BC patients, but it has low central nervous system penetrance, being ineffective in treating BM. Previous studies showed that ferritin nanoparticles (HFn) may cross the blood brain barrier (BBB) through binding to the transferrin receptor 1 (TfR1). However, whether this has efficacy in promoting the trans-BBB delivery of TZ and combating BC BM was not studied yet. Here, we investigated the potential of HFn to drive TZ brain delivery and promote a targeted antitumor response in a murine model of BC BM established by stereotaxic injection of engineered BC cells overexpressing human HER2. HFn were covalently conjugated with TZ to obtain a nanoconjugate endowed with HER2 and TfR1 targeting specificity (H-TZ). H-TZ efficiently achieved TZ brain delivery upon intraperitoneal injection and triggered stable targeting of cancer cells. Treatment with H-TZ plus docetaxel significantly reduced tumor growth and shaped a protective brain microenvironment by engaging macrophage activation toward cancer cells. H-TZ-based treatment also avoided TZ-associated cardiotoxicity by preventing drug accumulation in the heart and did not induce any other major side effects when combined with docetaxel. These results provided in vivo demonstration of the pharmacological potential of H-TZ, able to tackle BC BM in combination with docetaxel. Indeed, upon systemic administration, the nanoconjugate guides TZ brain accumulation, reduces BM growth and limits side effects in off-target organs, thus showing promise for the management of HER2 + BC metastatic to the brain. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2023
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26. Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1.
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Rey, Federica, Maghraby, Erika, Messa, Letizia, Esposito, Letizia, Barzaghini, Bianca, Pandini, Cecilia, Bordoni, Matteo, Gagliardi, Stella, Diamanti, Luca, Raimondi, Manuela Teresa, Mazza, Massimiliano, Zuccotti, Gianvincenzo, Carelli, Stephana, and Cereda, Cristina
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NEUROBLASTOMA , *LINCRNA , *AMYOTROPHIC lateral sclerosis , *MONONUCLEAR leukocytes , *INDUCED pluripotent stem cells , *NEURAL stem cells , *RILUZOLE - Abstract
Deregulation of transcription in the pathogenesis of sporadic Amyotrophic Lateral Sclerosis (sALS) is taking central stage with RNA-sequencing analyses from sALS patients tissues highlighting numerous deregulated long non-coding RNAs (lncRNAs). The oncogenic lncRNA ZEB1-AS1 is strongly downregulated in peripheral blood mononuclear cells of sALS patients. In addition, in cancer-derived cell lines, ZEB1-AS1 belongs to a negative feedback loop regulation with hsa-miR-200c, acting as a molecular sponge for this miRNA. The role of the lncRNA ZEB1-AS1 in sALS pathogenesis has not been characterized yet, and its study could help identifying a possible disease-modifying target. the implication of the ZEB1-AS1/ZEB1/hsa-miR-200c/BMI1 pathway was investigated in multiple patients-derived cellular models (patients-derived peripheral blood mononuclear cells and induced pluripotent stem cells-derived neural stem cells) and in the neuroblastoma cell line SH-SY5Y, where its function was inhibited via RNA interference. Molecular techniques such as Real Time PCR, Western Blot and Immunofluorescence were used to assess the pathway dysregulation. Our results show a dysregulation of a signaling pathway involving ZEB1-AS1/hsa-miR-200c/β-Catenin in peripheral blood mononuclear cells and in induced pluripotent stem cells-derived neural stem cells from sALS patients. These results were validated in vitro on the cell line SH-SY5Y with silenced expression of ZEB1-AS1. Moreover, we found an increase for ZEB1-AS1 during neural differentiation with an aberrant expression of β-Catenin, highlighting also its aggregation and possible impact on neurite length. Our results support and describe the role of ZEB1-AS1 pathway in sALS and specifically in neuronal differentiation, suggesting that an impairment of β-Catenin signaling and an alteration of the neuronal phenotype are taking place. • Long non-coding RNAs play a role in sporadic Amyotrophic Lateral Sclerosis (sALS). • The oncogenic lncRNA ZEB1-AS1 is strongly downregulated in sALS. • The ZEB1-AS1/ZEB1/hsa-miR-200c/BMI1 pathway is altered in sALS. • ZEB1-AS1 affects neuronal differentiation through an impairment of β-Catenin. [ABSTRACT FROM AUTHOR]
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- 2023
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27. Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.
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Tosetti, Valentina, Sassone, Jenny, Ferri, Anna L. M., Taiana, Michela, Bedini, Gloria, Nava, Sara, Brenna, Greta, Di Resta, Chiara, Pareyson, Davide, Di Giulio, Anna Maria, Carelli, Stephana, Parati, Eugenio A., and Gorio, Alfredo
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ANDROGEN receptors , *GENETIC transcription , *DEVELOPMENTAL neurobiology , *EMBRYOLOGY , *GENE expression in mammals - Abstract
The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT. [ABSTRACT FROM AUTHOR]
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- 2017
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28. RNA Molecular Signature Profiling in PBMCs of Sporadic ALS Patients: HSP70 Overexpression Is Associated with Nuclear SOD1.
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Garofalo, Maria, Pandini, Cecilia, Bordoni, Matteo, Jacchetti, Emanuela, Diamanti, Luca, Carelli, Stephana, Raimondi, Manuela Teresa, Sproviero, Daisy, Crippa, Valeria, Carra, Serena, Poletti, Angelo, Pansarasa, Orietta, Gagliardi, Stella, and Cereda, Cristina
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AMYOTROPHIC lateral sclerosis , *MONONUCLEAR leukocytes , *RNA metabolism , *MOLECULAR chaperones , *IMMOBILIZED proteins , *DNA repair , *GENETIC overexpression - Abstract
Superoxide dismutase 1 (SOD1) is one of the causative genes associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder. SOD1 aggregation contributes to ALS pathogenesis. A fraction of the protein is localized in the nucleus (nSOD1), where it seems to be involved in the regulation of genes participating in the oxidative stress response and DNA repair. Peripheral blood mononuclear cells (PBMCs) were collected from sporadic ALS (sALS) patients (n = 18) and healthy controls (n = 12) to perform RNA-sequencing experiments and differential expression analysis. Patients were stratified into groups with "high" and "low" levels of nSOD1. We obtained different gene expression patterns for high- and low-nSOD1 patients. Differentially expressed genes in high nSOD1 form a cluster similar to controls compared to the low-nSOD1 group. The pathways activated in high-nSOD1 patients are related to the upregulation of HSP70 molecular chaperones. We demonstrated that, in this condition, the DNA damage is reduced, even under oxidative stress conditions. Our findings highlight the importance of the nuclear localization of SOD1 as a protective mechanism in sALS patients. [ABSTRACT FROM AUTHOR]
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- 2022
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29. SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes.
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Valeri, Andrea, Chiricosta, Luigi, Gugliandolo, Agnese, Biasin, Mara, Avanzini, Maria Antonietta, Calcaterra, Valeria, Cappelletti, Gioia, Carelli, Stephana, Zuccotti, Gian Vincenzo, Silvestro, Serena, Mazzon, Emanuela, and Pelizzo, Gloria
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SARS-CoV-2 , *COVID-19 , *STROMAL cells , *TRANSCRIPTOMES , *LUNGS , *ANGIOTENSIN converting enzyme , *GENE expression - Abstract
The inflammatory response plays a central role in the complications of congenital pulmonary airway malformations (CPAM) and severe coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the transcriptional changes induced by SARS-CoV-2 exposure in pediatric MSCs derived from pediatric lung (MSCs-lung) and CPAM tissues (MSCs-CPAM) in order to elucidate potential pathways involved in SARS-CoV-2 infection in a condition of exacerbated inflammatory response. MSCs-lung and MSCs-CPAM do not express angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TRMPSS2). SARS-CoV-2 appears to be unable to replicate in MSCs-CPAM and MSCs-lung. MSCs-lung and MSCs-CPAM maintained the expression of stemness markers MSCs-lung show an inflammatory response (IL6, IL1B, CXCL8, and CXCL10), and the activation of Notch3 non-canonical pathway; this route appears silent in MSCs-CPAM, and cytokine genes expression is reduced. Decreased value of p21 in MSCs-lung suggested no cell cycle block, and cells did not undergo apoptosis. MSCs-lung appears to increase genes associated with immunomodulatory function but could contribute to inflammation, while MSCs-CPAM keeps stable or reduce the immunomodulatory receptors expression, but they also reduce their cytokines expression. These data indicated that, independently from their perilesional or cystic origin, the MSCs populations already present in a patient affected with CPAM are not permissive for SARS-CoV-2 entry, and they will not spread the disease in case of infection. Moreover, these MSCs will not undergo apoptosis when they come in contact with SARS-CoV-2; on the contrary, they maintain their staminality profile. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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30. Adult neural precursors isolated from post mortem brain yield mostly neurons: An erythropoietin-dependent process
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Marfia, Giovanni, Madaschi, Laura, Marra, Francesca, Menarini, Mauro, Bottai, Daniele, Formenti, Alessandro, Bellardita, Carmelo, Di Giulio, Anna Maria, Carelli, Stephana, and Gorio, Alfredo
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NEURONS , *ERYTHROPOIETIN , *SPINAL cord injuries , *NEUROPLASTICITY , *GENETIC regulation , *HYPOXEMIA , *IMMUNOGLOBULINS - Abstract
Abstract: This study was aimed at the isolation of neural precursor cells (NPCs) capable of resisting to a prolonged ischemic insult as this may occur at the site of traumatic and ischemic CNS injuries. Adult mice were anesthetized and then killed by cervical dislocation. The cadavers were maintained at room temperature or at 4°C for different time periods. Post mortem neural precursors (PM-NPCs) were isolated, grown in vitro and their differentiation capability was investigated by evaluating the expression of different neuronal markers. PM-NPCs differentiate mostly in neurons, show activation of hypoxia-inducible factor-1 and MAPK, and express both erythropoietin (EPO) and its receptor (EPO-R). The exposure of PM-NPCs to neutralizing antibodies to EPO or EPO-R dramatically reduced the extent of neuronal differentiation to about 11% of total PM-NPCs. The functionality of mTOR and MAPK is also required for the expression of the neuronal phenotype by PM-NPCs. These results suggest that PM-NPCs can be isolated from animal cadaver even several hours after death and their self-renewable capability is comparable to normal neural precursors. Differently, their ability to achieve a neural phenotype is superior to that of NPCs, and this is mediated by the activation of hypoxia-induced factor 1 and EPO signaling. PM-NPCs may represent good candidates for transplantation studies in animal models of neurodegenerative diseases. [Copyright &y& Elsevier]
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- 2011
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31. Acute spinal cord injury persistently reduces R/G RNA editing of AMPA receptors.
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Barbon, Alessandro, Fumagalli, Fabio, Caracciolo, Luca, Madaschi, Laura, Lesma, Elena, Mora, Cristina, Carelli, Stephana, Slotkin, Theodore A., Racagni, Giorgio, Di Giulio, Anna Maria, Gorio, Alfredo, and Barlati, Sergio
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SPINAL cord injuries , *NEUROTRANSMITTERS , *GLUTAMIC acid , *RNA , *ADENOSINES - Abstract
J. Neurochem. (2010) 114, 397–407. Spinal cord injury (SCI) triggers a complex ischemic and inflammatory reaction, involving activation of neurotransmitter systems, in particular glutamate, culminating in cell death. We hypothesized that SCI might lead to alteration in the RNA editing of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors that govern critical determinants of neuronal survival. To this end, we examined the molecular changes set in motion by SCI that affect the channel properties of AMPA receptors. SCI strongly reduced the level of AMPA receptor R/G editing, involving not only the site of the lesion but also adjacent areas of the cord spared by the lesion. The effects, with changes for some subunits and loci, were observed as long as 30 days after lesioning and may correlate with a partial decrease in enzymatic activity of adenosine deaminase acting on RNA 2 (ADAR2), as deduced from the analysis of ADAR2 self-editing. The reduced editing at the R/G site of glutamate receptor subunits (GluRs) is likely to reduce post-synaptic excitatory responses to glutamate, thus limiting the progression of cell death; however, prolonged suppression of GluR function in later stages may hinder synaptic plasticity. These observations provide the first direct evidence of the potential contribution of RNA editing to excitatory neural injury and recovery after SCI. [ABSTRACT FROM AUTHOR]
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- 2010
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32. Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC2¯/¯ Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM.
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Lesma, Elena, Grande, Vera, Ancona, Silvia, Carelli, Stephana, Di Giulio, Anna Maria, and Gorio, Alfredo
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HAMARTOMA , *GENES , *CELL proliferation , *EPIDERMAL growth factor , *GENETIC research , *TUBEROUS sclerosis , *PHENOTYPES , *RAPAMYCIN , *PHOSPHORYLATION - Abstract
Background: Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2-/- ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2-/- ASM cell proliferation is EGF-dependent. Methods and Findings: Effects of EGF on proliferation of TSC2-/- ASM cells and TSC2-/- ASM cells transfected with TSC2 gene were determined. In contrast to TSC2-/- ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2-/- ASM cells. Exposure of TSC2-/- ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2-/- cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2-/- ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2-/- ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed. Conclusion: Our results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC-/- ASM cells, and such EGF-dependency is the result of the lack of tuberin. [ABSTRACT FROM AUTHOR]
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- 2008
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33. Transcriptomic Analysis of HCN-2 Cells Suggests Connection among Oxidative Stress, Senescence, and Neuron Death after SARS-CoV-2 Infection.
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Valeri, Andrea, Chiricosta, Luigi, Calcaterra, Valeria, Biasin, Mara, Cappelletti, Gioia, Carelli, Stephana, Zuccotti, Gian Vincenzo, Bramanti, Placido, Pelizzo, Gloria, Mazzon, Emanuela, and Gugliandolo, Agnese
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CELL death , *SARS-CoV-2 , *OXIDATIVE stress , *CELL analysis , *TRANSCRIPTOMES , *WESTERN immunoblotting - Abstract
According to the neurological symptoms of SARS-CoV-2 infection, it is known that the nervous system is influenced by the virus. We used pediatric human cerebral cortical cell line HCN-2 as a neuronal model of SARS-CoV-2 infection, and, through transcriptomic analysis, our aim was to evaluate the effect of SARS-CoV-2 in this type of cells. Transcriptome analyses revealed impairment in TXN gene, resulting in deregulation of its antioxidant functions, as well as a decrease in the DNA-repairing mechanism, as indicated by the decrease in KAT5. Western blot analyses of SOD1 and iNOS confirmed the impairment of reduction mechanisms and an increase in oxidative stress. Upregulation of CDKN2A and a decrease in CDK4 and CDK6 point to the blocking of the cell cycle that, according to the deregulation of repairing mechanism, has apoptosis as the outcome. A high level of proapoptotic gene PMAIP1 is indeed coherent with neuronal death, as also supported by increased levels of caspase 3. The upregulation of cell-cycle-blocking genes and apoptosis suggests a sufferance state of neurons after SARS-CoV-2 infection, followed by their inevitable death, which can explain the neurological symptoms reported. Further analyses are required to deeply explain the mechanisms and find potential treatments to protect neurons from oxidative stress and prevent their death. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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34. SARS-CoV-2 Infected Pediatric Cerebral Cortical Neurons: Transcriptomic Analysis and Potential Role of Toll-like Receptors in Pathogenesis.
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Gugliandolo, Agnese, Chiricosta, Luigi, Calcaterra, Valeria, Biasin, Mara, Cappelletti, Gioia, Carelli, Stephana, Zuccotti, Gianvincenzo, Avanzini, Maria Antonietta, Bramanti, Placido, Pelizzo, Gloria, and Mazzon, Emanuela
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TOLL-like receptors , *NEURON analysis , *SARS-CoV-2 , *PATHOGENESIS , *COVID-19 , *PATTERN perception receptors - Abstract
Different mechanisms were proposed as responsible for COVID-19 neurological symptoms but a clear one has not been established yet. In this work we aimed to study SARS-CoV-2 capacity to infect pediatric human cortical neuronal HCN-2 cells, studying the changes in the transcriptomic profile by next generation sequencing. SARS-CoV-2 was able to replicate in HCN-2 cells, that did not express ACE2, confirmed also with Western blot, and TMPRSS2. Looking for pattern recognition receptor expression, we found the deregulation of scavenger receptors, such as SR-B1, and the downregulation of genes encoding for Nod-like receptors. On the other hand, TLR1, TLR4 and TLR6 encoding for Toll-like receptors (TLRs) were upregulated. We also found the upregulation of genes encoding for ERK, JNK, NF-κB and Caspase 8 in our transcriptomic analysis. Regarding the expression of known receptors for viral RNA, only RIG-1 showed an increased expression; downstream RIG-1, the genes encoding for TRAF3, IKKε and IRF3 were downregulated. We also found the upregulation of genes encoding for chemokines and accordingly we found an increase in cytokine/chemokine levels in the medium. According to our results, it is possible to speculate that additionally to ACE2 and TMPRSS2, also other receptors may interact with SARS-CoV-2 proteins and mediate its entry or pathogenesis in pediatric cortical neurons infected with SARS-CoV-2. In particular, TLRs signaling could be crucial for the neurological involvement related to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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35. Methyiprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury.
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Gorio, Alfredo, Madaschi, Laura, Di Stefano, Barbara, Carelli, Stephana, Di Giulio, Anna Maria, De Biasi, Silvia, Coleman, Thomas, Cerami, Anthony, and Brines, Michael
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SPINAL cord injuries , *GLUCOCORTICOIDS , *ERYTHROPOIETIN , *ADRENOCORTICAL hormones , *HEMATOPOIETIC growth factors , *CLINICAL trials , *CELLULAR immunity - Abstract
Inflammation plays a major pathological role in spinal cord injury (SCI). Although antiinflammatory treatment using the glucocorticoid methyprednisolone sodium succinate (MPSS) improved outcomes in several multicenter clinical trials, additional clinical experience suggests that MPSS is only modestly beneficial in SCI and poses a risk for serious complications. Recent work has shown that erythropoietin (EPO) moderates CNS tissue injury, in part by reducing inflammation, limiting neuronal apoptosis, and restoring vascular autoregulation. We determined whether EPO and MPSS act synergistically in SCI. Using a rat model of contusive SCI, we compared the effects of EPO [500-5,000 units/kg of body weight (kg-bw)] with MPSS (30 mg/kg-bw) for proinflammatory cytokine production, histological damage, and motor function at 1 month after a compression injury. Although high-dose EPO and MPSS suppressed proinflammatory cytokines within the injured spinal cord, only EPO was associated with reduced microglial infiltration, attenuated scar formation, and sustained neurological improvement. Unexpectedly, coadministration of MPSS antagonized the protective effects of EPO, even though the EPO receptor was up-regulated normally after injury. These data illustrate that the suppression of proinflammatory cytokines alone does not necessarily prevent secondary injury and suggest that glucocorticoids should not be coadministered in clinical trials evaluating the use of EPO for treatment of SCI. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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36. RNA-seq Characterization of Sex-Differences in Adipose Tissue of Obesity Affected Patients: Computational Analysis of Differentially Expressed Coding and Non-Coding RNAs.
- Author
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Rey, Federica, Messa, Letizia, Pandini, Cecilia, Maghraby, Erika, Barzaghini, Bianca, Garofalo, Maria, Micheletto, Giancarlo, Raimondi, Manuela Teresa, Bertoli, Simona, Cereda, Cristina, Zuccotti, Gian Vincenzo, Cancello, Raffaella, Carelli, Stephana, and Glusman, Gustavo
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NON-coding RNA , *OBESITY in women , *LINCRNA , *RNA sequencing , *METABOLIC disorders , *ADIPOSE tissues - Abstract
Obesity is a multifactorial disease presenting sex-related differences including adipocyte functions, sex hormone effects, genetics, and metabolic inflammation. These can influence individuals' risk for metabolic dysfunctions, with an urgent need to perform sex-based analysis to improve prevention, treatment, and rehabilitation programs. This research work is aimed at characterizing the transcriptional differences present in subcutaneous adipose tissue (SAT) of five obesity affected men versus five obesity affected women, with an additional focus on the role of long non-coding RNAs. Through RNA-sequencing, we highlighted the presence of both coding and non-coding differentially expressed RNAs, and with numerous computational analyses we identified the processes in which these genes are implicated, along with their role in co-morbidities development. We report 51 differentially expressed transcripts, 32 of which were coding genes and 19 were non-coding. Using the WGCNA R package (Weighted Correlation Network Analysis, version 1.70-3), we describe the interactions between coding and non-coding RNAs, and the non-coding RNAs association with the insurgence of specific diseases, such as cancer development, neurodegenerative diseases, and schizophrenia. In conclusion, our work highlights a specific gender sex-related transcriptional signature in the SAT of obesity affected patients. [ABSTRACT FROM AUTHOR]
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- 2021
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37. Transcriptome Analysis of Subcutaneous Adipose Tissue from Severely Obese Patients Highlights Deregulation Profiles in Coding and Non-Coding Oncogenes.
- Author
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Rey, Federica, Messa, Letizia, Pandini, Cecilia, Launi, Rossella, Barzaghini, Bianca, Micheletto, Giancarlo, Raimondi, Manuela Teresa, Bertoli, Simona, Cereda, Cristina, Zuccotti, Gian Vincenzo, Cancello, Raffaella, Carelli, Stephana, and Nixon, Daniel W.
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ONCOGENES , *OBESITY , *TYPE 2 diabetes , *NON-coding RNA , *ADIPOSE tissues , *GENETIC transcription regulation - Abstract
Obesity is a major risk factor for a large number of secondary diseases, including cancer. Specific insights into the role of gender differences and secondary comorbidities, such as type 2 diabetes (T2D) and cancer risk, are yet to be fully identified. The aim of this study is thus to find a correlation between the transcriptional deregulation present in the subcutaneous adipose tissue of obese patients and the oncogenic signature present in multiple cancers, in the presence of T2D, and considering gender differences. The subcutaneous adipose tissue (SAT) of five healthy, normal-weight women, five obese women, five obese women with T2D and five obese men were subjected to RNA-sequencing, leading to the identification of deregulated coding and non-coding RNAs, classified for their oncogenic score. A panel of DE RNAs was validated via Real-Time PCR and oncogene expression levels correlated the oncogenes with anthropometrical parameters, highlighting significant trends. For each analyzed condition, we identified the deregulated pathways associated with cancer, the prediction of possible prognosis for different cancer types and the lncRNAs involved in oncogenic networks and tissues. Our results provided a comprehensive characterization of oncogenesis correlation in SAT, providing specific insights into the possible molecular targets implicated in this process. Indeed, the identification of deregulated oncogenes also in SAT highlights hypothetical targets implicated in the increased oncogenic risk in highly obese subjects. These results could shed light on new molecular targets to be specifically modulated in obesity and highlight which cancers should receive the most attention in terms of better prevention in obesity-affected patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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38. Alzheimer's, Parkinson's Disease and Amyotrophic Lateral Sclerosis Gene Expression Patterns Divergence Reveals Different Grade of RNA Metabolism Involvement.
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Garofalo, Maria, Pandini, Cecilia, Bordoni, Matteo, Pansarasa, Orietta, Rey, Federica, Costa, Alfredo, Minafra, Brigida, Diamanti, Luca, Zucca, Susanna, Carelli, Stephana, Cereda, Cristina, and Gagliardi, Stella
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RNA metabolism , *AMYOTROPHIC lateral sclerosis , *PARKINSON'S disease , *GENE expression , *LINCRNA , *PERIPHERAL nervous system - Abstract
Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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39. Dissecting the Effect of a 3D Microscaffold on the Transcriptome of Neural Stem Cells with Computational Approaches: A Focus on Mechanotransduction.
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Rey, Federica, Pandini, Cecilia, Barzaghini, Bianca, Messa, Letizia, Giallongo, Toniella, Pansarasa, Orietta, Gagliardi, Stella, Brilli, Matteo, Zuccotti, Gian Vincenzo, Cereda, Cristina, Raimondi, Manuela Teresa, and Carelli, Stephana
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NEURAL stem cells , *STEM cells , *GENE expression , *RNA sequencing , *CELL culture , *TISSUE scaffolds - Abstract
3D cell cultures are becoming more and more important in the field of regenerative medicine due to their ability to mimic the cellular physiological microenvironment. Among the different types of 3D scaffolds, we focus on the Nichoid, a miniaturized scaffold with a structure inspired by the natural staminal niche. The Nichoid can activate cellular responses simply by subjecting the cells to mechanical stimuli. This kind of influence results in different cellular morphology and organization, but the molecular bases of these changes remain largely unknown. Through RNA-Seq approach on murine neural precursors stem cells expanded inside the Nichoid, we investigated the deregulated genes and pathways showing that the Nichoid causes alteration in genes strongly connected to mechanobiological functions. Moreover, we fully dissected this mechanism highlighting how the changes start at a membrane level, with subsequent alterations in the cytoskeleton, signaling pathways, and metabolism, all leading to a final alteration in gene expression. The results shown here demonstrate that the Nichoid influences the biological and genetic response of stem cells thorough specific alterations of cellular signaling. The characterization of these pathways elucidates the role of mechanical manipulation on stem cells, with possible implications in regenerative medicine applications. [ABSTRACT FROM AUTHOR]
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- 2020
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40. Advances in Tissue Engineering and Innovative Fabrication Techniques for 3-D-Structures: Translational Applications in Neurodegenerative Diseases.
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Rey, Federica, Barzaghini, Bianca, Nardini, Alessandra, Bordoni, Matteo, Zuccotti, Gian Vincenzo, Cereda, Cristina, Raimondi, Manuela Teresa, and Carelli, Stephana
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NEURODEGENERATION , *TISSUE engineering , *TISSUE scaffolds , *REGENERATIVE medicine , *THREE-dimensional printing , *PRINTMAKING - Abstract
In the field of regenerative medicine applied to neurodegenerative diseases, one of the most important challenges is the obtainment of innovative scaffolds aimed at improving the development of new frontiers in stem-cell therapy. In recent years, additive manufacturing techniques have gained more and more relevance proving the great potential of the fabrication of precision 3-D scaffolds. In this review, recent advances in additive manufacturing techniques are presented and discussed, with an overview on stimulus-triggered approaches, such as 3-D Printing and laser-based techniques, and deposition-based approaches. Innovative 3-D bioprinting techniques, which allow the production of cell/molecule-laden scaffolds, are becoming a promising frontier in disease modelling and therapy. In this context, the specific biomaterial, stiffness, precise geometrical patterns, and structural properties are to be considered of great relevance for their subsequent translational applications. Moreover, this work reports numerous recent advances in neural diseases modelling and specifically focuses on pre-clinical and clinical translation for scaffolding technology in multiple neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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41. A New Selective PPARγ Modulator Inhibits Triglycerides Accumulation during Murine Adipocytes' and Human Adipose-Derived Mesenchymal Stem Cells Differentiation.
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Al Haj, Ghina, Rey, Federica, Giallongo, Toniella, Colli, Mattia, Marzani, Barbara, Giuliani, Giammaria, Gorio, Alfredo, Zuccotti, Gian Vicenzo, Di Giulio, Anna Maria, and Carelli, Stephana
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ADIPOGENESIS , *MESENCHYMAL stem cell differentiation , *FAT cells , *PEROXISOME proliferator-activated receptors , *TRIGLYCERIDES , *STEM cells - Abstract
Understanding the molecular basis of adipogenesis is vital to identify new therapeutic targets to improve anti-obesity drugs. The adipogenic process could be a new target in the management of this disease. Our aim was to evaluate the effect of GMG-43AC, a selective peroxisome proliferator-activated receptor γ (PPARγ) modulator, during adipose differentiation of murine pre-adipocytes and human Adipose Derived Stem Cells (hADSCs). We differentiated 3T3-L1 cells and primary hADSCs in the presence of various doses of GMG-43AC and evaluated the differentiation efficiency measuring lipid accumulation, the expression of specific differentiation markers and the quantification of accumulated triglycerides. The treatment with GMG-43AC is not toxic as shown by cell viability assessments after the treatments. Our findings demonstrate the inhibition of lipid accumulation and the significant decrease in the expression of adipocyte-specific genes, such as PPARγ, FABP-4, and leptin. This effect was long lasting, as the removal of GMG-43AC from culture medium did not allow the restoration of adipogenic process. The above actions were confirmed in hADSCs exposed to adipogenic stimuli. Together, these results indicate that GMG-43AC efficiently inhibits adipocytes differentiation in murine and human cells, suggesting its possible function in the reversal of adipogenesis and modulation of lipolysis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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42. Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach.
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Bordoni, Matteo, Scarian, Eveljn, Rey, Federica, Gagliardi, Stella, Carelli, Stephana, Pansarasa, Orietta, and Cereda, Cristina
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BIOMATERIALS , *NEURODEGENERATION , *AMYOTROPHIC lateral sclerosis , *PARKINSON'S disease , *PATHOLOGY , *SPINAL cord injuries - Abstract
Neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinal cord injury) represent a great problem worldwide and are becoming prevalent because of the increasing average age of the population. Despite many studies having focused on their etiopathology, the exact cause of these diseases is still unknown and until now, there are only symptomatic treatments. Biomaterials have become important not only for the study of disease pathogenesis, but also for their application in regenerative medicine. The great advantages provided by biomaterials are their ability to mimic the environment of the extracellular matrix and to allow the growth of different types of cells. Biomaterials can be used as supporting material for cell proliferation to be transplanted and as vectors to deliver many active molecules for the treatments of neurodegenerative disorders. In this review, we aim to report the potentiality of biomaterials (i.e., hydrogels, nanoparticles, self-assembling peptides, nanofibers and carbon-based nanomaterials) by analyzing their use in the regeneration of neural and glial cells their role in axon outgrowth. Although further studies are needed for their use in humans, the promising results obtained by several groups leads us to suppose that biomaterials represent a potential therapeutic approach for the treatments of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Bioink Composition and Printing Parameters for 3D Modeling Neural Tissue.
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Fantini, Valentina, Bordoni, Matteo, Scocozza, Franca, Conti, Michele, Scarian, Eveljn, Carelli, Stephana, Di Giulio, Anna Maria, Marconi, Stefania, Pansarasa, Orietta, Auricchio, Ferdinando, and Cereda, Cristina
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BIOPRINTING , *NERVE tissue , *INDUCED pluripotent stem cells , *THREE-dimensional printing , *CENTRAL nervous system , *NEURAL stem cells , *PLURIPOTENT stem cells , *TISSUE scaffolds - Abstract
Neurodegenerative diseases (NDs) are a broad class of pathologies characterized by the progressive loss of neurons in the central nervous system. The main problem in the study of NDs is the lack of an adequate realistic experimental model to study the pathogenic mechanisms. Induced pluripotent stem cells (iPSCs) partially overcome the problem, with their capability to differentiate into almost every cell types; even so, these cells alone are not sufficient to unveil the mechanisms underlying NDs. 3D bioprinting allows to control the distribution of cells such as neurons, leading to the creation of a realistic in vitro model. In this work, we analyzed two biomaterials: sodium alginate and gelatin, and three different cell types: a neuroblastoma cell line (SH-SY5Y), iPSCs, and neural stem cells. All cells were encapsulated inside the bioink, printed and cultivated for at least seven days; they all presented good viability. We also evaluated the maintenance of the printed shape, opening the possibility to obtain a reliable in vitro neural tissue combining 3D bioprinting and iPSCs technology, optimizing the study of the degenerative processes that are still widely unknown. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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44. From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases.
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Bordoni, Matteo, Rey, Federica, Fantini, Valentina, Pansarasa, Orietta, Di Giulio, Anna Maria, Carelli, Stephana, and Cereda, Cristina
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NEURONAL differentiation , *NEURAL development , *ORGANOIDS , *BIOMEDICAL engineering , *NEURODEGENERATION - Abstract
In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture in vitro all types of patient-specific neural cells, facilitating not only the investigation of diseases' etiopathology, but also the testing of new drugs and cell therapies, leading to the innovative concept of personalized medicine. Moreover, iPSCs can be differentiated and organized into 3D organoids, providing a tool which mimics the complexity of the brain's architecture. Furthermore, recent developments in 3D bioprinting allowed the study of physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bio-plotter and biomaterials in which several types of cells, such as iPSCs or differentiated neurons, can be encapsulated in order to develop an innovative cellular model. IPSCs and 3D cell cultures technologies represent the first step towards the obtainment of a more reliable model, such as organoids, to facilitate neurodegenerative diseases' investigation. The combination of iPSCs, 3D organoids and bioprinting will also allow the development of new therapeutic approaches. Indeed, on the one hand they will lead to the development of safer and patient-specific drugs testing but, also, they could be developed as cell-therapy for curing neurodegenerative diseases with a regenerative medicine approach. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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