Publications by authors named "Nunzio Vicario"

35 Publications

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing.

Cell Death Dis 2021 Jun 16;12(7):625. Epub 2021 Jun 16.

Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123, Catania, Italy.

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.
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http://dx.doi.org/10.1038/s41419-021-03907-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209072PMC
June 2021

Neural stem cells traffic functional mitochondria via extracellular vesicles.

PLoS Biol 2021 04 7;19(4):e3001166. Epub 2021 Apr 7.

Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
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http://dx.doi.org/10.1371/journal.pbio.3001166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055036PMC
April 2021

Focus on Osteosclerotic Progression in Primary Myelofibrosis.

Biomolecules 2021 01 19;11(1). Epub 2021 Jan 19.

Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", University of Catania, 95123 Catania, Italy.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.
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http://dx.doi.org/10.3390/biom11010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832894PMC
January 2021

Connexin expression decreases during adipogenic differentiation of human adipose-derived mesenchymal stem cells.

Mol Biol Rep 2020 Dec 3;47(12):9951-9958. Epub 2020 Nov 3.

Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, via Santa Sofia 97, 95123, Catania, Italy.

Adipose-derived stem cells (ASCs) represent a valuable tool for regenerative medicine being able to differentiate toward several cell lines, such as adipocytes, chondrocytes and osteocytes. During ASC adipogenic differentiation, changes in connexin (Cx) expression were evaluated in the present study. Three different Cxs were investigated: Cx43, Cx32 and Cx31.9. Cx43 is the most abundant in human tissues, Cx32 is prevalently found in nervous tissue and Cx31.9 is found at the myocardial level. Human ASCs undergoing adipogenic differentiation were isolated from raw lipoaspirate and characterized as mesenchymal stem cells. After multiple days of culture (1, 7, 14, 21 and 28 days), adipogenic differentiation was assessed by Oil Red O staining and Acetyl-CoA carboxylase (ACC) levels by western blotting. Cx expression was evaluated by western blotting at the same time points. In treated ASCs, lipidic vacuoles were detected from day 7 of treatment. Their number and size progressively increased over the entire period of observation. A parallel increase of ACC expression was also found. Lower levels of Cx expression were detected during adipogenic differentiation. Such decreases were particularly evident for Cx32, already after the first day of treatment. Cx31.9 and Cx43 also decreased, but starting from day 7. Our results suggest that ASCs may initially be equipped with a variety of Cxs, which is not surprising assuming their multipotential differentiation ability. Although some Cxs may be selectively enhanced depending on specific induction strategies toward different tissues, they seem markedly downregulated during adipogenic differentiation.
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http://dx.doi.org/10.1007/s11033-020-05950-1DOI Listing
December 2020

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance.

Cancers (Basel) 2020 Oct 4;12(10). Epub 2020 Oct 4.

Department of Biomedical and Biotechnological Sciences (BIOMETEC), Section of Physiology, University of Catania, 95123 Catania, Italy.

Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment.
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http://dx.doi.org/10.3390/cancers12102860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599682PMC
October 2020

Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib.

Redox Biol 2020 09 24;36:101611. Epub 2020 Jun 24.

Section of Hematology, Department of Medical and Surgical Specialties, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy.

Iron plays a major role in multiple processes involved in cell homeostasis such as metabolism, respiration and DNA synthesis. Cancer cells exhibit pronounced iron retention as compared to healthy counterpart. This phenomenon also occurs in multiple myeloma (MM), a hematological malignancy characterized by terminally differentiated plasma cells (PCs), in which serum ferritin levels have been reported as a negative prognostic marker. The aim of current study is to evaluate the potential role of iron metabolism in promoting drug resistance in myeloma cancer cells with particular regard to the interactions between PCs and tumor-associated macrophages (TAMs) as a source of iron. Our data showed that myeloma cell lines are able to intake and accumulate iron and thus, increasing their scavenger antioxidant-related genes and mitochondrial mass. We further demonstrated that PCs pre-treated with ferric ammonium citrate (FAC) decreased bortezomib (BTZ)-induced apoptosis in vitro and successfully engrafted in zebrafish larvae treated with BTZ. Treating human macrophages with FAC, we observed a switch toward a M2-like phenotype associated with an increased expression of anti-inflammatory markers such as ARG1, suggesting the establishment of an iron-mediated immune suppressive tumor microenvironment favouring myeloma growth. Using mfap4:tomato mutant zebrafish larvae, we further confirmed the increase of PCs-monocytes interactions after FAC treatment which favour BTZ-resistance. Taken together our data support the hypothesis that targeting iron trafficking in myeloma microenvironment may represent a promising strategy to counteract a tumor-supporting milieu and drug resistance.
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http://dx.doi.org/10.1016/j.redox.2020.101611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327252PMC
September 2020

Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells.

Cancers (Basel) 2020 Jul 22;12(8). Epub 2020 Jul 22.

Division of Hematology, Azienda Ospedaliero Universitaria, Policlinico Vittorio Emanuele, 95123 Catania, Italy.

Multiple myeloma (MM) is a B-cell malignancy requiring inflammatory microenvironment signals for cell survival and proliferation. Despite improvements in pharmacological tools, MM remains incurable mainly because of drug resistance. The present study aimed to investigate the implication of Toll-like receptor 4 (TLR4) as the potential mechanism of bortezomib (BTZ) resistance. We found that TLR4 activation induced mitochondrial biogenesis and increased mitochondrial mass in human MM cell lines. Moreover, TLR4 signaling was activated after BTZ exposure and was increased in BTZ-resistant U266 (U266-R) cells. A combination of BTZ with TAK-242, a selective TLR4 inhibitor, overcame drug resistance through the generation of higher and extended oxidative stress, strong mitochondrial depolarization and severe impairment of mitochondrial fitness which in turn caused cell energy crisis and activated mitophagy and apoptosis. We further confirmed the efficacy of a TAK-242/BTZ combination in plasma cells from refractory myeloma patients. Consistently, inhibition of TLR4 increased BTZ-induced mitochondrial depolarization, restoring pharmacological response. Taken together, these findings indicate that TLR4 signaling acts as a stress-responsive mechanism protecting mitochondria during BTZ exposure, sustaining mitochondrial metabolism and promoting drug resistance. Inhibition of TLR4 could be therefore be a possible target in patients with refractory MM to overcome BTZ resistance.
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http://dx.doi.org/10.3390/cancers12081999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463509PMC
July 2020

Increased expression of connexin 43 in a mouse model of spinal motoneuronal loss.

Aging (Albany NY) 2020 06 24;12(13):12598-12608. Epub 2020 Jun 24.

Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy.

Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuronal disease, characterized by motoneuronal loss and progressive paralysis. Despite research efforts, ALS remains a fatal disease, with a survival of 2-5 years after disease onset. Numerous gene mutations have been correlated with both sporadic (sALS) and familiar forms of the disease, but the pathophysiological mechanisms of ALS onset and progression are still largely uncertain. However, a common profile is emerging in ALS pathological features, including misfolded protein accumulation and a cross-talk between neuroinflammatory and degenerative processes. In particular, astrocytes and microglial cells have been proposed as detrimental influencers of perineuronal microenvironment, and this role may be exerted via gap junctions (GJs)- and hemichannels (HCs)-mediated communications. Herein we investigated the role of the main astroglial GJs-forming connexin, Cx43, in human ALS and the effects of focal spinal cord motoneuronal depletion onto the resident glial cells and Cx43 levels. Our data support the hypothesis that motoneuronal depletion may affect glial activity, which in turn results in reactive Cx43 expression, further promoting neuronal suffering and degeneration.
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http://dx.doi.org/10.18632/aging.103561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377853PMC
June 2020

Intercellular communication and ion channels in neuropathic pain chronicization.

Inflamm Res 2020 Sep 12;69(9):841-850. Epub 2020 Jun 12.

Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

Background: Neuropathic pain is caused by primary lesion or dysfunction of either peripheral or central nervous system. Due to its complex pathogenesis, often related to a number of comorbidities, such as cancer, neurodegenerative and neurovascular diseases, neuropathic pain still represents an unmet clinical need, lacking long-term effective treatment and complex case-by-case approach.

Aim And Methods: We analyzed the recent literature on the role of selective voltage-sensitive sodium, calcium and potassium permeable channels and non-selective gap junctions (GJs) and hemichannels (HCs) in establishing and maintaining chronic neuropathic conditions. We finally focussed our review on the role of extracellular microenvironment modifications induced by resident glial cells and on the recent advances in cell-to-cell and cell-to-extracellular environment communication in chronic neuropathies.

Conclusion: In this review, we provide an update on the current knowledge of neuropathy chronicization processes with a focus on both neuronal and glial ion channels, as well as on channel-mediated intercellular communication.
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http://dx.doi.org/10.1007/s00011-020-01363-9DOI Listing
September 2020

SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France.

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of γ-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance.
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http://dx.doi.org/10.3390/ijms21113917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312922PMC
May 2020

Chronic α-Synuclein Accumulation in Rat Hippocampus Induces Lewy Bodies Formation and Specific Cognitive Impairments.

eNeuro 2020 May/Jun;7(3). Epub 2020 Jun 15.

Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Laboratory of Prion Biology, Trieste 34127, Italy

Occurrence of Lewy bodies (LBs)/Lewy neurites (LNs) containing misfolded fibrillar α-synuclein (α-syn) is one of the pathologic hallmarks of memory impairment-linked synucleinopathies, such as Parkinson's disease (PD) and dementia with LBs (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropathological substrates for cognitive symptoms are still elusive. Here, recombinant mouse α-syn fibrils were bilaterally injected in the hippocampus of female Sprague Dawley rats, which underwent behavioral testing for sensorimotor and spatial learning and memory abilities. No sensorimotor deficits affecting Morris water maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months postinjection. These deficits were associated to a time-dependent increase in the levels of phosphorylated α-syn at Ser129 and in the stereologically estimated numbers of proteinase K (PK)-resistant α-syn aggregates within the hippocampus. Interestingly, pathologic α-syn aggregates were found in the entorhinal cortex and, by 12 months postinjection, also in the vertical limb of the diagonal band and the piriform cortices. No pathologic α-syn deposits were found within the substantia nigra (SN), the ventral tegmental area (VTA), or the striatum, nor was any loss of dopaminergic, noradrenergic, or cholinergic neurons detected in α-syn-injected animals, compared with controls. This would suggest that the behavioral impairments seen in the α-syn-injected animals might be determined by the long-term α-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits.
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http://dx.doi.org/10.1523/ENEURO.0009-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307628PMC
June 2021

Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells.

Biomolecules 2020 04 30;10(5). Epub 2020 Apr 30.

Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.

The proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used two different clones of multiple myeloma cell lines exhibiting different sensitivities to BTZ (U266 and U266-R) and compared them in terms of metabolic profile, mitochondrial fitness and redox balance homeostasis capacity. Our results showed that the BTZ-resistant clone (U266-R) presented increased glycosylated UDP-derivatives when compared to BTZ-sensitive cells (U266), thus also suggesting higher activities of the hexosamine biosynthetic pathway (HBP), regulating not only protein and glycosylation but also mitochondrial functions. Notably, U266-R displayed increased mitochondrial biogenesis and mitochondrial dynamics associated with stronger antioxidant defenses. Furthermore, U266-R maintained a significantly higher concentration of substrates for protein glycosylation when compared to U266, particularly for UDP-GlcNac, thus further suggesting the importance of glycosylation in the BTZ pharmacological response. Moreover, BTZ-treated U266-R showed significantly higher ATP/ADP ratios and levels of ECP and also exhibited increased mitochondrial fitness and antioxidant response. In conclusions, our findings suggest that the HBP may play a major role in mitochondrial fitness, driving BTZ resistance in multiple myeloma and thus representing a possible target for new drug development for BTZ-resistant patients.
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http://dx.doi.org/10.3390/biom10050696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277183PMC
April 2020

Ixazomib Improves Bone Remodeling and Counteracts sonic Hedgehog signaling Inhibition Mediated by Myeloma Cells.

Cancers (Basel) 2020 Jan 30;12(2). Epub 2020 Jan 30.

Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. "Policlinico-Vittorio Emanuele", University of Catania, 95123 Catania, Italy.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients.
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http://dx.doi.org/10.3390/cancers12020323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073172PMC
January 2020

Olfactory Ensheathing Cells express both Ghrelin and Ghrelin Receptor in vitro: a new hypothesis in favor of a neurotrophic effect.

Neuropeptides 2020 Feb 22;79:101997. Epub 2019 Nov 22.

Dept Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.

Olfactory Ensheathing Cells (OECs) are glial cells able to secrete different neurotrophic growth factors and thus promote axonal growth, also acting as a mechanical support. In the olfactory system, during development, they drive the non-myelinated axons of the Olfactory Receptor Neurons (ORNs) towards the Olfactory Bulb (OB). Ghrelin (Ghre), a gut-brain peptide hormone, and its receptor (GHS-R 1a) are expressed in different parts of the central nervous system. In the last few years, this peptide has stimulated particular interest as results show it to be a neuroprotective factor with antioxidant, anti-inflammatory and anti-apoptotic properties. Our previous studies showed that OB mitral cells express Ghre, thus being able to play an important role in regulating food behavior in response to odors. In this study, we investigated the presence of Ghre and GHS-R 1a in primary mouse OECs. The expression of both Ghre and its receptor was assessed by an immunocytochemical technique, Western Blot and Polymerase Chain Reaction (PCR) analysis. Our results demonstrated that OECs are able to express both Ghre and GHS-R 1a and that these proteins are detectable after extensive passages in vitro; in addition, PCR analysis further confirmed these data. Therefore, we can hypothesize that Ghre and GHS-R 1a interact with a reinforcement function, in the peripheral olfactory circuit, providing a neurotrophic support to the synaptic interaction between ORNs and mitral cells.
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http://dx.doi.org/10.1016/j.npep.2019.101997DOI Listing
February 2020

A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition.

Oncoimmunology 2019;8(12):e1678921. Epub 2019 Oct 21.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.

Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8 T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.
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http://dx.doi.org/10.1080/2162402X.2019.1678921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844311PMC
October 2019

Compensatory changes in degenerating spinal motoneurons sustain functional sparing in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

J Comp Neurol 2020 02 7;528(2):231-243. Epub 2019 Aug 7.

B.R.A.I.N. Laboratory for Neurogenesis and Repair, Department of Life Sciences, University of Trieste, Trieste, Italy.

Plastic changes have been reported in the SOD1-G93A mouse model of amyotrophic lateral sclerosis, a disorder characterized by progressive motoneuronal loss; however, whether these changes related with the onset and development of motor impairments is still unclear. Here, the functional and anatomical changes taking place in SOD1-G93A mice and their time course were investigated during ongoing motoneuronal degeneration. Starting from about 4 postnatal weeks, SOD1-G93A and wild-type (WT) mice were evaluated in the rotarod test, to be sacrificed at about 12-13 or 19 weeks of age, and their lumbar spinal cords were processed for histo- and immunohistochemistry. Compared to age-matched WT controls, 12 weeks-old SOD1-G93A mice exhibited relatively mild or no motor impairments in the rotarod test, in spite of a dramatic (≈60%, as estimated by stereology) loss of choline acetyl-transferase (ChAT)-immunoreactive motoneurons which remained virtually unchanged in SOD1-G93A mice surviving up to 19 weeks. Notably, the functional sparing in SOD1-G93A mice at 12 weeks was paralleled by a marked ≈50% increase in motoneuron volume and a near-normal density of acetylcholinesterase-positive process arborization, which was significantly increased when analyzed as ratio to the decreased number of ChAT-positive motoneurons. By contrast, at 19 weeks, when motor deficits had become dramatically evident, both measures were found reverted to about 50-60% of control values. Thus, at specific stages during the progression of the disease, robust compensatory events take place in surviving motoneurons of SOD1-G93A mice, which sustain motor performance, and whose full understanding may highlight a valuable therapeutic opportunity window.
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http://dx.doi.org/10.1002/cne.24751DOI Listing
February 2020

Simultaneous Activation of Mu and Delta Opioid Receptors Reduces Allodynia and Astrocytic Connexin 43 in an Animal Model of Neuropathic Pain.

Mol Neurobiol 2019 Nov 28;56(11):7338-7354. Epub 2019 Apr 28.

Department of Drug Sciences, Section of Pharmacology and Toxicology, University of Catania, 95125, Catania, Italy.

Neuropathic pain is a chronic condition triggered by lesions to the somatosensory nervous system in which pain stimuli occur spontaneously or as pathologically amplified responses. In this scenario, the exchange of signaling molecules throughout cell-to-cell and cell-to-extracellular environment communications plays a key role in the transition from acute to chronic pain. As such, connexin 43 (Cx43), the core glial gap junction and hemichannel-forming protein, is considered a triggering factor for disease chronicization in the central nervous system (CNS). Drugs targeting μ opioid receptors (MOR) are currently used for moderate to severe pain conditions, but their use in chronic pain is limited by the tolerability profile. δ opioid receptors (DOR) have become attractive targets for the treatment of persistent pain and have been associated with the inhibition of pain-sustaining factors. Moreover, it has been shown that simultaneous targeting of MOR and DOR leads to an improved pharmacological fingerprint. Herein, we aimed to study the effects of the benzomorphan ligand LP2, a multitarget MOR/DOR agonist, in an experimental model of neuropathic pain induced by the unilateral sciatic nerve chronic constriction injury (CCI) on male Sprague-Dawley rats. Results showed that LP2 significantly ameliorated mechanical allodynia from the early phase of treatment up to 21 days post-ligatures. We additionally showed that LP2 prevented CCI-induced Cx43 alterations and pro-apoptotic signaling in the CNS. These findings increase the knowledge of neuropathic pain development and the role of spinal astrocytic Cx43, suggesting new approaches for the treatment of neuropathic pain.
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http://dx.doi.org/10.1007/s12035-019-1607-1DOI Listing
November 2019

Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation.

Int J Mol Sci 2019 Apr 23;20(8). Epub 2019 Apr 23.

Lab of Neurophysiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy.

Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.
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http://dx.doi.org/10.3390/ijms20081991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514872PMC
April 2019

SUMOylation in Glioblastoma: A Novel Therapeutic Target.

Int J Mol Sci 2019 Apr 15;20(8). Epub 2019 Apr 15.

Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA.

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.
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http://dx.doi.org/10.3390/ijms20081853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514907PMC
April 2019

Neuroprotective effects of L. extract in oxygen glucose deprivation (OGD)-injured human neural-like cells.

Nat Prod Res 2021 Feb 2;35(4):669-675. Epub 2019 Apr 2.

Department of Drug Sciences, Pharmacology Section, University of Catania, Catania, Italy.

L. (RO), an aromatic plant used as food condiment and in traditional medicine, exerts numerous beneficial properties including antioxidant, analgesic and neuroprotective effects. Onset and progression of homeostatic imbalances observed in the early phases of a number of neurodegenerative diseases, have been associated with a gap junction (GJ)-dependent increased membrane permeability and alterations of connexins (Cxs), including Cx43. Here, we evaluate spray-dried RO extract (SDROE)-mediated effects on cell viability, apoptosis and Cx43-based intercellular communication using human SH-SY5Y neuron-like and human A-172 glial-like cells in an in vitro model of oxygen glucose deprivation (OGD) injury. We found that SDROE exerts a protective action in OGD-injured cells, increasing cell viability and metabolic turnover and decreasing Cx43-based cell coupling. These data suggest that SDROE-mediated Cx43 reduction may be the molecular basis for its beneficial effects to be exploited for preventive treatment against the risk of some neurodegenerative disorders.
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http://dx.doi.org/10.1080/14786419.2019.1587428DOI Listing
February 2021

Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice.

Cancer Gene Ther 2020 04 28;27(3-4):246-255. Epub 2019 Mar 28.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.

Primary malignant central nervous system (CNS) tumors are the leading cause of childhood cancer-related death and morbidity. While advances in surgery, radiation, and chemotherapy have improved the survival rates in children with malignant brain tumors, mortality persists in certain subpopulations and current therapies are associated with extreme morbidity. This is especially true for children with malignant infratentorial tumors. Accordingly, G207, a genetically engineered herpes simplex virus (HSV-1) capable of selectively targeting cancer cells has emerged as a promising therapeutic option for this patient population. Herein, we demonstrate that cerebellar inoculation of G207 was systemically non-toxic in an immunocompetent, HSV-1 sensitive mouse strain (CBA/J). Mice had neither abnormal brain/organ pathology nor evidence of G207 replication by immunohistochemistry at days 7 and 30 after cerebellar G207 inoculation. While a minute amount viral DNA was recovered in the cerebellum and brainstem of mice at day 7, no viral DNA persisted at day 30. Critically, G207 delivered to the cerebellum was able to target/treat the highly aggressive MYC-overexpressed group 3 murine medulloblastoma increasing survival vs controls. These results provide critical safety and efficacy data to support the translation of G207 for pediatric clinical trials in intractable cerebellar malignancies.
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http://dx.doi.org/10.1038/s41417-019-0091-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416750PMC
April 2020

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss.

Int J Mol Sci 2019 Mar 26;20(6). Epub 2019 Mar 26.

Laboratory of Cellular and Molecular Physiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy.

Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.
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http://dx.doi.org/10.3390/ijms20061500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471664PMC
March 2019

SUMOylation promotes survival and integration of neural stem cell grafts in ischemic stroke.

EBioMedicine 2019 Apr 21;42:214-224. Epub 2019 Mar 21.

Department of Clinical Neurosciences, University of Cambridge, UK; NIHR Biomedical Research Centre, University of Cambridge, UK. Electronic address:

Background: Neural stem cell (NSC)-based therapies hold great promise for treating diseases of the central nervous system (CNS). However, several fundamental problems still need to be overcome to fully exploit the clinical potential of NSC therapeutics. Chief among them is the limited survival of NSC grafts within hostile microenvironments.

Methods: Herein, we sought to engineer NSCs in an effort to increase graft survival within ischemic brain lesions via upregulation of global SUMOylation, a post-translational modification critically involved in mediating tolerance to ischemia/reperfusion.

Findings: NSCs overexpressing the SUMO E2-conjugase Ubc9 displayed resistance to oxygen-glucose-deprivation/restoration of oxygen/glucose (OGD/ROG) and enhanced neuronal differentiation in vitro, as well as increased survival and neuronal differentiation when transplanted in mice with transient middle cerebral artery occlusion in vivo.

Interpretation: Our work highlights a critical role for SUMOylation in NSC biology and identifies a biological pathway that can be targeted to increase the effectiveness of exogenous stem cell medicines in ischemic stroke. FUND: Intramural Research Program of the NINDS/NIH, the Italian Multiple Sclerosis Foundation (FISM), the Bascule Charitable Trust, NIH-IRTA-OxCam and Wellcome Trust Research Training Fellowships.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491415PMC
April 2019

Middle-aged healthy women and Alzheimer's disease patients present an overlapping of brain cell transcriptional profile.

Neuroscience 2019 May 12;406:333-344. Epub 2019 Mar 12.

Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Catania, Italy. Electronic address:

Exploring sexual dimorphisms in the brain morphology is important for their impact and therapeutic implications for several neurological diseases. The hypothesis that sex could influence the transcriptome of brain cells could be the basis regarding the different response to cognitive decline identified in men and women. In this paper, we analyzed several prefrontal cortices (PFC) microarrays datasets of young/middle-aged healthy subjects and then Alzheimer's disease (AD) patients, according to the sex. The significant transcriptomes were overlapped with the main genes characterizing cells of the central nervous system (CNS) in order to determine the respective weighted percentages of significantly expression gene modulation (WPSEG). We identified differences in brain transcriptional activity between young and middle-aged. In middle-aged women, the WPSEG were higher for the Astrocytes, the Endotheliocytes, and the Microglia. In addition, the sex-matched analysis of transcriptome identified a convergent molecular signature in men and women AD patients. Furthermore, the WPSEG belonging to CNS cells in PFC of healthy middle-aged subjects was correlated to AD profiles according to the sex. Since our results, it is possible to conclude that during the aging the PFC' cells adopt transcriptional strategies sex-dependent that could potentially control the development of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neuroscience.2019.03.008DOI Listing
May 2019

An innovative silicon-chip for sensitive real time PCR improvement in pathogen detection.

Analyst 2019 Mar;144(7):2353-2358

Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.

An innovative miniaturized silicon-chip was developed for highly sensitive detection of pathogen genomes of both viruses and bacteria through real time PCR (qRT-PCR). The device was properly designed to enhance the optical signal and perform accurate thermal control. Results show an improvement of PCR amplification by one order of magnitude in sensitivity compared to the standard RT-PCR method. In particular for hepatitis B virus a decrease of the mean value of Ct of about 2.9 ± 0.9 compared to the standard system was observed. Similarly, for the bacteria Pseudomonas aeruginosa, Staphylococcus aureus and Acinetobacter baumannii, a decrease of the mean values of Ct of 1.8 ± 0.5, 3.1 ± 0.5 and 3.9 ± 0.9, respectively, was observed.
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http://dx.doi.org/10.1039/c9an00006bDOI Listing
March 2019

The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases.

Int J Mol Sci 2019 Feb 1;20(3). Epub 2019 Feb 1.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95125 Catania, Italy.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.
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http://dx.doi.org/10.3390/ijms20030634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387239PMC
February 2019

α-Lipoic Acid Reduces Iron-induced Toxicity and Oxidative Stress in a Model of Iron Overload.

Int J Mol Sci 2019 Jan 31;20(3). Epub 2019 Jan 31.

Department of Medical, Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, 95123 Catania, Italy.

Iron toxicity is associated with organ injury and has been reported in various clinical conditions, such as hemochromatosis, thalassemia major, and myelodysplastic syndromes. Therefore, iron chelation therapy represents a pivotal therapy for these patients during their lifetime. The aim of the present study was to assess the iron chelating properties of α-lipoic acid (ALA) and how such an effect impacts on iron overload mediated toxicity. Human mesenchymal stem cells (HS-5) and animals (zebrafish, = 10 for each group) were treated for 24 h with ferric ammonium citrate (FAC, 120 µg/mL) in the presence or absence of ALA (20 µg/mL). Oxidative stress was evaluated by reduced glutathione content, reactive oxygen species formation, mitochondrial dysfunction, and gene expression of heme oxygenase-1b and mitochondrial superoxide dismutase; organ injury, iron accumulation, and autophagy were measured by microscopical, cytofluorimetric analyses, and inductively coupled plasma‒optical mission Spectrometer (ICP-OES). Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment. In conclusion, ALA possesses excellent iron chelating properties that may be exploited in a clinical setting for organ preservation, as well as exhibiting a good safety profile and low cost for the national health system.
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http://dx.doi.org/10.3390/ijms20030609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387298PMC
January 2019

An Advanced, Silicon-Based Substrate for Sensitive Nucleic Acids Detection.

Sensors (Basel) 2018 Sep 17;18(9). Epub 2018 Sep 17.

STMicroelectronics Stradale Primosole, 50, 95121 Catania, Italy.

Surface substrate and chemical functionalization are crucial aspects for the fabrication of the sensitive biosensor based on microarray technology. In this paper, an advanced, silicon-based substrate (A-MA) allowing enhancement of optical signal for microarray application is described. The substrate consists in a multilayer of Si/Al/SiO₂ layers. The optical signal enhancement is reached by a combination of the mirror effect of Al film and the SiO₂ thickness around 830 nm, which is able to reach the maximum of interference for the emission wavelength of the Cy5 fluorescent label. Moreover, SiO₂ layer is suitable for the immobilization of single-strand DNA through standard silane chemistry, and probe densities of about 2000 F/um² are reached. The microarray is investigated in the detection of HBV (Hepatitis B Virus) pathogen with analytical samples, resulting in a dynamic linear range of 0.05⁻0.5 nM, a sensitivity of about 18000 a.u. nM, and a Limit of Detection in the range of 0.031⁻0.043 Nm as a function of the capture probe sequence.
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http://dx.doi.org/10.3390/s18093138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165574PMC
September 2018

Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation.

Cell Stem Cell 2018 03 22;22(3):355-368.e13. Epub 2018 Feb 22.

Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. Electronic address:

Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain.
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http://dx.doi.org/10.1016/j.stem.2018.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842147PMC
March 2018

Evaluation of RGD functionalization in hybrid hydrogels as 3D neural stem cell culture systems.

Biomater Sci 2018 Feb;6(3):501-510

Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy.

The use of neural stem cells (NSCs) in cell therapy has become a powerful tool used for the treatment of central nervous system diseases, including traumatic brain and spinal cord injuries. However, a significant drawback is related to the limited viability after transplantation in situ. The design of three-dimensional (3D) scaffolds that are capable of resembling the architecture and physico-chemical features of an extracellular environment could be a suitable approach to improve cell survival and preserve their cellular active phase over time. In this study, we investigated NSC adhesion and proliferation in hydrogel systems. In particular, we evaluated the effect of RGD binding domains on cell fate within the polymeric scaffold. The introduction of a tripeptide via hydrogel chemical functionalization improved the percentage of proliferating cells until 8 days after seeding when compared to the unmodified scaffold. The beneficial effects of this 3D culture system was further evident when compared to a NSC monolayer (2D) culture, resulting in an approximately 40% increase in cells in the active phases at 4 and 8 days, and maintained a difference of 25% until 21 days after seeding.
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http://dx.doi.org/10.1039/c7bm01056gDOI Listing
February 2018
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