Publications by authors named "Laura Calzà"

83 Publications

Nuclear receptors and differentiation of oligodendrocyte precursor cells.

Vitam Horm 2021 9;116:389-407. Epub 2021 Mar 9.

Montecatone Rehabilitation Institute, Imola, Bologna, Italy; IRET Foundation, Ozzano Emilia, Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Oligodendrocytes are the cells responsible for myelin formation during development and in adulthood, both for normal myelin turnover and myelin repair. These highly specialized cells derive from the oligodendrocyte precursor cells (OPCs), through a complex differentiation process involving genetic and epigenetic regulation mechanisms, which switch the phenotype from a migratory and replicative precursor to a mature post-mitotic cell. The process is regulated by a plethora of molecules, involving neurotransmitters, growth factors, hormones and other small molecules, and is mainly driven by nuclear receptors (NRs). NRs are transcription factors with heterogeneous ligand-dependent and independent actions which differ for the cell target, the responsive gene and the formation of NR homo- or heterodimers. This chapter highlights the role of NRs in regulating OPC differentiation, also in view of drug discovery strategies aimed at targeting pathological conditions which interfere with both developmental myelination and remyelination in adulthood.
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http://dx.doi.org/10.1016/bs.vh.2021.02.002DOI Listing
March 2021

Time-Course Changes of Extracellular Matrix Encoding Genes Expression Level in the Spinal Cord Following Contusion Injury-A Data-Driven Approach.

Int J Mol Sci 2021 Feb 9;22(4). Epub 2021 Feb 9.

Interdepartmental Center for Industrial Research in Life Sciences and Technologies, University of Bologna, Ozzano dell'Emilia, 40064 Bologna, Italy.

The involvement of the extracellular matrix (ECM) in lesion evolution and functional outcome is well recognized in spinal cord injury. Most attention has been dedicated to the "core" area of the lesion and scar formation, while only scattered reports consider ECM modification based on the temporal evolution and the segments adjacent to the lesion. In this study, we investigated the expression profile of 100 genes encoding for ECM proteins at 1, 8 and 45 days post-injury, in the spinal cord segments rostral and caudal to the lesion and in the scar segment, in a rat model. During both the active lesion phases and the lesion stabilization, we observed an asymmetric gene expression induced by the injury, with a higher regulation in the rostral segment of genes involved in ECM remodeling, adhesion and cell migration. Using bioinformatic approaches, the metalloproteases inhibitor and the hyaluronan receptor emerged as the hub genes at all post-lesion times. Results from the bioinformatic gene expression analysis were then confirmed at protein level by tissue analysis and by cell culture using primary astrocytes. These results indicated that ECM regulation also takes place outside of the lesion area in spinal cord injury.
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http://dx.doi.org/10.3390/ijms22041744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916102PMC
February 2021

Early CSF Biomarkers and Late Functional Outcomes in Spinal Cord Injury. A Pilot Study.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Spinal Unit, Montecatone Rehabilitation Institute, 40026 Imola, Italy.

Although, biomarkers are regarded as an important tool for monitoring injury severity and treatment efficacy, and for predicting clinical evolution in many neurological diseases and disorders including spinal cord injury, there is still a lack of reliable biomarkers for the assessment of clinical course and patient outcome. In this study, a biological dataset of 60 cytokines/chemokines, growth factorsm and intracellular and extracellular matrix proteins, analyzed in CSF within 24 h of injury, was used for correlation analysis with the clinical dataset of the same patients. A heat map was generated of positive and negative correlations between biomarkers and clinical rating scale scores at discharge, and between biomarkers and changes in clinical scores during the observation period. Using very stringent statistical criteria, we found 10 molecules which correlated with clinical scores at discharge, and five molecules, which correlated with changes in clinical scores. The proposed methodology may be useful for generating hypotheses regarding "predictive" and "treatment effectiveness" biomarkers, thereby suggesting potential candidates for disease-modifying therapies using a "bed-to-bench" approach.
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http://dx.doi.org/10.3390/ijms21239037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729583PMC
November 2020

Thyroid Hormone Signaling in Embryonic Stem Cells: Crosstalk with the Retinoic Acid Pathway.

Int J Mol Sci 2020 Nov 25;21(23). Epub 2020 Nov 25.

Department of Veterinary Medical Science, University of Bologna, Via Tolara di Sopra, 50, 40064 Ozzano Emilia, BO, Italy.

While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated from rat (RESC) to study the effects of THs and retinoic acid (RA) on early embryonic development during the pre-implantation stage. The results showed that THs play an important role in the differentiation/maturation processes of cells obtained from embryoid bodies (EB), with thyroid hormone nuclear receptors (TR) (TRα and TRβ), metabolic enzymes (deiodinases 1, 2, 3) and membrane transporters (Monocarboxylate transporters -MCT- 8 and 10) being expressed throughout in vitro differentiation until the Embryoid body (EB) stage. Moreover, thyroid hormone receptor antagonist TR (1-850) impaired RA-induced neuroectodermal lineage specification. This effect was significantly higher when cells were treated with retinoic acid (RA) to induce neuroectodermal lineage, studied through the gene and protein expression of nestin, an undifferentiated progenitor marker from the neuroectoderm lineage, as established by nestin mRNA and protein regulation. These results demonstrate the contribution of the two nuclear receptors, TR and RA, to the process of neuroectoderm maturation of the in vitro model embryonic stem cells obtained from rat.
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http://dx.doi.org/10.3390/ijms21238945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728128PMC
November 2020

Oligodendrocytes in a dish for the drug discovery pipeline: the risk of oversimplification.

Neural Regen Res 2021 Feb;16(2):291-293

Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna; Department of Pharmacy and Biotechnology, University of Bologna; Montecatone Rehabilitation Institute, Bologna, Italy.

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http://dx.doi.org/10.4103/1673-5374.290888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896220PMC
February 2021

Boosting the Intra-Articular Efficacy of Low Dose Corticosteroid through a Biopolymeric Matrix: An In Vivo Model of Osteoarthritis.

Cells 2020 06 28;9(7). Epub 2020 Jun 28.

IRCCS Istituto Ortopedico Rizzoli, Laboratory of Preclinical and Surgical Studies, via di Barbiano 1/10, 40136 Bologna, Italy.

The purpose of this study was to verify the efficacy of a single intra-articular (i.a.) injection of a hyaluronic acid-chitlac (HY-CTL) enriched with two low dosages of triamcinolone acetonide (TA, 2.0 mg/mL and 4.5 mg/mL), in comparison with HY-CTL alone, with a clinical control (TA 40 mg/mL) and with saline solution (NaCl) in an in vivo osteoarthritis (OA) model. Seven days after chemical induction of OA, 80 Sprague Dawley male rats were grouped into five arms (n = 16) and received a single i.a. injection of: 40 mg/mL TA, HY-CTL alone, HY-CTL with 2.0 mg/mL TA (RV2), HY-CTL with 4.5 mg/mL TA (RV4.5) and 0.9% NaCl. Pain sensitivity and Catwalk were performed at baseline and at 7, 14 and 21 days after the i.a. treatments. The histopathology of the joint, meniscus and synovial reaction, type II collagen expression and aggrecan expression were assessed 21 days after treatments. RV4.5 improved the local pain sensitivity in comparison with TA and NaCl. RV4.5 and TA exerted similar beneficial effects in all gait parameters. Histopathological analyses, measured by Osteoarthritis Research Society International (OARSI) and Kumar scores and by immunohistochemistry, evidenced that RV4.5 and TA reduced OA features in the same manner and showed a stronger type II collagen and aggrecan expression; both treatments reduced synovitis, as measured by Krenn score and, at the meniscus level, RV4.5 improved degenerative signs as evaluated by Pauli score. TA or RV4.5 treatments limited the local articular cartilage deterioration in knee OA with an improvement of the physical structure of articular cartilage, gait parameters, the sensitivity to local pain and a reduction of the synovial inflammation.
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http://dx.doi.org/10.3390/cells9071571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408199PMC
June 2020

Improved Functional Recovery in Rat Spinal Cord Injury Induced by a Drug Combination Administered with an Implantable Polymeric Delivery System.

J Neurotrauma 2020 08 14;37(15):1708-1719. Epub 2020 May 14.

Health Sciences and Technologies (HST) CIRI-SDV, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun poly (l-lactic acid) [PLLA]) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. efficacy was tested by implanting the drug-loaded PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e., controls), the recovery stabilized at 21 days post-lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA + ibuprofen (Ibu) + T3 (PLLA-Ibu-T3) rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49 DPL. Glutamate release at 24 h and 8 DPL was reduced in PLLA-Ibu-T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60 DPL. The myelin- and 200-neurofilament-positive area fraction was higher in PLLA-Ibu-T3-implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with Ibu and T3 significantly improves the endogenous regeneration, leading to an improvement of functional locomotion outcome in the SCI.
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http://dx.doi.org/10.1089/neu.2019.6949DOI Listing
August 2020

White Matter and Neuroprotection in Alzheimer's Dementia.

Molecules 2020 Jan 23;25(3). Epub 2020 Jan 23.

Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia (BO), Italy.

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer's dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.
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http://dx.doi.org/10.3390/molecules25030503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038211PMC
January 2020

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells-derived oligodendrocyte precursor cells.

Glia 2020 05 22;68(5):898-917. Epub 2019 Nov 22.

Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Bologna, Italy.

Impaired myelination is a key feature in neonatal hypoxia/ischemia (HI), the most common perinatal/neonatal cause of death and permanent disabilities, which is triggered by the establishment of an inflammatory and hypoxic environment during the most critical period of myelin development. This process is dependent on oligodendrocyte precursor cells (OPCs) and their capability to differentiate into mature oligodendrocytes. In this study, we investigated the vulnerability of fetal and adult OPCs derived from neural stem cells (NSCs) to inflammatory and HI insults. The resulting OPCs/astrocytes cultures were exposed to cytokines to mimic inflammation, or to oxygen-glucose deprivation (OGD) to mimic an HI condition. The differentiation of both fetal and adult OPCs is completely abolished following exposure to inflammatory cytokines, while only fetal-derived OPCs degenerate when exposed to OGD. We then investigated possible mechanisms involved in OGD-mediated toxicity: (a) T3-mediated maturation induction; (b) glutamate excitotoxicity; (c) glucose metabolism. We found that while no substantial differences were observed in T3 intracellular content regulation and glutamate-mediated toxicity, glucose deprivation lead to selective OPC cell death and impaired differentiation in fetal cultures only. These results indicate that the biological response of OPCs to inflammation and demyelination is different in fetal and adult cells, and that the glucose metabolism perturbation in fetal central nervous system (CNS) may significantly contribute to neonatal pathologies. An understanding of the underlying molecular mechanism will contribute greatly to differentiating myelination enhancing and neuroprotective therapies for neonatal and adult CNS white matter lesions.
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http://dx.doi.org/10.1002/glia.23750DOI Listing
May 2020

A dynamic culture platform enhances the efficiency of the 3D HUVEC-based tube formation assay.

Biotechnol Bioeng 2020 03 28;117(3):789-797. Epub 2019 Nov 28.

Health Sciences and Technologies-Interdepartmental Center for Industrial Research, University of Bologna, Bologna, Italy.

Cell-based in vitro biological models traditionally use monolayer cell cultures grown over plastic surfaces bathing in static media. Higher fidelity to a natural biological tissue is expected to result from growing the cells in a three-dimensional (3D) matrix. However, due to the decreased rate of diffusion inherent to increased distances within a tridimensional space, proper fluidic conditions are needed in this setting to better approximate a physiological environment. To this aim, we here propose a prototypal dynamic cell culture platform for the automatic medium replacement, via periodic perfusion flow, in a human umbilical vein endothelial cell (HUVECs) culture seeded in a Geltrex™ matrix. A state-of-the-art angiogenesis assay performed in these dynamic conditions showed sizable effects with respect to conventional static control cultures, with significantly enhanced pro-(dual antiplatelet therapy [DAPT]) and anti-(EDTA) angiogenic compound activity. In particular, dynamic culture conditions (a) enhance the 3D-organization of HUVECs into microtubule structure; (b) accelerate and improve endothelial tube formation by HUVECs in the presence of DAPT; (c) are able to completely revert the blocking effects of EDTA. These evidence emphasize the need of setting proper fluidic conditions for a better approximation of a physiological environment as an appropriate evolution of current cell culture paradigms.
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http://dx.doi.org/10.1002/bit.27227DOI Listing
March 2020

Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat.

J Neuroinflammation 2019 Oct 28;16(1):194. Epub 2019 Oct 28.

Health Science and Technologies Interdepartmental Center for Industrial Research, University of Bologna, Via Tolara di Sopra 41/E, I-40064, Ozzano Emilia, BO, Italy.

Background: Hypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies.

Methods: In order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array.

Results: We found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-α in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-α, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury.

Conclusions: Our work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.
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http://dx.doi.org/10.1186/s12974-019-1595-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819609PMC
October 2019

Possible Strategies to Optimize a Biomarker Discovery Approach to Correlate with Neurological Outcome in Patients with Spinal Cord Injury: A Pilot Study.

J Neurotrauma 2020 02 1;37(3):431-440. Epub 2019 Aug 1.

Department of Health Sciences and Technologies - Interdepartmental Center for Industrial Research-CIRI-SDV, University of Bologna, Bologna, Italy.

The lack of reliable diagnostic and prognostic markers for spinal cord injured (SCI) patients is a severe obstacle in development and testing of new therapies, and it also impairs appropriate rehabilitation care. The sparse available data on the biochemical composition of cerebrospinal fluid (CSF) during the acute and/or chronic phase of the lesion provide, up until now, inconsistent results. In this pilot study, we then explored the possibility of combining a multi-parametric and bioinformatic analysis of CSF for its biological properties tested on different cells types, suitable for investigating inflammation and re-myelination. The patient enrollment was based on stringent inclusion criteria; that is, cervical and thoracic SCI trauma, CSF collection within 24 h of trauma, type of surgical approach for spine stabilization, and absence of steroid therapy before CSF collection. Eleven SCI patients and four healthy controls were included, and in three patients, CSF was also collected at 3 months after lesion. We identified 19 proteins among the 60 investigated cytokines, chemokines, growth factors, and structural biomarkers, which are transiently regulated 24 h after SCI. A bioinformatic analysis indicated that interleukin (IL)-6 and IL-10 are in the core of the interconnected net of activated proteins. Cell-based experiments indicate that CSF from SCI patients stimulates astroglia derivation from neural precursor cells, and an inverse correlation between IL-8 CSF level and oligodendrocyte precursor cells generated from neural stem cells was also observed. Results from this pilot study suggest that using a combined bioanalytic and biological approach to analyze SCI CSF at different times after injury could be a useful approach for identifying reliable diagnostic and prognostic markers in SCI.
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http://dx.doi.org/10.1089/neu.2018.6362DOI Listing
February 2020

Constitutive and LPS-stimulated secretome of porcine Vascular Wall-Mesenchymal Stem Cells exerts effects on in vitro endothelial angiogenesis.

BMC Vet Res 2019 Apr 27;15(1):123. Epub 2019 Apr 27.

Department of Veterinary Medical Sciences DIMEVET, University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Bologna, Italy.

Background: MSCs secretome is under investigation as an alternative to whole-cell-based therapies, since it is enriched of bioactive molecules: growth factors, cytokines and chemokines. Taking into account the translational value of the pig model, the leading aim of the present paper was to characterize the secretome of porcine Vascular Wall-Mesenchymal Stem Cells (pVW-MSCs) and its change in presence of LPS stimulation. Moreover, considering the importance of angiogenesis in regenerative mechanisms, we analysed the effect of pVW-MSCs secretome on in vitro angiogenesis.

Results: Our results demonstrated that conditioned medium from unstimulated pVW-MSCs contained high levels of IL-8, GM-CSF, IFN-γ and other immunomodulatory proteins: IL-6 IL-18 IL-4 IL-2 IL-10. LPS modulates pVW-MSCs gene expression and secretome composition, in particular a significant increase of IL-6 and IL-8 was observed; conversely, the amount of GM-CSF, IFN-γ, IL-2, IL-4, IL-10 and IL-18 showed a significant transient decrease with the LPS stimulation. Conditioned medium from unstimulated pVW-MSCs induced in vitro endothelial angiogenesis, which is more evident when the conditioned medium was from LPS stimulated pVW-MSCs.

Conclusions: The lines of evidence here presented shed a light on possible future application of secretome derived by pVW-MSCs on research studies in translational regenerative medicine.
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http://dx.doi.org/10.1186/s12917-019-1873-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487069PMC
April 2019

The role of nuclear receptors in the differentiation of oligodendrocyte precursor cells derived from fetal and adult neural stem cells.

Stem Cell Res 2019 05 17;37:101443. Epub 2019 Apr 17.

Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Italy; IRET Foundation, Ozzano Emilia, Italy.

Oligodendrocyte precursor cells (OPCs) differentiation from multipotent neural stem cells (NSCs) into mature oligodendrocytes is driven by thyroid hormone and mediated by thyroid hormone receptors (TRs). We show that several nuclear receptors display strong changes in expression levels between fetal and adult NSCs, with an overexpression of TRβ and a lower expression of RXRγ in adult. Such changes may determine the reduced capacity of adult OPCs to differentiate as supported by reduced yield of maturation and compromised mRNA expression of key genes. RXRγ may be the determinant of these differences, on the evidence of reduced number of mature oligodendrocytes and increased number of proliferating OPCs in RXRγ-/- cultures. Such data also points to RXRγ as an important regulator of the cell cycle exit, as proved by the dysregulation of T3-induced cell cycle exit-related genes. Our data highlight the biological differences between fetal and adult OPCs and demonstrate the essential role of RXRγ in the T3-mediated OPCs maturation process.
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http://dx.doi.org/10.1016/j.scr.2019.101443DOI Listing
May 2019

Ultra-Low-Level Laser Therapy and Acupuncture Libralux: What Is so Special?

Medicines (Basel) 2019 Mar 14;6(1). Epub 2019 Mar 14.

Eng. Freelance MD Consultant, Sal. Maggiolo di Nervi, 16167 Genova, Italy.

Background: Contrary to the most credited theories on laser therapy that see power/energy as the major factors to its effectiveness, a technique using an extremely low power/energy laser stimulation to treat musculoskeletal pain and dysfunction is proposed. The stimulus consists of a 20 s train of modulated pulses with an average power below 0.02 mW and is applied on sequences of acupuncture points selected according to the impaired segment of the patient's body. : Modifications on the extracellular soft tissue matrix and on the "fascia" were sonographically demonstrated. Laboratory and clinical tests confirmed the effectiveness. : Responses similar to those experienced in acupuncture were observed. The device-a CE Class IIa certified medical device named Libralux-affords a clinically proven effectiveness exceeding 80% in the treatment of musculoskeletal conditions and associated motor dysfunctions. An average of just three application sessions was generally sufficient to overcome the dysfunction. : The development of the method is supported by over 20 years of R&D activities, with a range of experiments discussed in several papers published in indexed peer-reviewed journals. A few considerations regarding the possible physiological action mechanisms involved are proposed in this paper.
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http://dx.doi.org/10.3390/medicines6010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473762PMC
March 2019

Age-Related Changes of the Neurovascular Unit in the Cerebral Cortex of Alzheimer Disease Mouse Models: A Neuroanatomical and Molecular Study.

J Neuropathol Exp Neurol 2019 02;78(2):101-112

Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.

We describe age-related histological structure and molecular changes of the neurovascular unit (NVU) in the cerebral cortex of Tg2576 and age-matched wild-type (WT) mice. Major results can be summarized as follows: (i) β-amyloid (6E10)-immunoreactivity progressively increases in neurons and astrocytes of Tg2576 mice, reaching the highest concentration at 5 months and then decreasing as soon as extracellular plaque deposition begins; (ii) the synaptic puncta density of glutamatergic and GABAergic neurons in Tg2576 mice is unbalanced versus WT at all investigated ages, with a decrease in synaptophysin and VGLUT1; density of VGAT contacts is higher in 27-month-old Tg2576 versus WT mice; (iii) capillary density is higher in 5-month-old Tg2576 versus WT mice, then decreases to a lower density at 27 months, when the capillary-astrocyte interface is lower; and (iv) mRNA expression of genes involved in microvessel dynamics indicates age- and genotype-dependent changes in the expression levels of hypoxia-related genes, i.e. the highest level is in 5-month-old animals and there is impaired regulation in Tg2576. We conclude that at 5 months, when learning and memory impairment is already present in the absence of extracellular amyloid plaque deposition, Tg2576 mice display alterations in the structure and molecular regulation of the NVU.
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http://dx.doi.org/10.1093/jnen/nly125DOI Listing
February 2019

Speech Analysis by Natural Language Processing Techniques: A Possible Tool for Very Early Detection of Cognitive Decline?

Front Aging Neurosci 2018 13;10:369. Epub 2018 Nov 13.

Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy.

The discovery of early, non-invasive biomarkers for the identification of "preclinical" or "pre-symptomatic" Alzheimer's disease and other dementias is a key issue in the field, especially for research purposes, the design of preventive clinical trials, and drafting population-based health care policies. Complex behaviors are natural candidates for this. In particular, recent studies have suggested that speech alterations might be one of the earliest signs of cognitive decline, frequently noticeable years before other cognitive deficits become apparent. Traditional neuropsychological language tests provide ambiguous results in this context. In contrast, the analysis of spoken language productions by Natural Language Processing (NLP) techniques can pinpoint language modifications in potential patients. This interdisciplinary study aimed at using NLP to identify early linguistic signs of cognitive decline in a population of elderly individuals. We enrolled 96 participants (age range 50-75): 48 healthy controls (CG) and 48 cognitively impaired participants: 16 participants with single domain amnestic Mild Cognitive Impairment (aMCI), 16 with multiple domain MCI (mdMCI) and 16 with early Dementia (eD). Each subject underwent a brief neuropsychological screening composed by MMSE, MoCA, GPCog, CDT, and verbal fluency (phonemic and semantic). The spontaneous speech during three tasks (describing a complex picture, a typical working day and recalling a last remembered dream) was then recorded, transcribed and annotated at various linguistic levels. A multidimensional parameter computation was performed by a quantitative analysis of spoken texts, computing rhythmic, acoustic, lexical, morpho-syntactic, and syntactic features. Neuropsychological tests showed significant differences between controls and mdMCI, and between controls and eD participants; GPCog, MoCA, PF, and SF also discriminated between controls and aMCI. In the linguistic experiments, a number of features regarding lexical, acoustic and syntactic aspects were significant in differentiating between mdMCI, eD, and CG (non-parametric statistical analysis). Some features, mainly in the acoustic domain also discriminated between CG and aMCI. Linguistic features of spontaneous speech transcribed and analyzed by NLP techniques show significant differences between controls and pathological states (not only eD but also MCI) and seems to be a promising approach for the identification of preclinical stages of dementia. Long duration follow-up studies are needed to confirm this assumption.
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http://dx.doi.org/10.3389/fnagi.2018.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243042PMC
November 2018

Thyroid Hormone and the White Matter of the Central Nervous System: From Development to Repair.

Vitam Horm 2018 12;106:253-281. Epub 2017 Jun 12.

CIRI-SDV, University of Bologna, Bologna, Italy; IRET Foundation, Ozzano Emilia, Italy; DIMEVET, University of Bologna, Bologna, Italy.

The role of thyroid hormone (TH) on brain development, and particularly in myelination, is well known since many decades, as testified by the severe structural and functional consequences of congenital hypothyroidism. This role during development, the consideration that the early TH supplementation restores myelination capability, and the fact the cell responsible for developmental myelination and remyelination is the same, i.e., the oligodendrocyte precursor cell (OPC), claimed the attempt to improve myelin repair in the adulthood via TH supplementation. In this chapter, the impact of TH on development, homeostasis, and repair of the myelin in the CNS will be reviewed, focusing on the regulation of the TH tissue signaling during physiological and pathological conditions affecting myelination and/or myelin repair during early postnatal age and during the adulthood. The impact of the tissue inflammation on molecular mediators of the TH cellular action and metabolism will be discussed, with regard to the consequences on the biology of the OPC.
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http://dx.doi.org/10.1016/bs.vh.2017.04.003DOI Listing
October 2018

In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates.

Drug Deliv 2018 Nov;25(1):376-387

b Department of Food and Drug , University of Parma , Parma , Italy.

Nasal administration has been proposed as a potential approach for the delivery of drugs to the central nervous system. Ribavirin (RBV), an antiviral drug potentially useful to treat viral infections both in humans and animals, has been previously demonstrated to attain several brain compartments after nasal administration. Here, a powder formulation in the form of agglomerates comprising micronized RBV and spray-dried microparticles containing excipients with potential absorption enhancing properties, i.e. mannitol, chitosan, and α-cyclodextrin, was developed for nasal insufflation. The agglomerates were characterized for particle size, agglomeration yield, and ex vivo RBV permeation across rabbit nasal mucosa as well as delivery from an animal dry powder insufflator device. Interestingly, permeation enhancers such as chitosan and mannitol showed a lower amount of RBV permeating across the excised nasal tissue, whereas α-cyclodextrin proved to outperform the other formulations and to match the highly soluble micronized RBV powder taken as a reference. In vivo nasal administration to rats of the agglomerates containing α-cyclodextrin showed an overall higher accumulation of RBV in all the brain compartments analyzed as compared with the micronized RBV administered as such without excipient microparticles. Hence, powder agglomerates are a valuable approach to obtain a nasal formulation potentially attaining nose-to-brain delivery of drugs with minimal processing of the APIs and improvement of the technological and biopharmaceutical properties of micronized API and excipients, as they combine optimal flow properties for handling and dosing, suitable particle size for nasal deposition, high surface area for drug dissolution, and penetration enhancing properties from excipients such as cyclodextrins.
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http://dx.doi.org/10.1080/10717544.2018.1428242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058489PMC
November 2018

Growth and Neurotrophic Factors in Embryonic Stem Cells.

Methods Mol Biol 2018 ;1727:275-294

Department of Veterinary Medical Science, University of Bologna, Ozzano Emilia, Bologna, Italy.

In this chapter we illustrate protocols to investigate growth and neurotrophic factors in human and rodent (rat and mouse)-derived embryonic stem cells. The conventional two-dimensional cell monolayer system to grow embryonic stem cells is presented, focusing on the coating strategies also using extracellular matrix components. Then, different approaches for three-dimensional stem cell culture are presented, using hydrogels and scaffolds. Quantitative polymerase chain reaction, immunocytochemistry, immunoenzymatic ELISA assay, and multiparametric assays to quantify growth and neurotrophic factor production are presented.
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http://dx.doi.org/10.1007/978-1-4939-7571-6_21DOI Listing
July 2018

PARP activity and inhibition in fetal and adult oligodendrocyte precursor cells: Effect on cell survival and differentiation.

Stem Cell Res 2017 07 30;22:54-60. Epub 2017 May 30.

Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Italy; IRET Foundation, Ozzano Emilia, Italy. Electronic address:

Poly (ADP-ribose) polymerase (PARP) family members are ubiquitously expressed and play a key role in cellular processes, including DNA repair and cell death/survival balance. Accordingly, PARP inhibition is an emerging pharmacological strategy for cancer and neurodegenerative diseases. Consistent evidences support the critical involvement of PARP family members in cell differentiation and phenotype maturation. In this study we used an oligodendrocyte precursor cells (OPCs) enriched system derived from fetal and adult brain to investigate the role of PARP in OPCs proliferation, survival, and differentiation. The PARP inhibitors PJ34, TIQ-A and Olaparib were used as pharmacological tools. The main results of the study are: (i) PARP mRNA expression and PARP activity are much higher in fetal than in adult-derived OPCs; (ii) the culture treatment with PARP inhibitors is cytotoxic for OPCs derived from fetal, but not from adult, brain; (iii) PARP inhibition reduces cell number, according to the inhibitory potency of the compounds; (iv) PARP inhibition effect on fetal OPCs is a slow process; (v) PARP inhibition impairs OPCs maturation into myelinating OL in fetal, but not in adult cultures, according to the inhibitory potency of the compounds. These results have implications for PARP-inhibition therapies for diseases and lesions of the central nervous system, in particular for neonatal hypoxic/ischemic encephalopathy.
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http://dx.doi.org/10.1016/j.scr.2017.05.011DOI Listing
July 2017

Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome.

Neurobiol Dis 2017 Jul 28;103:11-23. Epub 2017 Mar 28.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address:

Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS.
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http://dx.doi.org/10.1016/j.nbd.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439029PMC
July 2017

Vulnerability of primary neurons derived from Tg2576 Alzheimer mice to oxygen and glucose deprivation: role of intraneuronal amyloid-β accumulation and astrocytes.

Dis Model Mech 2017 05 24;10(5):671-678. Epub 2017 Feb 24.

Interdepartmental Centre for Industrial Research in Health Science and Technologies (ICIR - HST), University of Bologna, 40064 Ozzano Emilia, Bologna, Italy

Microvascular dysfunction is considered an integral part of Alzheimer disease (AD) pathogenesis, but the possible relationship between amyloid pathology, microvascular dysfunction and cell death is still unclear. In order to investigate the influence of intraneuronal amyloid-β (Aβ) accumulation on vulnerability to hypoxia, we isolated primary cortical neurons from Tg2576 (carrying the amyloid precursor protein APPSwe mutation) and wild-type fetal mice. We first demonstrated that neurons isolated from Tg2576 newborn mice show an increase in VEGFa mRNA expression and a decrease in the expression of the two VEGF receptors, Flt1 and Kdr, compared with wild-type cells. Moreover, APPSwe primary neurons displayed higher spontaneous and glutamate-induced cell death. We then deprived the cultures of oxygen and glucose (OGD) as an model of hypoxia. After OGD, APPSwe neurons display higher levels of cell death in terms of percentage of pyknotic/fragmented nuclei and mitochondrial depolarization, accompanied by an increase in the intraneuronal Aβ content. To explore the influence of intraneuronal Aβ peptide accumulation, we used the γ-secretase inhibitor LY450139, which showed that the reduction of the intracellular amyloid fully protects APPSwe neurons from OGD-induced degeneration. Conditioned medium from OGD-exposed APPSwe or wild-type astrocytes protected APPswe neurons but not wild-type neurons, during OGD. In conclusion, the presence of the mutated human APP gene, leading to the intracellular accumulation of APP and Aβ fragments, worsens OGD toxicity. Protection of APPSwe neurons can be obtained either using a γ-secretase inhibitor or astrocyte conditioned medium.
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http://dx.doi.org/10.1242/dmm.028001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451168PMC
May 2017

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis.

J Neuroinflammation 2016 11 15;13(1):291. Epub 2016 Nov 15.

Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, Bologna, Ozzano Emilia I, 40064, Italy.

Background: Experimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset.

Methods: In this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma.

Results: The macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10.

Conclusions: This early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.
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http://dx.doi.org/10.1186/s12974-016-0757-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111339PMC
November 2016

REAC technology modifies pathological neuroinflammation and motor behaviour in an Alzheimer's disease mouse model.

Sci Rep 2016 10 24;6:35719. Epub 2016 Oct 24.

IRET Foundation, Ozzano Emilia, Italy.

The search for new therapeutic approaches to Alzheimer disease (AD) is a major goal in medicine and society, also due to the impressive economic and social costs of this disease. In this scenario, biotechnologies play an important role. Here, it is demonstrated that the Radio Electric Asymmetric Conveyer (REAC), an innovative technology platform for neuro- and bio-modulation, used according to the neuro-regenerative protocol (RGN-N), significantly increases astroglial reaction around the amyloid plaques in an AD mouse model, as evaluated by GFAP-immunoreactivity, and reduces microglia-associated neuroinflammation markers, as evaluated by Iba1-immunoreactivity and mRNA expression level of inflammatory cytokines TREM. IL1beta, iNOS and MRC1 were not affected neither by the genotype or by REAC RGN-N treatment. Also observed was an increase in locomotion in treated animals. The study was performed in 24-month-old male Tg2576 mice and age-matching wild-type animals, tested for Y-maze, contextual fear conditioning and locomotion immediately after the end of a specific REAC treatment administered for 15 hours/day for 15 days. These results demonstrated that REAC RGN-N treatment modifies pathological neuroinflammation, and mitigates part of the complex motor behaviour alterations observed in very old Tg2576 mice.
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http://dx.doi.org/10.1038/srep35719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075930PMC
October 2016

Affinity of (nat/68)Ga-Labelled Curcumin and Curcuminoid Complexes for β-Amyloid Plaques: Towards the Development of New Metal-Curcumin Based Radiotracers.

Int J Mol Sci 2016 Sep 6;17(9). Epub 2016 Sep 6.

Nuclear Medicine Unit, Oncology and Advanced Technologies Department, Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.

Curcumin derivatives labelled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Nevertheless, no study by exploiting the labelling with gallium-68 has been performed so far, in spite of its suitable properties (positron emitter, generator produced radionuclide). Herein, an evaluation of the affinity for synthetic β-amyloid fibrils and for amyloid plaques of three (nat/68)Ga-labelled curcumin analogues, namely curcumin curcumin (CUR), bis-dehydroxy-curcumin (bDHC) and diacetyl-curcumin (DAC), was performed. Affinity and specificity were tested in vitro on amyloid synthetic fibrils by using gallium-68 labelled compounds. Post-mortem brain cryosections from Tg2576 mice were used for the ex vivo visualization of amyloid plaques. The affinity of (68)Ga(CUR)₂⁺, (68)Ga(DAC)₂⁺, and (68)Ga(bDHC)₂⁺ for synthetic β-amyloid fibrils was moderate and their uptake could be observed in vitro. On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the blood-brain barrier. Like curcumin, all (nat/68)Ga-curcuminoid complexes maintain a high affinity for β-amyloid plaques. However, structural modifications are still needed to improve their applicability as radiotracers in vivo.
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http://dx.doi.org/10.3390/ijms17091480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037758PMC
September 2016

In Vitro Testing of Biomaterials for Neural Repair: Focus on Cellular Systems and High-Content Analysis.

Biores Open Access 2016 1;5(1):201-11. Epub 2016 Aug 1.

Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Bologna, Italy.; Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.

Biomimetic materials are designed to stimulate specific cellular responses at the molecular level. To improve the soundness of in vitro testing of the biological impact of new materials, appropriate cell systems and technologies must be standardized also taking regulatory issues into consideration. In this study, the biological and molecular effects of different scaffolds on three neural systems, that is, the neural cell line SH-SY5Y, primary cortical neurons, and neural stem cells, were compared. The effect of poly(L-lactic acid) scaffolds having different surface geometry (conventional two-dimensional seeding flat surface, random or aligned fibers as semi3D structure) and chemical functionalization (laminin or ECM extract) were studied. The endpoints were defined for efficacy (i.e., neural differentiation and neurite elongation) and for safety (i.e., cell death/survival) using high-content analysis. It is demonstrated that (i) the definition of the biological properties of biomaterials is profoundly influenced by the test system used; (ii) the definition of the in vitro safety profile of biomaterials for neural repair is also influenced by the test system; (iii) cell-based high-content screening may well be successfully used to characterize both the efficacy and safety of novel biomaterials, thus speeding up and improving the soundness of this critical step in material science having medical applications.
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http://dx.doi.org/10.1089/biores.2016.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991583PMC
September 2016

Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure.

Glia 2016 09 12;64(9):1573-89. Epub 2016 Jul 12.

Health Science and Technology Interdepartmental Center for Industrial Research, University of Bologna, Bologna, Italy.

Differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is severely impaired by inflammatory cytokines and this could lead to remyelination failure in inflammatory/demyelinating diseases. Due to the role of thyroid hormone in the maturation of OPCs and developmental myelination, in this study we investigated (i) the possible occurrence of dysregulation of thyroid hormone signaling in the CNS tissue during experimental neuroinflammation; (ii) the possible impact of inflammatory cytokines on thyroid hormone signaling and OPCs differentiation in vitro. The disease model is the experimental allergic encephalomyelitis in female Dark-Agouti rats, whereas in vitro experiments were carried out in OPCs derived from neural stem cells. The main results are the following: (i) a strong upregulation of cytokine mRNA expression level was found in the spinal cord during experimental allergic encephalomyelitis; (ii) thyroid hormone signaling in the spinal cord (thyroid hormone receptors; deiodinase; thyroid hormone membrane transporter) is substantially downregulated, due to the upregulation of the thyroid hormone inactivating enzyme deiodinase 3 and the downregulation of thyroid hormone receptors, as investigated at mRNA expression level; (iii) when exposed to inflammatory cytokines, deiodinase 3 is upregulated in OPCs as well, and OPCs differentiation is blocked; (iv) deiodinase 3 inhibition by iopanoic acid recovers OPCs differentiation in the presence on inflammatory cytokines. These data suggest that cellular hypothyroidism occurs during experimental allergic encephalomyelitis, possibly impacting on thyroid hormone-dependent cellular processes, including maturation of OPCs into myelinating oligodendrocytes. GLIA 2016;64:1573-1589.
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http://dx.doi.org/10.1002/glia.23025DOI Listing
September 2016

Models for preclinical studies in aging-related disorders: One is not for all.

Transl Med UniSa 2015 Dec 31;13:4-12. Epub 2016 Jan 31.

Department of Medicine and Surgery, University of Salerno, Italy.

Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment-effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811343PMC
December 2015