Publications by authors named "Salvatore Salomone"

118 Publications

The Role of Regional Anesthesia During the SARS-CoV2 Pandemic: Appraisal of Clinical, Pharmacological and Organizational Aspects.

Front Pharmacol 2021 4;12:574091. Epub 2021 Jun 4.

Department of Anesthesia, Critical Care and Pain Medicine, Niguarda Ca' Granda Hospital, Milan, Italy.

The severe acute respiratory syndrome coronavirus SARS-CoV2 is spreading over millions of people worldwide, leading to thousands of deaths, even among the healthcare providers. Italy has registered the deaths of 337 physicians and more than 200 nurses as of March 14, 2021. Anesthesiologists are at higher risk as they are the care providers in both ICU and operating rooms.Although the vaccination of healthcare providers has been the prioirity, physicians are still continually exposed to the virus and potentially risk contagion and must thus protect themselves and their patients from the risks of infection while providing the best care to their surgical patients.Regional anesthesia allows for a reduction in airway manipulation, reducing environmental contamination as a result. Furthermore, regional anesthesia reduces the opioid requirements as well as the muscle paralysis due to muscle-relaxants and should be recommended whenever possible in COVID-19 patients. Our aim is to evaluate the advantages and criticisms of regional anesthesia in the management of surgical patients in the pandemic age.
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http://dx.doi.org/10.3389/fphar.2021.574091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213435PMC
June 2021

Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice.

Int J Mol Sci 2021 May 13;22(10). Epub 2021 May 13.

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

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder occurring in susceptible individuals following a traumatic event. Understanding the mechanisms subserving trauma susceptibility/resilience is essential to develop new effective treatments. Increasing evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), may play a prominent role in mediating trauma susceptibility/resilience. In this study, we evaluated the transcriptional expression of two key PTSD-related genes (FKBP5 and BDNF) and the relative targeting miRNAs (miR-15a-5p, miR-497a-5p, miR-511-5p, let-7d-5p) in brain areas of PTSD-related susceptible and resilient mice identified through our recently developed mouse model of PTSD (arousal-based individual screening (AIS) model). We observed lower transcript levels of miR-15a-5p, miR-497a-5p, and miR-511a-5p in the hippocampus and hypothalamus of susceptible mice compared to resilient mice, suggesting that the expression of these miRNAs could discriminate the two different phenotypes of stress-exposed mice. These miRNA variations could contribute, individually or synergically, to the inversely correlated transcript levels of FKBP5 and BDNF. Conversely, in the medial prefrontal cortex, downregulation of miR-15a-5p, miR-511-5p, and let-7d-5p was observed both in susceptible and resilient mice, and not accompanied by changes in their mRNA targets. Furthermore, miRNA expression in the different brain areas correlated to stress-induced behavioral scores (arousal score, avoidance-like score, social memory score and PTSD-like score), suggesting a linear connection between miRNA-based epigenetic modulation and stress-induced phenotypes. Pathway analysis of a miRNA network showed a statistically significant enrichment of molecular processes related to PTSD and stress. In conclusion, our results indicate that PTSD susceptibility/resilience might be shaped by brain-area-dependent modulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes.
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http://dx.doi.org/10.3390/ijms22105157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153003PMC
May 2021

Pharmacological and Genetic Evidence of Dopamine Receptor 3-Mediated Vasoconstriction in Isolated Mouse Aorta.

Biomolecules 2021 03 11;11(3). Epub 2021 Mar 11.

Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia 97, 95123 Catania, Italy.

Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R/ mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R/; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R/, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R/, whereas SB-277011-A significantly reduced it in WT but did not in D3R/. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R/. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R/ and/or in the presence of D3R antagonist is likely to be unrelated to DRs.
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http://dx.doi.org/10.3390/biom11030418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001456PMC
March 2021

A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice.

Neurobiol Stress 2021 May 24;14:100286. Epub 2020 Dec 24.

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

Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic-pituitary-adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.
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http://dx.doi.org/10.1016/j.ynstr.2020.100286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772817PMC
May 2021

Multidisciplinary Approach to the Diagnosis and In-Hospital Management of COVID-19 Infection: A Narrative Review.

Front Pharmacol 2020 9;11:572168. Epub 2020 Dec 9.

Struttura Complessa di Neurologia, Ospedale Santa Croce di Moncalieri, Asl TO5, Moncalieri (TO), Italy.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or COVID-19 disease) was declared a pandemic on 11th March 2020 by the World Health Organization. This unprecedented circumstance has challenged hospitals' response capacity, requiring significant structural and organizational changes to cope with the surge in healthcare demand and to minimize in-hospital risk of transmission. As our knowledge advances, we now understand that COVID-19 is a multi-systemic disease rather than a mere respiratory tract infection, therefore requiring holistic care and expertise from various medical specialties. In fact, the clinical spectrum of presentation ranges from respiratory complaints to gastrointestinal, cardiac or neurological symptoms. In addition, COVID-19 pandemic has created a global burden of mental illness that affects the general population as well as healthcare practitioners. The aim of this manuscript is to provide a comprehensive and multidisciplinary insight into the complexity of this disease, reviewing current scientific evidence on COVID-19 management and treatment across several medical specialties involved in the in-hospital care of these patients.
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http://dx.doi.org/10.3389/fphar.2020.572168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758731PMC
December 2020

An Italian Guidance Model for the Management of Suspected or Confirmed COVID-19 Patients in the Primary Care Setting.

Front Public Health 2020;8:572042. Epub 2020 Nov 24.

Anesthesiology and Pain Department, Fondazione Istituto G. Giglio, Cefalù, Italy.

An outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 started in China's Hubei province at the end of 2019 has rapidly become a pandemic. In Italy, a great number of patients was managed in primary care setting and the role of general practitioners and physicians working in the first-aid emergency medical service has become of utmost importance to coordinate the network between the territory and hospitals during the pandemic. Aim of this manuscript is to provide a guidance model for the management of suspected, probable, or confirmed cases of SARS-CoV-2 infection in the primary care setting, from diagnosis to treatment, applying also the recommendations of the Italian Society of General Medicine. Moreover, this multidisciplinary contribution would analyze and synthetize the preventive measures to limit the spread of SARS-CoV-2 infection in the general population as well as the perspective for vaccines.
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http://dx.doi.org/10.3389/fpubh.2020.572042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732472PMC
January 2021

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.

Pharmacol Res 2021 02 4;164:105357. Epub 2020 Dec 4.

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic. Electronic address:

Perinatal exposure to Δ-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
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http://dx.doi.org/10.1016/j.phrs.2020.105357DOI Listing
February 2021

Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family.

J Pers Med 2020 Dec 2;10(4). Epub 2020 Dec 2.

Institute for Research and Biomedical Innovation (IRIB), Italian National Research Council (CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy.

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement.

Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members.

Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with , may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in and , two ALS-linked genes involved in the regulation of RNA metabolism, similarly to , suggesting a selective role for this pathway in ALS pathogenesis.

Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.
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http://dx.doi.org/10.3390/jpm10040262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712010PMC
December 2020

From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis.

Front Neurosci 2020 30;14:577755. Epub 2020 Oct 30.

Institute for Research and Biomedical Innovation (IRIB), Italian National Research Council (CNR), Catania, Italy.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder, caused by the degeneration of upper and lower motor neurons for which there is no truly effective cure. The lack of successful treatments can be well explained by the complex and heterogeneous nature of ALS, with patients displaying widely distinct clinical features and progression patterns, and distinct molecular mechanisms underlying the phenotypic heterogeneity. Thus, stratifying ALS patients into consistent and clinically relevant subgroups can be of great value for the development of new precision diagnostics and targeted therapeutics for ALS patients. In the last years, the use and integration of high-throughput "omics" approaches have dramatically changed our thinking about ALS, improving our understanding of the complex molecular architecture of ALS, distinguishing distinct patient subtypes and providing a rational foundation for the discovery of biomarkers and new individualized treatments. In this review, we discuss the most significant contributions of omics technologies in unraveling the biological heterogeneity of ALS, highlighting how these approaches are revealing diagnostic, prognostic and therapeutic targets for future personalized interventions.
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http://dx.doi.org/10.3389/fnins.2020.577755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661549PMC
October 2020

Pericyte-like differentiation of human adipose-derived mesenchymal stem cells: An study.

World J Stem Cells 2020 Oct;12(10):1152-1170

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

Background: Adipose-derived mesenchymal stem cells (ASCs) are characterized by long-term self-renewal and a high proliferation rate. Under adequate conditions, they may differentiate into cells belonging to mesodermal, endodermal or ectodermal lineages. Pericytes support endothelial cells and play an important role in stabilizing the vessel wall at the microcirculation level. The loss of pericytes, as occurs in diabetic retinopathy, results in a breakdown of the blood-retina barrier (BRB) and infiltration of inflammatory cells. In this context, the use of pericyte-like differentiated ASCs may represent a valuable therapeutic strategy for restoring BRB damage.

Aim: To test strategies to obtain pericyte-like differentiation of human ASCs (hASCs).

Methods: Different culture conditions were tested: hASCs cultured in a basal medium supplemented with transforming growth factor β1; and hASCs cultured in a specific pericyte medium (PM-hASCs). In a further sample, pericyte growth supplement was omitted from the PM. In addition, cultures of human retinal pericytes (hRPCs) were used for comparison. Pericyte-like differentiation of hASCs was tested by immunocytochemical staining and western blotting to evaluate the expression of α-smooth muscle actin (α-SMA) and neural/glial antigen 2 (NG2). Interactions between human retinal endothelial cells (hRECs) and different groups of hASCs were investigated in co-culture experiments. In these cases, the expression of typical junctional proteins such as vascular endothelial-Cadherin, zonula occludens-1 and Occludin were assessed in hRECs. In an model of the BRB, values of trans-endothelial electrical resistance were measured when hRECs were co-cultured with various groups of pretreated hASCs. The values observed were compared with co-cultures of hRECs and hRPCs as well as with cultures of hRECs alone. Three-dimensional co-cultures of hRECs and hRPCs or pericyte-like hASCs in Matrigel were designed to assess their reciprocal localization.

Results: After 3-6 d of culture, α-SMA and NG2 immunocytochemistry showed that the closest pericyte-like phenotype was observed when hASCs were cultured in Pericyte Medium (PM-hASCs). In particular, α-SMA immunoreactivity, already visible at the basal level in pericytes and ASCs, was strongly increased only when transforming growth factor was added to the culture medium. NG2 expression, almost undetectable in most conditions, was substantially increased only in PM-hASCs. Immunocytochemical results were confirmed by western blot analysis. The presence of pericyte growth supplement seems to increase NG2 expression rather than α-SMA, in agreement with its role in maintaining pericytes in the proliferative state. In co-culture experiments, immunoreactivity of vascular endothelial-Cadherin, zonula occludens-1 and Occludin was considerably increased in hRECs when hRPCs or PM-hASCs were also present. Supporting results were found by trans-endothelial electrical resistance measurements, gathered at 3 and 6 d of co-culture. The highest resistance values were obtained when hRECs were co-cultured with hRPCs or PM-hASCs. The pericyte-like phenotype of PM-hASCs was also confirmed in three-dimensional co-cultures in Matrigel, where PM-hASCs and hRPCs similarly localized around the tubular formations made by hRECs.

Conclusion: PM-hASCs seem able to strengthen the intercellular junctions between hRECs, likely reinforcing the BRB; thus, hASC-based therapeutic approaches may be developed to restore the integrity of retinal microcirculation.
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http://dx.doi.org/10.4252/wjsc.v12.i10.1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596446PMC
October 2020

Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments.

Pharmaceuticals (Basel) 2020 Nov 5;13(11). Epub 2020 Nov 5.

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

The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.
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http://dx.doi.org/10.3390/ph13110365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694365PMC
November 2020

Editorial: Delivery of Locally-Acting Agents to Intracellular Targets.

Front Pharmacol 2020 23;11:593064. Epub 2020 Sep 23.

Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.

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http://dx.doi.org/10.3389/fphar.2020.593064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538642PMC
September 2020

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, via S.Sofia 97, 95123 Catania, Italy.

Early blood retinal barrier (BRB) dysfunction induced by hyperglycemia was related to increased pro-inflammatory activity of phospholipase A2 (PLA2) and the upregulation of vascular endothelial growth factor A (VEGF-A). Here, we tested the role of VEGF-A in high glucose (HG)-induced damage of human retinal endothelial cells (HRECs) mediated by Ca++-dependent (cPLA2) and Ca++-independent (iPLA2) PLA2s. HRECs were treated with normal glucose (5 mM, NG) or high glucose (25 mM, HG) for 48 h with or without the VEGF-trap Aflibercept (Afl, 40 µg/mL), the cPLA2 inhibitor arachidonoyl trifluoromethyl ketone (AACOCF3; 15 µM), the iPLA2 inhibitor bromoenol lactone (BEL; 5 µM), or VEGF-A (80 ng/mL). Both Afl and AACOCF3 prevented HG-induced damage (MTT and LDH release), impairment of angiogenic potential (tube-formation), and expression of VEGF-A mRNA. Furthermore, Afl counteracted HG-induced increase of phospho-ERK and phospho-cPLA2 (immunoblot). VEGF-A in HG-medium increased glucose toxicity, through upregulation of phospho-ERK, phospho-cPLA2, and iPLA2 (about 55%, 45%, and 50%, respectively); immunocytochemistry confirmed the activation of these proteins. cPLA2 knockdown by siRNA entirely prevented cell damage induced by HG or by HG plus VEGF-A, while iPLA2 knockdown produced a milder protective effect. These data indicate that VEGF-A mediates the early glucose-induced damage in retinal endothelium through the involvement of ERK1/2/PLA2 axis activation.
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http://dx.doi.org/10.3390/ijms21207528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589177PMC
October 2020

MicroRNAs in the Vitreous Humor of Patients with Retinal Detachment and a Different Grading of Proliferative Vitreoretinopathy: A Pilot Study.

Transl Vis Sci Technol 2020 05 22;9(6):23. Epub 2020 May 22.

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

Purpose: Although the expression of microRNAs (miRNAs) in retinal pigment epithelial (RPE) cells undergoing epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of proliferative vitreoretinopathy (PVR), its expression in the vitreous of patients with primary retinal detachment (RD) and different PVR grading has not yet been investigated. We assessed the expression of miRNAs in the vitreous humor (VH) of patients diagnosed with RD and different grading of PVR.

Methods: The VH was extracted from the core of the vitreous chamber in patients who had undergone standard vitrectomy for primary RD. RNA was extracted and TaqMan Low-Density Arrays (TLDAs) were used for miRNA profiling that was performed by single TaqMan assays. A gene ontology (GO) analysis was performed on the differentially expressed miRNAs.

Results: A total of 15 eyes with RD, 3 eyes for each grade of PVR (A, B, C, and D) and 3 from unaffected individuals, were enrolled in this prospective comparative study. Twenty miRNAs were altered in the comparison among pathological groups. Interestingly, the expression of miR-143-3p, miR-224-5p, miR-361-5p, miR-452-5p, miR-486-3p, and miR-891a-5p increased with the worsening of PVR grading. We also identified 34 miRNAs showing differential expression in PVR compared to control vitreous samples. GO analysis showed that the deregulated miRNAs participate in processes previously associated with PVR pathogenesis.

Conclusions: The present pilot study suggested that dysregulated vitreal miRNAs may be considered as a biomarker of PVR and associated with the PVR-related complications in patients with RD.

Translational Relevance: The correlation between vitreal miRNAs and the pathological phenotypes are essential to identify the novel miRNA-based mechanisms underlying the PVR disease that would improve the diagnosis and treatment of the condition.
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http://dx.doi.org/10.1167/tvst.9.6.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409223PMC
May 2020

Parasomnias, sleep-related movement disorders and physiological sleep variants in focal epilepsy: A polysomnographic study.

Seizure 2020 Oct 31;81:84-90. Epub 2020 Jul 31.

Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Neuroscience Section, University of Catania, Via S. Sofia 78, 95123, Catania, Italy.

Purpose: The link existing between epilepsy and sleep is widely recognized. However, little is known about the prevalence and the clinical consequences of the comorbidity between focal epilepsy and sleep disorders, especially those sleep phenomena classified as isolated symptoms or normal variants. Objective of the study was to evaluate the frequency of sleep disorders and physiological sleep variants in a group of adult patients with focal epilepsy as compared to healthy controls by means of nocturnal polysomnography.

Methods: We performed a retrospective observational study in the Neurological Clinic of the University of Catania in adult patients with a diagnosis of focal epilepsy and in a group of control subjects. All subjects underwent an overnight polysomnography. The following sleep disorders were considered: NREM-related parasomnias; REM-related parasomnias; sleep-related movement disorders; isolated symptoms or normal variants.

Results: 100 patients [mean age 30.3 ± 14.7 years, 40 men] and 62 controls [mean age 36.4 ± 15.9, 20 men] were studied. A significant higher percentage of sleep disorders was recorded in patients as compared to controls (73 % vs 48.4 %; p = 0.002). In particular, we found a higher frequency of periodic limb movements (PLM) (20 % vs 4.8 %; p = 0.007), bruxism (20 % vs 4.8 %; p = 0.007) and neck myoclonus (22 % vs 4.8 %; p = 0.003). Moreover, alternating limb muscle activation was associated with sleep-related hypermotor epilepsy (OR = 7.9; p = 0.01).

Conclusion: Sleep disorders and physiological sleep variants are common in adult patients with focal epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2020.07.026DOI Listing
October 2020

New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin.

F1000Res 2020 8;9. Epub 2020 Jul 8.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123, Catania, Italy.

Behavioral and psychological symptoms of dementia are symptoms of disturbed perception, mood, behavior, and thought content that occurred frequently. These symptoms, which include apathy, depression, anxiety, psychosis, agitation, and aggression, can serve as predictors of and early clinical diagnostic markers for Alzheimer's disease (AD) and are common precipitants of institutional care. Agitation and psychosis are associated with accelerated disease progression and increased tau phosphorylation in patients with AD. Current guidelines recommend the use of second-generation antipsychotics for the treatment of agitation and psychosis in AD, but only after first-line non-pharmacological interventions and for no longer than 12 weeks because long-term use of these drugs is associated with an increased risk of mortality and an increased frequency of cerebrovascular events. Therefore, new antipsychotic drugs with improved efficacy and safety are needed as an alternative to current antipsychotic drugs. In this report, we discuss some of the most relevant advances in the field of agitation and psychosis in AD and focus on the recent positive clinical evidence observed with two new antipsychotics drugs: brexpiprazole and pimavanserin. Brexpiprazole is a receptor partial agonist (D2, D3, 5-HT1A), receptor antagonist (5-HT2A/B, α1B/α2C) according to the neuroscience-based nomenclature. Two recent phase III clinical trials have shown that brexpiprazole 2 mg/day is effective for the treatment of agitation in patients with AD and has an improved tolerability and safety profile compared with currently available second-generation antipsychotics. Pimavanserin is a receptor antagonist (5-HT2A, 5-HT2C) that has been given market authorization for psychosis occurring in Parkinson's disease. Recent phase II studies suggest that this drug is effective in AD patients with more severe psychosis, although further long-term studies are needed to better define the efficacy and long-term safety profile of pimavanserin for the treatment of psychosis in AD.
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http://dx.doi.org/10.12688/f1000research.22662.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344175PMC
October 2020

Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR).

Biochem Pharmacol 2020 08 20;178:114110. Epub 2020 Jun 20.

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

The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases.
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http://dx.doi.org/10.1016/j.bcp.2020.114110DOI Listing
August 2020

Editorial: New Paradigms in Neuroscience and Related Targets for Drug Discovery.

Front Pharmacol 2020 15;11:750. Epub 2020 May 15.

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

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http://dx.doi.org/10.3389/fphar.2020.00750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243264PMC
May 2020

Asymmetry index of Blink Reflex Recovery Cycle differentiates Parkinson's disease from atypical Parkinsonian syndromes.

J Neurol 2020 Jun 11;267(6):1859-1863. Epub 2020 May 11.

Department of Medical, Surgical Sciences and Advanced Technologies GF Ingrassia, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy.

Background: Differential diagnosis between Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), is often difficult because of overlap of common clinical features. We evaluated R2 Blink Reflex Recovery Cycle (R2BRRC) in drug-naive PD patients and in MSA and PSP patients to differentiate early PD from APS.

Methods: We investigated 43 patients: 15 drug-naive PD patients, 16 MSA patients, and 12 PSP patients. R2BRRC was evaluated bilaterally at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500, and 750 ms. An asymmetry index (AI) of R2BRRC for each ISI was computed.

Results: R2BRRC of PD patients showed an increased brainstem excitability for less affected side (LAS) stimulation at ISIs of 100, 150, 200 (p < 0.001), and 300 ms (p = 0.03) compared to more affected side (MAS) stimulation, whereas no differences between LAS and MAS stimulation were found in APS. AI of 0.87 at ISI of 100 ms differentiated PD from MSA with a sensitivity of 86.7% and a specificity of 100%, whereas AI of 0.78 at ISI of 100 ms permitted to discriminate PD from PSP with a sensitivity of 86.7% and a specificity of 91.7%.

Conclusion: AI of R2BRRC may represent a reliable tool in differentiating PD from APS, especially at the early stage of the disease.
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http://dx.doi.org/10.1007/s00415-020-09900-6DOI Listing
June 2020

Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Biochem Pharmacol 2020 07 28;177:114004. Epub 2020 Apr 28.

Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic. Electronic address:

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
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http://dx.doi.org/10.1016/j.bcp.2020.114004DOI Listing
July 2020

Retinal biomarkers and pharmacological targets for Hermansky-Pudlak syndrome 7.

Sci Rep 2020 03 4;10(1):3972. Epub 2020 Mar 4.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.

Deletion of dystrobrevin binding protein 1 has been linked to Hermansky-Pudlak syndrome type 7 (HPS-7), a rare disease characterized by oculocutaneous albinism and retinal dysfunction. We studied dysbindin-1 null mutant mice (Dys) to shed light on retinal neurodevelopment defects in HPS-7. We analyzed the expression of a focused set of miRNAs in retina of wild type (WT), Dys and Dys mice. We also investigated the retinal function of these mice through electroretinography (ERG). We found that miR-101-3p, miR-137, miR-186-5p, miR-326, miR-382-5p and miR-876-5p were up-regulated in Dysmice retina. Dys mice showed significant increased b-wave in ERG, compared to WT mice. Bioinformatic analysis highlighted that dysregulated miRNAs target synaptic plasticity and dopaminergic signaling pathways, affecting retinal functions of Dys mice. Overall, the data indicate potential mechanisms in retinal neurodevelopment of Dys mice, which may have translational significance in HSP-7 patients, both in terms of diagnostic/prognostic biomarkers and novel pharmacological targets.
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http://dx.doi.org/10.1038/s41598-020-60931-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055265PMC
March 2020

A New Human Blood-Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes.

Int J Mol Sci 2020 Feb 27;21(5). Epub 2020 Feb 27.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95125 Catania, Italy.

Blood-retinal barrier (BRB) dysfunction represents one of the most significant changes occurring during diabetic retinopathy. We set up a high-reproducible human-based in vitro BRB model using retinal pericytes, retinal astrocytes, and retinal endothelial cells in order to replicate the human in vivo environment with the same numerical ratio and layer order. Our findings showed that high glucose exposure elicited BRB breakdown, enhanced permeability, and reduced the levels of junction proteins such as ZO-1 and VE-cadherin. Furthermore, an increased expression of pro-inflammatory mediators (IL-1β, IL-6) and oxidative stress-related enzymes (iNOS, Nox2) along with an increased production of reactive oxygen species were observed in our triple co-culture paradigm. Finally, we found an activation of immune response-regulating signaling pathways (Nrf2 and HO-1). In conclusion, the present model mimics the closest human in vivo milieu, providing a valuable tool to study the impact of high glucose in the retina and to develop novel molecules with potential effect on diabetic retinopathy.
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http://dx.doi.org/10.3390/ijms21051636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084779PMC
February 2020

Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway.

Biochem Pharmacol 2019 10 25;168:341-351. Epub 2019 Jul 25.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy. Electronic address:

Diabetic retinopathy (DR) is a secondary complication of diabetes. DR can cause irreversible blindness, and its pathogenesis is considered multifactorial. DR can progress from non-proliferative DR to proliferative DR, characterized by retinal neovascularization. The main cause of vision loss in diabetic patients is diabetic macular edema, caused by vessel leakage and blood retinal barrier breakdown. Currently, aflibercept is an anti-VEGF approved for diabetic macular edema. Aflibercept can bind several members of vascular permeability factors, namely VEGF-A, B, and PlGF. We analyzed the aflibercept-PlGF complex at molecular level, through an in silico approach. In order to explore the role of PlGF in DR, we treated primary human retinal endothelial cells (HRECs) and mouse retinal epithelial cells (RPEs) with aflibercept and an anti-PlGF antibody. We explored the hypothesis that aflibercept has anti-inflammatory action through blocking of PlGF signaling and the ERK axis in an in vitro and in vivo model of DR. Both aflibercept and the anti-PlGF antibody exerted protective effects on retinal cells, by inhibition of the ERK pathway. Moreover, aflibercept significantly decreased (p < 0.05) the expression of TNF-α in an in vitro and in vivo model of DR. Therefore, our data suggest that inhibition of PlGF signaling, or a selective blocking, may be useful in the management of early phases of DR when the inflammatory process is largely involved.
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http://dx.doi.org/10.1016/j.bcp.2019.07.021DOI Listing
October 2019

Blood-retinal barrier protection against high glucose damage: The role of P2X7 receptor.

Biochem Pharmacol 2019 10 11;168:249-258. Epub 2019 Jul 11.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy. Electronic address:

Blood retinal barrier (BRB) breakdown is a hallmark of diabetic retinopathy, whose occurrence in early or later phases of the disease has not yet been completely clarified. Recent evidence suggests that hyperglycemia induces activation of the P2X7 receptor (P2X7R) leading to pericyte cell death. We herein investigated the role of P2X7R on retinal endothelial cells viability and expression of tight- and adherens-junctions following high glucose (HG) exposure. We found that HG elicited P2X7R activation and expression and release of the pro-inflammatory cytokine IL-1β in human retinal endothelial cells (HRECs). Furthermore, HG exposure caused a decrease in HRECs viability and a damage of the BRB. JNJ47965567, a P2X7R antagonist, protected HRECs from HG-induced damage (LDH release) and preserved the BRB, as shown by transendothelial electrical resistance and cell junction morphology (ZO-1, claudin-5 and VE-cadherin). Moreover, JNJ47965567 treatment significantly decreased IL-1β expression and release, elicited by HG. These data indicate that P2X7R plays an important role to regulate BRB integrity, in particular the block of this receptor was useful to counteract the damage elicited by HG in HRECs, and warranting further clinical evaluation of P2X7R antagonists for the treatment of diabetic macular edema.
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http://dx.doi.org/10.1016/j.bcp.2019.07.010DOI Listing
October 2019

Dopamine outside the brain: The eye, cardiovascular system and endocrine pancreas.

Pharmacol Ther 2019 11 9;203:107392. Epub 2019 Jul 9.

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

Dopamine (DA) and DA receptors (DR) have been extensively studied in the central nervous system (CNS), but their role in the periphery is still poorly understood. Here we summarize data on DA and DRs in the eye, cardiovascular system and endocrine pancreas, three districts where DA and DA-related drugs have been studied and the expression of DR documented. In the eye, DA modulates ciliary blood flow and aqueous production, which impacts on intraocular pressure and glaucoma. In the cardiovascular system, DA increases blood pressure and heart activity, mostly through a stimulation of adrenoceptors, and induces vasodilatation in the renal circulation, possibly through D1R stimulation. In pancreatic islets, beta cells store DA and co-release it with insulin. D1R is mainly expressed in beta cells, where it stimulates insulin release, while D2R is expressed in both beta and delta cells (in the latter at higher level), where it inhibits, respectively, insulin and somatostatin release. The formation of D2R-somatostatin receptor 5 heteromers (documented in the CNS), might add complexity to the system. DA may exert both direct autocrine effects on beta cells, and indirect paracrine effects through delta cells and somatostatin. Bromocriptine, an FDA approved drug for diabetes, endowed with both D1R (antagonistic) and D2R (agonistic) actions, may exert complex effects, resulting from the integration of direct effects on beta cells and paracrine effects from delta cells. A full comprehension of peripheral DA signaling deserves further studies that may generate innovative therapeutic drugs to manage conditions such as glaucoma, cardiovascular diseases and diabetes.
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http://dx.doi.org/10.1016/j.pharmthera.2019.07.003DOI Listing
November 2019

Fluoxetine and Vortioxetine Reverse Depressive-Like Phenotype and Memory Deficits Induced by Aβ Oligomers in Mice: A Key Role of Transforming Growth Factor-β1.

Front Pharmacol 2019 21;10:693. Epub 2019 Jun 21.

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

Depression is a risk factor for the development of Alzheimer's disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-β (1-42) (Aβ) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before Aβ injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after Aβ injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after Aβ injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-β1 (TGF-β1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of Aβ-injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-β1 levels in Aβ-injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-β1.
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http://dx.doi.org/10.3389/fphar.2019.00693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598642PMC
June 2019

Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS.

Sci Rep 2019 07 10;9(1):9968. Epub 2019 Jul 10.

Institute of Neurological Sciences, Italian National Research Council, Catania, Italy.

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive "omics" analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.
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http://dx.doi.org/10.1038/s41598-019-46355-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620285PMC
July 2019

Therapeutic Challenges of Post-traumatic Stress Disorder: Focus on the Dopaminergic System.

Front Pharmacol 2019 17;10:404. Epub 2019 Apr 17.

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

Post-traumatic stress disorder (PTSD) is a mental illness developed by vulnerable individuals exposed to life-threatening events. The pharmacological unresponsiveness displayed by the vast majority of PTSD patients has raised considerable interest in understanding the poorly known pathophysiological mechanisms underlying this disorder. Most studies in the field focused, so far, on noradrenergic mechanisms, because of their well-established role in either tuning arousal or in encoding emotional memories. However, less attention has been paid to other neural systems. Manipulations of the dopaminergic system alter behavioral responses to stressful situations and recent findings suggest that dopaminergic dysfunction might play an overriding role in the pathophysiology of PTSD. In the present review, dopaminergic mechanisms relevant for the pathogenesis of PTSD, as well as potential dopaminergic-based pharmacotherapies are discussed in the context of addressing the unmet medical need for new and effective drugs for treatment of PTSD.
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http://dx.doi.org/10.3389/fphar.2019.00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478703PMC
April 2019

Forehead Tremor: A Clinical Presentation of Myasthenia Gravis?

Mov Disord Clin Pract 2018 Mar-Apr;5(2):225-226. Epub 2018 Feb 18.

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

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http://dx.doi.org/10.1002/mdc3.12593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336434PMC
February 2018

Dopaminergic-GABAergic interplay and alcohol binge drinking.

Pharmacol Res 2019 03 12;141:384-391. Epub 2019 Jan 12.

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

The dopamine D receptor (DR), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of DR increases GABA α6 subunit in the ventral striatum. Here we tested the hypothesis that DR-dependent changes in GABA α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in DR knockout (DR ) mice and wild type littermates (DR ). Ro 15-4513, a high affinity α6-GABA ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in DR, whereas it was robust in DR; other relevant GABA subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in DR, but increased it in DR; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in DR compared to DR; Ro 15-4513 reduced the peak amplitude in the NAc of DR, but not in DR. We conclude that DR-dependent enhanced expression of α6 GABA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.
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http://dx.doi.org/10.1016/j.phrs.2019.01.022DOI Listing
March 2019
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