The complex CBX7-PRMT1 has a critical role in regulating E-cadherin gene expression and cell migration.
Publication Date: 28/02/2019, on Biochimica et biophysica acta. Gene regulatory mechanisms
by Federico A, Sepe R, Cozzolino F, Piccolo C, Iannone C, Iacobucci I, Pucci P, Monti M, Fusco A
The Chromobox protein homolog 7 (CBX7) belongs to the Polycomb Group (PcG) family, and, as part of the Polycomb repressive complex (PRC1), contributes to maintain transcriptional gene repression. Loss of CBX7 expression has been reported in several human malignant neoplasias, where it often correlates with an advanced cancer state and poor survival, proposing CBX7 as a candidate tumor-suppressor gene in cancer progression. Indeed, CBX7 is able to positively or negatively regulate the expression of genes involved in cell proliferation and cancer progression, such as E-cadherin, cyclin E, osteopontin, EGR1. To understand the molecular mechanisms that underlie the involvement of CBX7 in cancer progression, we designed a functional proteomic experiment based on CHIP-MS to identify novel CBX7 protein partners. Among the identified CBX7-interacting proteins we focused our attention on the Protein Arginine Methyltransferase 1 (PRMT1) whose critical role in epithelial-mesenchymal transition (EMT), cancer cell migration and invasion has been already reported. We confirmed the interaction between CBX7 and PRMT1 and demonstrated that this interaction is crucial for PRMT1 enzymatic activity both in vitro and in vivo and for the regulation of E-cadherin expression, an important hallmark of EMT. These results suggest a general mechanism by which CBX7 interacting with histone modification enzymes like HDAC2 and PRMT1 enhances E-cadherin expression. Therefore, disruption of this equilibrium may induce impairment of E-cadherin expression and increased cell migration eventually leading to EMT and, then, cancer progression.
Benzodifurans for biomedical applications: BZ4, a selective anti-proliferative and anti-amyloid lead compound.
Publication Date: 25/02/2019, on Future medicinal chemistry
by Vicidomini C, Cioffi F, Broersen K, Roviello V, Riccardi C, Montesarchio D, Capasso D, Gaetano SD, Musumeci D, Roviello GN
Our goal is to evaluate benzodifuran-based scaffolds for biomedical applications.
Effects of metformin therapy on COronary endothelial DYsfunction in prediabetic patients With stable angina and Non Obstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study.
Publication Date: 22/02/2019, on Diabetes care
by Sardu C, Paolisso P, Sacra C, Mauro C, Minicucci F, Portoghese M, Rizzo MR, Barbieri M, Sasso FC, D'Onofrio N, Balestrieri ML, Calabrò P, Paolisso G, Marfella R
To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with prediabetes with stable angina and nonobstructive coronary stenosis (NOCS).
Platinum(II) <i>O</i>,<i>S</i> Complexes Inhibit the Aggregation of Amyloid Model Systems.
Publication Date: 14/02/2019, on International journal of molecular sciences
by Florio D, Malfitano AM, Di Somma S, Mügge C, Weigand W, Ferraro G, Iacobucci I, Monti M, Morelli G, Merlino A, Marasco D
Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.
Does cognitive reserve play any role in multiple sclerosis? A meta-analytic study.
Publication Date: 14/02/2019, on Multiple sclerosis and related disorders
by Santangelo G, Altieri M, Gallo A, Trojano L
Inconsistent evidence is available about the possibility that cognitive reserve (CR) moderates the impact of disease progression, evaluated by MRI biomarkers (lesion load, white matter or gray matter volumes) or clinical proxies of physical disability (i.e. the Expanded Disability Status Scale, EDSS) on cognition in Multiple Sclerosis (MS). A meta-analytic study with a meta-regression approach was performed to investigate the possible role of CR as moderator of the impact of brain damage and physical disability on cognition.
Patients with HCV genotype-1 who have failed a direct-acting antiviral regimen: virological characteristics and efficacy of retreatment.
Publication Date: 13/02/2019, on Antiviral therapy
by Pisaturo M, Starace M, Minichini C, De Pascalis S, Macera M, Occhiello L, Messina V, Sangiovanni V, Claar E, Precone D, Stornaiuolo G, Stanzione M, Gentile I, Brancaccio G, Martini S, Masiello A, Megna AS, Coppola C, Federico A, Sagnelli E, Persico M, Lanza AG, Marrone A, Gaeta GB, Coppola N
This real-world clinical-setting study characterized the virological patterns in genotype-1 patients failing IFN-free regimens and evaluated the efficacy of re-treatment.
Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity.
Publication Date: 11/02/2019, on Journal of neurology
by Massa R, Greco G, Testi M, Rastelli E, Terracciano C, Frezza E, Garibaldi M, Marfia GA, Locatelli F, Mercuri NB, Pompeo E, Antonini G, Andreani M
The relative prevalence of myasthenia gravis (MG) subtypes is changing, and their differential features and association with HLA class II alleles are not completely understood.
Apathy as a herald of cognitive changes in multiple sclerosis: A 2-year follow-up study.
Publication Date: 07/02/2019, on Multiple sclerosis (Houndmills, Basingstoke, England)
by Raimo S, Spitaleri D, Trojano L, Santangelo G
Behavioral symptoms, such as apathy and depression, are common in multiple sclerosis (MS) but their relationship with cognitive and clinical characteristics often remains underinvestigated and not monitored over time.
Thrombus Aspiration in Hyperglycemic Patients With High Inflammation Levels in Coronary Thrombus.
Publication Date: 05/02/2019, on Journal of the American College of Cardiology
by Sardu C, D'Onofrio N, Mauro C, Balestrieri ML, Marfella R
Neural plasticity and adult neurogenesis: the deep biology perspective.
Publication Date: 01/02/2019, on Neural regeneration research
by Colangelo AM, Cirillo G, Alberghina L, Papa M, Westerhoff HV
The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.
Cognitive reserve and neuropsychological performance in multiple sclerosis: A meta-analysis.
Publication Date: 31/01/2019, on Neuropsychology
by Santangelo G, Altieri M, Enzinger C, Gallo A, Trojano L
Cognitive dysfunction is frequent in multiple sclerosis (MS), and its relationship with cognitive reserve (CR) has been investigated in several studies with conflicting results. In this meta-analysis, we here sought to determine the relationship between CR and cognition in MS patients and to ascertain whether demographic or clinical variables could moderate the above-mentioned relationship.
Specific Expression of a New Bruton Tyrosine Kinase Isoform (p65BTK) in the Glioblastoma Gemistocytic Histotype.
Publication Date: 24/01/2019, on Frontiers in molecular neuroscience
by Sala L, Cirillo G, Riva G, Romano G, Giussani C, Cialdella A, Todisco A, Virtuoso A, Cerrito MG, Bentivegna A, Grassilli E, Ardizzoia A, Bonoldi E, Giovannoni R, Papa M, Lavitrano M
Bruton's tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors ( = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors ( ≤ 0.05) and overall survival (OS) of patients with grade III gliomas ( ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
Encapsulation of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 in an apoferritin nanocage: structure and cytotoxicity.
Publication Date: 23/01/2019, on ChemMedChem
by Petruk G, Monti DM, Ferraro G, Pica A, D'Elia L, Pane F, Amoresano A, Furrer J, Kowalski K, Merlino A
The effects of the encapsulation of the cytotoxic dinuclear trithiolato-bridged arene Ru complex [(η6-p-MeC6H4Pri)2Ru2(μ2-S-p-C6H4But)3]Cl (DiRu-1) within the apoferritin (AFt) nanocage were investigated. The DiRu-1-AFt nanocarrier was characterized by UV-Vis spectroscopy, ICP MS, CD and X-ray crystallography. In contrast to previously reported Au- and Pt- based drug-loaded AFt carriers, no direct interactions between DiRu-1 and AFt were evidenced. DiRu-1-AFt is cytotoxic towards immortalized murine fibroblast BALB/c-3T3 transformed with SV40 virus (SVT2) and human epidermoid carcinoma A431 malignant cells and exhibits a moderate selectivity for these cancer cells over the normal BALB/c-3T3 cells. DiRu-1-AFt triggers ROS production, depolarization of mitochondrial membrane potential and induces cell death via p53-mediated apoptosis. The comparison between our data and previous results suggest that the existence of specific interactions between a metal-based drug and AFt within the protein cage is not essential for drug encapsulation.
Neutralization of interleukin-17 rescues amyloid-β-induced neuroinflammation and memory impairment.
Publication Date: 23/01/2019, on British journal of pharmacology
by Cristiano C, Volpicelli F, Lippiello P, Buono B, Raucci F, Piccolo M, Iqbal AJ, Irace C, Miniaci MC, Perrone Capano C, Calignano A, Mascolo N, Maione F
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of T helper 17 cells in the pathogenesis of AD-related neuroinflammation has been reported in several studies, however the role of the main cytokine, IL-17, has not been well addressed. Herein, we investigate the effects of IL-17 neutralizing antibody (IL-17Ab) injected by intracerebroventricular (ICV) or intranasal (IN) routes on amyloid-β-induced neuroinflammation and memory impairment in mice.
Antioxidant and Anti-Inflammatory Activities of Buffalo Milk δ-Valerobetaine.
Publication Date: 20/01/2019, on Journal of agricultural and food chemistry
by D'Onofrio N, Balestrieri A, Neglia G, Monaco A, Tatullo M, Casale R, Limone A, Balestrieri ML, Campanile G
δ-Valerobetaine (δVB), a constitutive metabolite of ruminant milk, is produced in the rumen from free dietary Nε-trimethyllysine occurring ubiquitously in vegetable kingdom. Biological role of δVB is poorly known. Here, the antioxidant and anti-inflammatory potential of buffalo milk δVB was tested in vitro during high-glucose (HG)-induced endothelial damage. Results indicated that δVB (0.5 mM) ameliorated the HG cytotoxicity (0.57±0.02 vs. 0.41±0.018 O.D. (P<0.01). Buffalo milk extracts enriched with δVB showed significant efficacy in decreasing reactive oxygen species, lipid peroxidation, and cytokine release during HG treatment compared to milk extracts alone (P<0.05). δVB reduced the HG-activated inflammatory signal by modulating SIRT1 (0.96±0.05 vs. 0.85±0.04 AU), SIRT6 (0.82±0.04 vs. 0.61±0.03 AU), and NF-κB (0.85±0.03 vs. 1.23±0.03 AU) (P<0.05). On the whole, our data show the first evidence of δVB efficacy in reducing endothelial oxidative stress and inflammation, suggesting a potential role of this betaine as a novel dietary compound with health-promoting properties.