The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation.

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets.

Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.

Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues - showing three substitution patterns -, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile).

Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning.

In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates.

Information specialists and researchers working together for health promotion: Benefits from school-work educational programmes at the National Institute of Health in Italy.

In 2015, the Italian Ministry of Education in Italy launched innovative upper school educational programmes envisaging school-work initiatives. In this framework, the National Institute of Health (Istituto Superiore di Sanità, ISS) was among the first scientific institutions to develop educational programmes with school. Involving school students in health research activities allowed health literacy improvement, acquisition of scientific communication skills and fostered student interest in science careers.

Connecting Immune Cell Infiltration to the Multitasking Microglia Response and TNF Receptor 2 Induction in the Multiple Sclerosis Brain.

Signaling from central nervous system (CNS)-infiltrating lymphocytes and macrophages is critical to activate microglia and cause tissue damage in multiple sclerosis (MS). We combined laser microdissection with high-throughput real time RT-PCR to investigate separately the CNS exogenous and endogenous inflammatory components in postmortem brain tissue of progressive MS cases. A previous analysis of immune infiltrates isolated from the white matter (WM) and the meninges revealed predominant expression of genes involved in antiviral and cytotoxic immunity, including IFNγ and TNF.

Oxidative Status in Multiple Sclerosis and Off-Targets of Antioxidants: The Case of Edaravone.

Background: MS is a chronic inflammatory disease of the CNS leading to demyelination and neurodegeneration, with a complex and still to be clarified aetiology. Several data, coming from patients' samples and from animal models, show that Oxidative Status (OS) plays an important role in MS pathogenesis. Overproduction of reactive oxidative species by macrophages/microglia can bring about cellular injury and ensuing cell death by oxidizing cardinal cellular components.

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials.

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects.

HIV-1 Myristoylated Nef Treatment of Murine Microglial Cells Activates Inducible Nitric Oxide Synthase, NO2 Production and Neurotoxic Activity.

Background: The potential role of the human immunodeficiency virus-1 (HIV-1) accessory protein Nef in the pathogenesis of neuroAIDS is still poorly understood. Nef is a molecular adapter that influences several cellular signal transduction events and membrane trafficking. In human macrophages, Nef expression induces the production of extracellular factors (e.

TNF receptor 2 protects oligodendrocyte progenitor cells against oxidative stress.

The neuroprotective role of TNF receptor 2 (TNFR2) has been shown in various studies. However, a direct role of TNFR2 in oligodendrocyte function has not yet been demonstrated. Using primary oligodendrocytes of transgenic mice expressing human TNFR2, we show here that TNFR2 is primarily expressed on oligodendrocyte progenitor cells.

Left ventricular cavity obliteration during dobutamine stress echocardiography in diabetic patients.

Prevalence of dynamic left ventricular outflow tract obstruction (DLVO) during dobutamine stress-echo (DSE) seems disproportionally high among diabetic patients. We retrospectively identified 212 diabetic (D+) and 212 non diabetic (D-) subjects, who underwent DSE for suspected coronary artery disease (CAD); we evaluated DSE-induced DLVO prevalence and correlates. During DSE, 105 patients in D+ (50%) and 83 in D- group (39%, P = 0.

Left ventricular remodeling in the elderly with acute anterior myocardial infarction treated with primary coronary intervention.

We compared left ventricular (LV) remodeling following a first time acute anterior ST-elevation myocardial infarction (aSTEMI) treated with primary coronary intervention (pPCI) in different age groups. A total of 116 patients, 61 aged <65 and 55 aged >or=65 years, who survived after a recent aSTEMI treated with pPCI, underwent dobutamine stress-echocardiography (DSE) and non-invasive measurement of left anterior descending coronary artery flow reserve (CFR) during intravenous adenosine infusion. Baseline LV dimensions and systolic function were similar between the two groups; wall motion score indices during all DSE stages and CFR were also similar.

Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways.

Fine regulation of the innate immune response following brain injury or infection is important to avoid excessive activation of microglia and its detrimental consequences on neural cell viability and function. To get insights on the molecular networks regulating microglia activation, we analyzed expression, regulation and functional relevance of tumor necrosis factor receptors (TNFR) 2 in cultured mouse microglia. We found that microglia upregulate TNFR2 mRNA and protein and shed large amounts of soluble TNFR2, but not TNFR1, in response to pro-inflammatory stimuli and through activation of TNFR2 itself.

Prognostic value of dobutamine stress echocardiography in diabetic patients.

CAD is the main cause of morbidity and mortality in diabetic patients; we need reliable clinical parameters to stratify cardiovascular risk in these patients. We thus assessed prognostic value of clinical parameters, rest and stress echocardiographic data in diabetic patients, with known or suspected CAD. We studied 322 type 2 diabetic patients, who underwent dobutamine stress echocardiography (DSE) for known or suspected CAD; for prognostic assessment, end-points were all-cause mortality and hard cardiac events (cardiac death and non fatal myocardial infarction).

Dendritic cells loaded with apoptotic oligodendrocytes as a source of myelin T-cell epitopes in multiple sclerosis.

Evidence suggests that T-cell response to myelin basic protein (MBP) plays an important role in multiple sclerosis (MS). However, the mechanism of generation for MBP immunogenic epitopes is unclear. A series of specific CD4(+) T-cell lines was obtained by stimulating peripheral blood mononuclear cells from MS patients with synthetic peptides spanning the entire MBP sequence.

Specific interactions between diphenhydramine and alpha-helical poly(glutamic acid)--a new ion-pairing complex for taste masking and pH-controlled diphenhydramine release.

Formation of drug/excipient complex through ionic interactions has proven to be very effective for both controlled release and taste masking. Unfortunately, the ionic interactions between drugs and small molecule excipients are usually weak, and the stability of the formed complexes can be greatly influenced by solution ionic strength. In this study, we explored to formulate diphenhydramine (DPH), a very bitter tasting drug, using small molecular weight and carboxyl group containing polymers.

Traditional and color M-mode parameters of left ventricular diastolic function during low-dose dobutamine stress echocardiography: relations to contractility reserve.

Background: Cross-sectional studies reported that left ventricular (LV) systolic and diastolic functions are correlated. However, whether changes in wall-motion score index (WMSI) or 2-dimensional ejection fraction (EF) predict changes of Doppler parameters of LV diastolic function is unclear.

Methods: Patients with known or suspected history of coronary artery disease underwent assessment of LV systolic function (WMSI, EF) and diastolic function at baseline and during stress echocardiography by low-dose dobutamine (LDD) (peak infusion 10 microg/kg/min).

ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors.

Extracellular nucleotides act as potent signaling molecules in the neuron-glia and glia-glia communication, via the activation of specific ligand-gated P2X and G-protein-coupled metabotropic P2Y receptors. Most of the data available about the effects of P2 receptor activation in the CNS concern astrocytes, microglia, and neurons. To gain insights into the role of purinergic receptors in oligodendrocyte development, we characterized the expression and functional activity of P2 receptors in rat oligodendrocyte progenitors (OPs) and investigated the effects of ATP and its breakdown products on their functions.

Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development.

To gain insights into the role of purinergic receptors in oligodendrocyte development, we characterized the expression and functional activity of P2 receptors in cultured rat oligodendrocyte progenitors and investigated the effects of ATP and its breakdown products on the migration and proliferation of this immature glial cell population. Using Western blot analysis, we show that oligodendrocyte progenitors express several P2X (P2X(1,2,3,4,7)) and P2Y (P2Y(1,2,4)) receptors. Intracellular Ca(2+) recording by Fura-2 video imaging allowed to determine the rank potency order of the P2 agonists tested: ADPbetaS = ADP = Benzoyl ATP > ATP > ATPgammaS > UTP, alpha,beta-meATP ineffective.

Nuclear factor kB-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor 2.

Most normal and neoplastic cell types are resistant to tumor necrosis factor (TNF) cytotoxicity unless cotreated with protein or RNA synthesis inhibitors, such as cycloheximide and actinomycin D. Cellular resistance to TNF requires TNF receptor-associated factor 2 (TRAF2), which has been hypothesized to act mainly by mediating activation of the transcription factors nuclear factor kB (NFkB) and activator protein 1 (AP1). NFkB was proposed to switch on transcription of yet unidentified anti-apoptotic genes.

Synergistic stimulation of MHC class I and IRF-1 gene expression by IFN-gamma and TNF-alpha in oligodendrocytes.

In order to understand the molecular basis of the synergistic action of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) on rat oligodendrocyte development, we studied some aspects of the signalling pathways involved in the regulation of the major histocompatibility complex (MHC) class I and the interferon regulatory factor 1 (IRF-1) gene expression. Two well-defined inducible enhancers of the MHC class I gene promoter, the MHC class I regulatory element (MHC-CRE) and the interferon consensus sequence (ICS), were analysed. Neither IFN-gamma nor TNF-alpha was capable of inducing MHC-CRE binding activity when administrated alone.

Microphone and electroglottographic data from dysphonic patients: type 1, 2 and 3 signals.

Recently, it has been suggested that statistics which are dependent upon the reliable extraction of a single fundamental period, such as jitter and shimmer, are valid only for nearly periodic signals. This study explored the incidence of nearly periodic and nonperiodic microphone and electroglottographic signals obtained from 202 dysphonic patients. It was found that approximately 42% were type 1 (nearly periodic); approximately 35% were type 2 (containing bifurcations, modulations or subharmonic structure); and approximately 22% were type 3 (chaotic).

5D4 keratan sulfate epitope identifies a subset of ramified microglia in normal central nervous system parenchyma.

Microglia expressing keratan sulfate (KS) was studied in normal central nervous system (CNS) and in rat neonatal brain cultures. The majority of KS+ cells are ramified microglia located in the brain parenchyma; positive cells were only exceptionally found in extraparenchymal structures. KS+ cells are ubiquitous, but their density is heterogeneous throughout the CNS.