phytotherapeutic compound yhk exerts an inhibitory effect on early stage of experimentally induced neoplastic liver lesions

The aim of this study was to investigate the effects of the herbal compound YHK on hepatocarcinogenesis induced by diethylntrosamine (DEN) in Sprague Dawley rats. Rats were randomly divided into 3 groups and followed up for 15 weeks. Groups 1 was given standard food and represented the healthy control. Liver preneoplastic foci were induced using the DEN method in groups 2 and 3 (20 rats each). However, group 3 was concomitantly given 50mg/kg/day of YHK. For quantitative assessment of liver preneoplastic foci, the placental form of glutathione-S-transferase (GST-P) positive foci were measured using immunohistochemical staining and image analysis. Treatment using DEN caused a significant decrease in body weight and increase in liver weight compared to the control group while concomitant supplementation with YHK prevented body weight loss and liver weight increase. As compared to DENonly treated rats, the group given YHK showed a significant decrease in the number, size and volume of GSTP-positive foci. Moreover, co-administration of YHK significantly reduced the incidence, number, size and volume of hepatocellular carcinoma. Anti-inflammatory, anti-fibrotic as well as antioxidative properties of this compound are mechanisms which are likely to be advocated for to explain its protective effect. It is concluded that herbal compound YHK by preventing hepatocarcinogenesis in DEN-induced liver preneoplastic lesions in rats has the potential to a large clinical application as a functional food

The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation

Statin-induced inhibition of HMG-CoA reductase reduces cholesterol production and prevents the formation of many non-steroidal isoprenoid compounds, such as farnesylpyrophosphate and geranylgeranylpyrophosphate, that act as lipid attachments for the post-translational modification of various proteins, including the G-proteins and transcription factors involved in a number of cell processes. However, the blockade of isoprenylation elicited by statin treatment also has biological effects on cell function that go beyond the decrease in cholesterol synthesis: these are the so-called “pleiotropic” effects that mainly relate to vascular function. Endothelial dysfunction is an independent predictor of cardiovascular events that correlates with inflammation markers/mediators and robust predictors of cardiovascular diseases such as increased high-sensitivity C-reactive protein levels. The results of in vivo and in vitro studies indicate that the statins have beneficial effects unrelated to cholesterol lowering, such as improving endothelial function, increasing myocardial perfusion, and enhancing the availability of nitric oxide. This review describes the pleiotropic effects of statins that may be involved in modulating/preventing endothelial dysfunction and inflammatory processes, as well as the cellular and molecular mechanisms through which they improve endothelial function

Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat

UCP2 maps nearby the lod score peak of STR1-stroke QTL in the SHRSP rat strain. We explored the potential contribution of UCP2 to the high-salt diet (JD)-dependent increased stroke susceptibility of SHRSP. Male SHRSP, SHRSR, two reciprocal SHRSR/SHRSP-STR1/QTL stroke congenic lines received JD for 4 weeks to detect brain UCP2 gene/protein modulation as compared with regular diet (RD). Brains were also analyzed for NF-κB protein expression, oxidative stress level and UCP2-targeted microRNAs expression level. Next, based on knowledge that fenofibrate and Brassica Oleracea (BO) stimulate UCP2 expression through PPARα activation, we monitored stroke occurrence in SHRSP receiving JD plus fenofibrate versus vehicle, JD plus BO juice versus BO juice plus PPARα inhibitor. Brain UCP2 expression was markedly reduced by JD in SHRSP and in the (SHRsr.SHRsp-(D1Rat134-Mt1pa)) congenic line, whereas NF-κB expression and oxidative stress level increased. The opposite phenomenon was observed in the SHRSR and in the (SHRsp.SHRsr-(D1Rat134-Mt1pa)) reciprocal congenic line. Interestingly, the UCP2-targeted rno-microRNA-503 was significantly upregulated in SHRSP and decreased in SHRSR upon JD, with consistent changes in the two reciprocal congenic lines. Both fenofibrate and BO significantly decreased brain microRNA-503 level, upregulated UCP2 expression and protected SHRSP from stroke occurrence. In vitro overexpression of microRNA-503 in endothelial cells suppressed UCP2 expression and led to a significant increase of cell mortality with decreased cell viability. Brain UCP2 downregulation is a determinant of increased stroke predisposition in high-salt-fed SHRSP. In this context, UCP2 can be modulated by both pharmacological and nutraceutical agents. The microRNA-503 significantly contributes to mediate brain UCP2 downregulation in JD-fed SHRSP

THE RADIO-DRAMA AS ARTISTIC MODALITY TO IMPROVE THE EXPRESSIVENESS SKILLS IN INTELLECTUAL DISABILITY AND AUTISM: AN EXPERIMENTAL STUDY

The paper presents an artistic experience aimed at developing the vocal and emotional expressiveness of young people with intellectual, relational and physical disabilities. It follows the Esagramma® methodology, called Affective Vocal Education (EVA), and focuses on the production of a radio-drama based on the Roman de la Rose by Guillaume de Lorris and Jean de Meun. It was realized by an actor and a sound engineer together with 5 girls and 1 boy with various diagnoses affecting their verbal and relational skills. A specific methodology allowed us to quantify macroscopic dialogic and prosodic variations before and after the artistic experience, by extracting a set of suprasegmental features thanks to a pre- and a post-test recording of spontaneous and elicited speech. Moreover, the paper describes the development of the theatrical script, the operational and artistic choices as well as the analysis of the complexity of the radio-drama from a linguistic point of view.   Il radiodramma come modalità artistica per migliorare le capacità espressive nella disabilità intellettive e nell’autismo: uno studio sperimentale L’articolo presenta un percorso artistico volto a sviluppare l’espressività vocale ed emotiva di giovani con disabilità intellettive, relazionali e fisiche. L’attività svolta segue la metodologia Esagramma®, denominata Affective Vocal Education (EVA) e si concentra sulla produzione di un dramma radiofonico basato sul Roman de la Rose di Guillaume de Lorris e Jean de Meun. Il prodotto audio è stato realizzato da un attore e un ingegnere del suono insieme a 5 ragazze e 1 ragazzo con varie disabilità che ne influenzano le capacità verbali e relazionali. Una specifica metodologia permette di quantificare le variazioni macroscopiche dialogiche e prosodiche prima e dopo il percorso artistico, tramite l’estrazione di un insieme di caratteristiche soprasegmentali da registrazioni raccolte sia prima che dopo il percorso. L’articolo descrive inoltre lo sviluppo della sceneggiatura teatrale, le scelte esecutive ed artistiche e l’analisi della complessità del radiodramma dal punto di vista linguistico

Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases

Cysteinyl leukotrienes (CysLTs) are potent lipid inflammatory mediators synthesized from arachidonic acid, through the 5-lipoxygenase (5-LO) pathway. Owing to their properties, CysLTs play a crucial role in the pathogenesis of inflammation; therefore, CysLT modifiers as synthesis inhibitors or receptor antagonists, central in asthma management, may become a potential target for the treatment of other inflammatory diseases such as the cardiovascular disorders. 5-LO pathway activation and increased expression of its mediators and receptors are found in cardiovascular diseases. Moreover, the cardioprotective effects observed by using CysLT modifiers are promising and contribute to elucidate the link between CysLTs and cardiovascular disease. The aim of this review is to summarize the state of present research about the role of the CysLTs in the pathogenesis and progression of atherosclerosis and myocardial infarction

Investigating the cross-talk between microglia and oligodendrocyte progenitors in brain ischemia

Oligodendrocytes, the myelin-forming cells in the brain, are severely affected by ischemia (Arai et al. 2009, Biol Pharm Bull), contributing to stroke-associated deficits. The possibility to implement spontaneous post-injury repair mechanisms still represents an unexplored field. Recent data obtained by fate-mapping analysis using the conditional GPR17-iCreERT2xCAG-eGFP transgenic mice, showed that the subpopulation of adult Oligodendrocyte Progenitor Cells (OPCs) expressing the GPR17 receptor (GFP+-cells) represent \u201ca reserve pool\u201d that is maintained for repair purposes after brain damage (Vigano\u300 et al. 2016, Glia). Accordingly, our data demonstrated that, after brain ischemia, GFP+-cells actively respond to injury increasing their proliferation rate and migratory capacity. However, at later stages, only a few percentage of these cells undergo maturation. This limited post-stroke repair is likely due to local unfavourable inflammatory milieu mediated by macrophages and resident microglia, which participate to post-ischemic inflammation assuming both detrimental and beneficial phenotypes. Here, we aimed at: (i) characterizing the spatio-temporal distribution of GFP+-cells in relation to microglia and macrophage polarization after brain ischemia in the middle cerebral artery occlusion MCAo, rodent model; (ii) exploring the cross-talk between microglia and OPCs, by assessing how vesicles released extracellularly (EVs) by microglia, polarized toward the pro- and anti- inflammatory states, influence OPC behaviour. In vivo studies showed that GFP+-cells accumulate at the border of the ischemic lesion starting from 72h after ischemia, when immune cells show both pro- and anti-inflammatory features. One week after stroke, the absolute number of pro-inflammatory cells increases, whereas immune cells with anti-inflammatory phenotype were found to be decreased. In vitro studies pointed out that EVs produced by pro-inflammatory microglia limit OPC proliferation. On the contrary, 48h exposure to EVs from either pro- or anti-inflammatory microglia (but not resting cells) promote OPC maturation and myelination. Interestingly, EVs from pro-rigenerative cells also increased OPC migration. These data suggest that EVs contain signals able to influence OPC proliferation, migration and maturation. Shedding light on the mechanisms by which microglia activation interferes with the regeneration potential of OPCs is important for developing therapeutic interventions to implement functional recovery after stroke

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2xCAG-eGFP mice) allowing to follow the final fate of GPR17+cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+cells at damaged areas. However, only in the cuprizone model reacting GFP+cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery