Sulfonamide-derived Dithiocarbamate Gold(i) complexes induce the apoptosis of colon cancer cells by the activation of Caspase 3 and redox imbalance

Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those with the phosphine PPh3—exhibited the highest anticancer activity whilst also displaying significant cancer cell selectivity. Au(S2CNHSO2C6H5)(PPh3)] (1) and Au(S2CNHSO2-p-Me-C6H4)(IMePropargyl)] (8) produce cell death, probably by intrinsic apoptosis (mitochondrial membrane potential modification) and caspase 3 activation, causing cell cycle arrest in the G1 phase with p53 activation. Besides this, both complexes might act as multi-target anticancer drugs, as they inhibit the activity of the enzymes thioredoxin reductase (TrxR) and carbonic anhydrase (CA IX) with the alteration of the redox balance, and show a pro-oxidant effect

The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.

In November 2004, 116 individuals in an elderly nursing home in El Grao de Castellón, Spain were symptomatically infected with genogroup II.4 (GII.4) norovirus. The global attack rate was 54.2%. Genotyping of 34 symptomatic individuals regarding the FUT2 gene revealed that one patient was, surprisingly, a non-secretor, hence indicating secretor-independent infection. Lewis genotyping revealed that Lewis-positive and negative individuals were susceptible to symptomatic norovirus infection indicating that Lewis status did not predict susceptibility. Saliva based ELISA assays were used to determine binding of the outbreak virus to saliva samples. Saliva from a secretor-negative individual bound the authentic outbreak GII.4 Valencia/2004/Es virus, but did not in contrast to secretor-positive saliva bind VLP of other strains including the GII.4 Dijon strain. Amino acid comparison of antigenic A and B sites located on the external loops of the P2 domain revealed distinct differences between the Valencia/2004/Es and Dijon strains. All three aa in each antigenic site as well as 10/11 recently identified evolutionary hot spots, were unique in the Valencia/2004/Es strain compared to the Dijon strain. To the best of our knowledge, this is the first example of symptomatic GII.4 norovirus infection of a Le(a+b-) individual homozygous for the G428A nonsense mutation in FUT2. Taken together, our study provides new insights into the host genetic susceptibility to norovirus infections and evolution of the globally dominating GII.4 viruses.Original Publication: Beatrice Carlsson, Elin Kindberg, Javier Buesa, Gustaf E Rydell, Marta Fos Lidón, Rebeca Montava, Reem Abu Mallouh, Ammi Grahn, Jesús Rodríguez-Díaz, Juan Bellido, Alberto Arnedo, Göran Larson and Lennart Svensson, The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection., 2009, PLoS ONE, (4), 5, e5593. http://dx.doi.org/10.1371/journal.pone.0005593 Licensed under Creative Common

Supplementing Maturation Medium With Insulin Growth Factor I and Vitrification-Warming Solutions With Reduced Glutathione Enhances Survival Rates and Development Ability of in vitro Matured Vitrified-Warmed Pig Oocytes

The present study sought to determine whether in vitro maturation (IVM) of pig oocytes in a medium supplemented with insulin growth factor-I (IGF-I) and subsequent vitrification with or without reduced glutathione (GSH) affect their quality and developmental competence, and the expression of genes involved in antioxidant, apoptotic and stress responses. In Experiment 1, cumulus-oocyte complexes were matured in the absence or presence of IGF-I (100 ng·mL−1) and then vitrified-warmed with or without 2 mM of GSH. Maturation rate was evaluated before vitrification, and oocyte viability, DNA fragmentation and relative transcript abundances of BCL-2-associated X protein (BAX), BCL2-like1 (BCL2L1), heat shock protein 70 (HSPA1A), glutathione peroxidase 1 (GPX1) and superoxide dismutase 1 (SOD1) genes were assessed in fresh and vitrified-warmed oocytes. In Experiment 2, fresh and vitrified-warmed oocytes were in vitro fertilized and their developmental competence determined. Whereas the addition of IGF-I to maturation medium had no effect on oocyte maturation, it caused an increase in the survival rate of vitrified-warmed oocytes. This effect was accompanied by a concomitant augment in the relative transcript abundance of HSPA1A and a decrease of BAX. Furthermore, the addition of GSH to vitrification-warming media increased survival rates at post-warming. Likewise, the action of GSH was concomitant with an increase in the relative abundance of GPX1 and a decrease of BAX transcript. Blastocyst rates of vitrified-warmed oocytes did not differ from their fresh counterparts when IGF-I and GSH were combined. In conclusion, supplementing maturation medium with 100 ng·mL−1 IGF-I and vitrification-warming solutions with 2 mM GSH improves the quality and cryotolerance of IVM pig oocytes, through a mechanism that involves BAX, GPX1 and HSPA1A expression

Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)], and compared them to neurons from an epileptic encephalopathy patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. By contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency, and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Intercultural Education through Religious Studies (IERS): COMENIUS Multilateral project

[EN] Religious and cultural diversity are today more than ever a critical and political challenge as the recent emergencies related to geo-political and economical global transformations clearly show. European countries are concerned by a big immigration flow that demands an educational effort in order to foster the mutual understanding and integration. According to Toledo guiding principles, IERS project meets the needs of an innovative approach in teaching about religions and beliefs at school by providing teachers of humanistic disciplines with new tools that help teachers and pupils to plunge deeper into religions and cultures of non-european countries, as well as raising the knowledge of the religious traditions that contributed to the common European cultural Identity, promoting it in the best way suited for encourage intra -and extra- European cultural dialogue attitudes. The Project aims to support the development of social, civic and intercultural transversal key competences by educating towards a positive understanding of cultural and religious differences, a readiness to engage in dialogue and to avoid or manage conflicts. By encouraging teachers and pupils to expose themselves to the differences and commonalities of religious topics, it promotes also the values of democracy, equality and human rights as it deals with social and civic dimensions of both intercultural and interreligious dialogue. The project will involve high school in-service teachers by developing a complete set of didactical tools and training experiences. The results will be: 1. A baseline study which analyzes the actual situation of teaching about religions throughout Europe; 2. New innovative didactic tools such as Multimedia Digital Modules to be used in classroom activities, accompanied by a Handbook with didactical guidelines for teachers. 3. Teacher support activities (virtual community, training activities, developing of didactical projects to apply in classroom)

The Role of School Social Support and School Social Climate in Dating Violence Victimization Prevention among Adolescents in Europe

The aim of the article is to show the role of school social support and school social climate in dating violence victimization prevention among adolescents in Europe. Study participants were students from secondary schools (age 13-16) in Spain, Italy, Romania, Portugal, Poland and UK. The analysis in this text concern student with dating experience (n=993) (57.2% of girls and 66.5% of boys). School social support was measured by School Social Climate, Factor 1 Scale (CECSCE) and by Student Social Support Scale (CASSS), subscales teachers and classmates. The association between school social support and different types of dating victimization (physical and/ or sexual dating violence, control dating violence and fear) was measured by calculating the prevalence ratios and their 95% confidence intervals, estimated by Poisson regression models with robust variance. All the models were adjusted by country and by sociodemographic variables. The results show that the average values of all types of social support are significantly lower in young people who have suffered any type of dating violence or were scared of their partner. The likelihood of suffering physical and/or sexual dating violence decreased when school social support increased [PR (CI95%): 0.96 (0.92; 0.99)]. In the same way, the likelihood of fear decreased when school social climate increased [PR (CI95%): 0.98 (0.96; 0.99)].There is an association between school social support and school social climate and experiences of being victim of dating violence among adolescents in Europe. Our results suggest that in the prevention of dating violence building a supportive climate at schools and building / using the support of peers and teachers is important