Antibacterial activity and mode of action of selected glucosinolate hydrolysis products against bacterial pathogens

Plants contain numerous components that are important sources of new bioactive molecules with antimicrobial properties. Isothiocyanates (ITCs) are plant secondary metabolites found in cruciferous vegetables that are arising as promising antimicrobial agents in food industry. The aim of this study was to assess the antibacterial activity of two isothiocyanates (ITCs), allylisothiocyanate (AITC) and 2-phenylethylisothiocyanate (PEITC) against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes. The antibacterial mode of action was also characterized by the assessment of different physiological indices: membrane integrity, intracellular potassium release, physicochemical surface properties and surface charge. The minimum inhibitory concentration (MIC) of AITC and PEITC was 100 g/mL for all bacteria. The minimum bactericidal concentration (MBC) of the ITCs was at least 10 times higher than the MIC. Both AITC and PEITC changed the membrane properties of the bacteria decreasing their surface charge and compromising the integrity of the cytoplasmatic membrane with consequent potassium leakage and propidium iodide uptake. The surface hydrophobicity was also non-specifically altered (E. coli and L. monocytogenes become less hydrophilic; P. aeruginosa and S. aureus become more hydrophilic). This study shows that AITC and PEITC have strong antimicrobial potential against the bacteria tested, through the disruption of the bacterial cell membranes. Moreover, phytochemicals are highlighted as a valuable sustainable source of new bioactive products.This work was supported by the Operational Programme for Competitiveness Factors - COMPETE and by the Portuguese Foundation for Science and Technology through Project Phytodisinfectants - PTDC/DTP-SAP/1078/2012 (COMPETE: FCOMP-01-0124-FEDER-028765), the PhD grant awarded to Ana Abreu (SFRH/BD/84393/2012), and the post-doctoral grants awarded to Anabela Borges (SFRH/BPD/98684/2013) and Lucia C. Simoes (SFRH/BPD/81982/2011). Also, this work was undertaken as part of the European Research Project SUSCLEAN (Contract no FP7-KBBE-2011-5, project number: 287514) and the COST Action FA1202. The authors are solely responsible for this work. It does not represent the opinion of the European Community, and the Community is not responsible for any use that might be made of data appearing herein

A Sox2–Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells

Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio

Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

PURPOSE: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. METHODS: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses. RESULTS: Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina. CONCLUSION: Our results provide a link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, an in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells

Necrolytic acral erythema: a rare skin disease associated with hepatitis C virus infection

Abstract: Necrolytic acral erythema is a rare skin disease associated with hepatitis C virus infection. We report a case of a 31-year-old woman with hepatitis C virus infection and decreased zinc serum level. Physical examination revealed scaly, lichenified plaques, well-demarcated with an erythematous peripheral rim located on the lower limbs. After blood transfusion and oral zinc supplementation the patient presented an improvement of lesions

Alteração vocal auto-referida em professores: prevalência e fatores associados

OBJETIVO: Estimar a prevalência de alteração vocal auto-referida em professores e identificar fatores associados. MÉTODOS: Estudo transversal com amostra de 393 professores do ensino fundamental de Florianópolis, SC, por meio de questionário autoaplicado em 2009. Foi realizada análise multivariável de regressão de Poisson estimando-se as razões de prevalência e intervalos de 95% de confiança. RESULTADOS: A prevalência de alteração vocal foi de 47,6% (IC95% 42,6;52,5). Após o ajuste, permaneceram associados à maior prevalência de alteração vocal ser do sexo feminino e a presença de rinite/sinusite e faringite. CONCLUSÕES: Foi observada elevada prevalência de alteração vocal auto-referida entre os professores estudados.OBJETIVO: Estimar la prevalencia de alteración vocal auto-referida en profesores e identificar factores asociados. MÉTODOS: Estudio transversal con muestra de 393 profesores de enseñanza fundamental de Florianópolis, Sur de Brasil, por medio de cuestionario auto-aplicado en 2009. Se realizó análisis multivariable de regresión de Poisson, estimándose las tasas de prevalencia e intervalos de 95% de confianza. RESULTADOS: La prevalencia de alteración vocal fue de 47,6% (IC95% 42,6;52,5). Posterior al ajuste, permanecieron asociados a la mayor prevalencia de alteración vocal ser del sexo femenino y la presencia de rinitis/sinusitis y faringitis. CONCLUSIONES: Se observó elevada prevalencia de alteración vocal auto-referida entre los profesores estudiados.OBJECTIVE: To estimate the prevalence of self-reported voice problems and to identify associated factors. METHODS: A cross-sectional study was carried out in a sample of 393 public elementary and middle school teachers in Florianópolis, Southern Brazil, in 2009. A self-administered questionnaire was used. A multivariable Poisson regression model was performed to estimate prevalence ratios and their related 95% confidence intervals. RESULTS: The prevalence of voice problems was 47.6% (95%CI 42.6;52.5). In the final adjusted analysis the following variables remained associated with a higher prevalence of voice problems: being female and the presence of rhinitis/sinusitis and pharyngitis. CONCLUSIONS: A high prevalence of self-reported voice problems was found among the teachers studied

Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of <it>CDH1 </it>germline mutations in gastric cancers coming from low- and high-risk areas.</p> <p>Methods</p> <p>English articles using MEDLINE access (from 1998 to 2011). Search terms included <it>CDH1</it>, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.</p> <p>The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.</p> <p>The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the <it>CDH1 </it>mutation frequency with gastric cancer incidence areas.</p> <p>Results</p> <p>A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (<it>p </it>< 0.001: overall identified mutations in low- vs. middle/high-risk areas).</p> <p>Conclusions</p> <p>E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of <it>CDH1 </it>germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the <it>CDH1 </it>genetic screening, geographic variability, alongside the family history should be considered.</p