Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents

<p>Abstract</p> <p>Background</p> <p>Insulin resistance is the primary metabolic disorder associated with obesity; yet little is known about its role as a determinant of the metabolic syndrome in obese children. The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among obese children and adolescents.</p> <p>Methods</p> <p>An analytical, cross-sectional and population-based study was performed in forty-four public primary schools in Campeche City, Mexico. A total of 466 obese children and adolescents between 11-13 years of age were recruited. Fasting glucose and insulin concentrations, high density lipoprotein cholesterol, triglycerides, waist circumference, systolic and diastolic blood pressures were measured; insulin resistance and metabolic syndrome were also evaluated.</p> <p>Results</p> <p>Out of the total population studied, 69% presented low values of high density lipoprotein cholesterol, 49% suffered from abdominal obesity, 29% had hypertriglyceridemia, 8% presented high systolic and 13% high diastolic blood pressure, 4% showed impaired fasting glucose, 51% presented insulin resistance and 20% metabolic syndrome. In spite of being obese, 13% of the investigated population did not present any metabolic disorder. For each one of the components of the metabolic syndrome, when insulin resistance increased so did odds ratios as cardiometabolic risk factors.</p> <p>Conclusions</p> <p>Regardless of age and gender an increased degree of insulin resistance is associated with a higher prevalence of disorders in each of the components of the metabolic syndrome and with a heightened risk of suffering metabolic syndrome among obese children and adolescents.</p

Fructooligosacharides Reduce Pseudomonas aeruginosa PAO1 Pathogenicity through Distinct Mechanisms

Pseudomonas aeruginosa is ubiquitously present in the environment and acts as an opportunistic pathogen on humans, animals and plants. We report here the effects of the prebiotic polysaccharide inulin and its hydrolysed form FOS on this bacterium. FOS was found to inhibit bacterial growth of strain PAO1, while inulin did not affect growth rate or yield in a significant manner. Inulin stimulated biofilm formation, whereas a dramatic reduction of the biofilm formation was observed in the presence of FOS. Similar opposing effects were observed for bacterial motility, where FOS inhibited the swarming and twitching behaviour whereas inulin caused its stimulation. In co-cultures with eukaryotic cells (macrophages) FOS and, to a lesser extent, inulin reduced the secretion of the inflammatory cytokines IL-6, IL-10 and TNF- a . Western blot experiments indicated that the effects mediated by FOS in macrophages are associated with a decreased activation of the NF- k B pathway. Since FOS and inulin stimulate pathway activation in the absence of bacteria, the FOS mediated effect is likely to be of indirect nature, such as via a reduction of bacterial virulence. Further, this modulatory effect is observed also with the highly virulent ptxS mutated strain. Co-culture experiments of P. aeruginosa with IEC18 eukaryotic cells showed that FOS reduces the concentration of the major virulence factor, exotoxin A, suggesting that this is a possible mechanism for the reduction of pathogenicity. The potential of these compounds as components of antibacterial and anti-inflammatory cocktails is discussed.The authors acknowledge financial support from FEDER funds and Fondo Social Europeo through grants from the Spanish Ministry of Economy and Competitiveness (grants SAF2011-22922, SAF2011-22812) the Andalusian regional government Junta de Andalucía (grant CVI-7335) and the Centre of Networked Biomedical Research on Hepatic and Digestive Diseases (CIBERehd) which is funded by the Carlos III Health Institute and the Ramón Areces Foundation, Spain

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

Novel Disease Susceptibility Factors for Fungal Necrotrophic Pathogens in Arabidopsis

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens.Funding: This work was supported by the Spanish MINECO (BFU2012 to PV), and Generalitat Valenciana (Prometeo2014/020 to PV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Dobón Alonso, A.; Canet Perez, JV.; García-Andrade Serrano, J.; Angulo, C.; Neumetzler, L.; Persson, S.; Vera Vera, P. (2015). Novel Disease Susceptibility Factors for Fungal Necrotrophic Pathogens in Arabidopsis. PLoS Pathogens. 11(4):1-30. https://doi.org/10.1371/journal.ppat.1004800S13011