43 research outputs found
The role of mercury, selenium and the Se-Hg antagonism on cognitive neurodevelopment: A 40-month follow-up of the Italian mother-child PHIME cohort
Despite a 15-year long effort to define the \u201csafety\u201d of fish intake during pregnancy, there remains still uncertainty on this important public health issue. The evaluation of the toxic effects of contaminants, particularly mercury (Hg) in fish-eating populations is complicated by the fact that sea-food is also rich in beneficial nutrients, such as selenium (Se). There is toxicological plausibility of an antagonistic effects between Se and Hg, and some theoretical support for the inclusion of the Se\u2013Hg interaction to better assess the risk linked with fish intake. To assess the effects of exposure to low-level Hg through fish consumption on the developing brain and the interaction between Hg and Se, we conducted an analysis at age 40 months in Italian children, enrolled in a prospective mother-child cohort, comparing additive and multiplicative models. Participant subjects were the 470 children born within the Northern Adriatic Cohort II (NAC-II) cohort who were tested by using the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) (BSID-III) at age 40. Family demographic and socioeconomic information, pregnancy and delivery history, parental and child medical history and food consumption were assessed through questionnaires. Maternal blood samples were collected during pregnancy, cord blood at birth and maternal milk 1 month after delivery. As other exposures of interest, we considered the level of Se in maternal and cord blood and in breast milk and the potential Se\u2013Hg antagonism. Se and inverse of THg (1:THg) concentrations were categorized according to the tertiles of their distributions, in low, medium and high levels of exposure. The lower end of the composite cognitive score distribution closest to 20% was defined as suboptimal development. Multiple logistic regression were applied to assess the association between the dichotomized composite cognitive score and the categorized exposure to Se and 1:THg, and the antagonism between Se and 1:THg. In the recruiting period, 900 pregnant women were enrolled in the cohort; 767 of these remained in the study at delivery and 470 children at 40 months. After excluding preterm births, 456 children were used in the final analyses. The larger difference in risk for suboptimal neurodevelopment was observed for the category with High THg and Low Se with OR = 2.55 (90% CI 1.02; 6.41) under the multiplicative and OR = 1.33 (90% CI 0.80; 1.87) under the additive model. The category High THg and High Se showed a very slightly better fit of the additive model (OR = 1.07, 90% CI 0.65; 1.50) versus the multiplicative (OR = 1.66, 90% CI 0.73; 1.77). A negative \u2013 antagonistic \u2013 interaction term for this category was estimated under the multiplicative model giving an OR = 1.17 (90% CI 0.42; 3.28). Although this evidence of the effects of the Se\u2013Hg antagonism on the children neuro-development needs to be confirmed, if Se can counterbalance Hg toxicity, the evaluation of the effect on human health of fish consumption, should also consider the diverse ratios between Se and Hg concentration in different fish species
Nutrient intake during pregnancy and adherence to dietary recommendations: The mediterranean phime cohort
Few studies provide a detailed description of dietary habits during pregnancy, despite the central role of nutrition for the health of the mother and offspring. This paper describes the dietary habits, energy and nutrient intake in pregnant women from four countries belonging to the Mediterranean PHIME cohort (Croatia, Greece, Italy and Slovenia) and evaluates their adherence to the European Food Safety Authority (EFSA) recommendations. A total of 1436 women were included in the present analysis. Maternal diet was assessed using a food frequency questionnaire (FFQ). The mean macro and micronutrient intakes were estimated and compared with the dietary reference values (DRVs). The percentage distribution of the 16 food groups in the total intake of each macronutrient was estimated. All women shared a similar diet during pregnancy; almost all the women in the four countries exceeded the DRV for sugars, and the total fat intake was above the DRV in most women in all the countries, as was the contribution of saturated fatty acids (SFAs) to the total energy intake. In all four countries, we observed an increased risk of micronutrient deficiency for iron, folate and vitamin D. Shared guidelines, implemented at both the national and European level, are essential to improve the maternal nutritional status during pregnancy
Gene expression profiling in white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease
Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon (CRBN), a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. CRBN plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the molecular mechanisms underpinning thalidomide action in pediatric IBD. In this study, ten IBD pediatric patients responsive to thalidomide were prospectively enrolled. RNA-sequencing (RNA-seq) analysis and functional enrichment analysis were carried out on peripheral blood mononuclear cells (PBMC) obtained before and after twelve weeks of treatment with thalidomide. RNA-seq analysis revealed 378 differentially expressed genes before and after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those exposed to MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on candidate altered pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in pediatric patients with IBD, providing novel potential targets associated with drug response
Circulating TRAIL Shows a Significant Post-Partum Decline Associated to Stressful Conditions
Background: Since circulating levels of TNF-related apoptosis inducing ligand (TRAIL) may be important in the physiopathology of pregnancy, we tested the hypothesis that TRAIL levels change at delivery in response to stressful conditions. Methods/Principal Findings: We conducted a longitudinal study in a cohort of 73 women examined at week 12, week 16, delivery and in the corresponding cord blood (CB). Serum TRAIL was assessed in relationship with maternal characteristics and to biochemical parameters. TRAIL did not vary between 12 (67.6627.6 pg/ml, means6SD) and 16 (64.0616.2 pg/ml) weeks â gestation, while displaying a significant decline after partum (49.3626.4 pg/ml). Using a cut-off decline.20 pg/ml between week 12 and delivery, the subset of women with the higher decline of circulating TRAIL (41.7%) showed the following characteristics: i) nullipara, ii) higher age, iii) operational vaginal delivery or urgent CS, iv) did not receive analgesia during labor, v) induced labor. CB TRAIL was significantly higher (131.6652 pg/ml) with respect to the corresponding maternal TRAIL, and the variables significantly associated with the first quartile of CB TRAIL (,90 pg/ml) were higher prepregnancy BMI, induction of labor and fetal distress. With respect to the biochemical parameters, maternal TRAIL at delivery showed an inverse correlation with C-reactive protein (CRP), total cortisol, glycemia and insulin at bivariate analysis, but only with CRP at multivariate analysis
A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl(D139V), that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl(D139V) homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO). Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field