Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways

Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment

Expression of angiogenic regulators, VEGF and leptin, is regulated by the EGF/PI3K/STAT3 pathway in colorectal cancer cells.

Abstract Both leptin and vascular endothelial growth factor (VEGF) are growth and angiogenic cytokines that are upregulated in different types of cancer and have been implicated in neoplastic progression. Here we investigated the molecular mechanism by which leptin and VEGF expression are regulated in colon cancer by epidermal growth factor (EGF). In colon cancer cell line HT-29, EGF induced the binding of signal transducer and activator transcription 3 (STAT3) to STAT3 consensus motifs within the VEGF and leptin promoters and stimulated leptin and VEGF mRNA and protein synthesis. All these EGF effects were significantly blocked when HT-29 cells were treated with an inhibitor of the phosphoinositide 3-kinase (PI3K) pathway, LY294002, or with small interfering RNA (siRNA) targeting STAT3. Thus, our study identified the EGF/PI3K/STAT3 signaling as an essential pathway regulating VEGF and leptin expression in EGF-responsive colon cancer cells. This suggests that STAT3 pathways might constitute attractive pharmaceutical targets in colon cancer patients where anti-EGF receptor drugs are ineffective

Estabilidad y predicción de la agresión física desde la infancia hasta la adolescencia: un estudio con múltiples informantes

El objetivo del estudio es examinar la estabilidad y el valor predictivo de la agresión física y verbal evaluada por múltiples informantes (los propios niños, sus profesores y compañeros) desde la última etapa de la niñez a la adolescencia media, la convergencia entre informantes y el valor predictivo a largo plazo de la agresión física y verbal con respecto a diferentes indicadores de ajuste (rendimiento escolar, aceptación social, comportamiento prosocial) y desequilibrio (depresión, delincuencia). Como parte de un proyecto longitudinal italiano se examinaron a 372 niños (204 varones y 168 mujeres) que fueron evaluados anualmente desde el momento 1 (edad 9.5) hasta el momento 5 (edad 13.5). Los resultados evidenciaron diferencias de género en la frecuencia y estabilidad de la agresión física y verbal en las evaluaciones de los diferentes informantes. Además ponen de relieve la estabilidad de las diferencias individuales en agresión fisica y verbal y un descenso generalizado en los valores medios. Los resultados confirman aquellas hipótesis que señalan la agresión infantil referida por diferentes informantes a la edad de 9.5 años como un factor de riesgo que anticipa diferentes manifestaciones desadaptativas futuras

Three-dimensional geometrical models of the inguinal region. Towards a new stereology

In this work we studied the inguinal-abdominal region and the inguinal canal using three-dimensional geometrical models. We built the models through computer aided geometric modeling techniques on the basis of observations during real dissections, operations and diagnostic medical imaging. The obtained models show in a complete modular synthesis and with a schematic iconology the structural organization of the anatomical districts in a logic sequence of layers and topographic and spatial relationships among its components. The models represent an amazing support to anatomy and clinical anatomy for teaching and research purposes on organogenesis, surgery and diagnosis

Exploring the protective function of positivity and regulatory emotional self-efficacy in time of pandemic covid-19

Despite several empirical studies on the 2019 coronavirus disease (COVID-19) pandemic that have highlighted its detrimental effect on individuals’ mental health, the identification of psychological factors that may moderate its impact on individuals’ behavior and well-being remains partly unexplored. The present study was conceived to examine the mediation role of regulatory emotional self-efficacy in the relationship between positivity and anxiety, depression, and perceived self-efficacy in complying with the containment measures to contrast the COVID-19 spread. Furthermore, the moderation role of age was tested. A sample of 1258 participants (64.2% women; Mage = 42.09, SD = 13.62) enrolled from the Italian general population answered an online survey aimed at investigating the role of individual differences in facing the COVID-19 pandemic. We opted for a snowball recruiting procedure to find participants. The online survey was disseminated through email invitation and using social media platforms (i.e., Facebook, Instagram). A multi-group path analysis model was performed using Mplus 8.4 to explore the hypothesized relations among variables. The following criteria were employed to evaluate the goodness of fit: χ2 likelihood ratio statistic, CFI and TLI > 0.95, RMSEA < 0.06 and SRMR < 0.08. The findings corroborated the protective role of both positivity and regulatory emotional self-efficacy in reducing individuals’ anxiety and depressive symptoms, as well as in fostering individuals’ capabilities in complying with the containment measures imposed by the government to reduce the risk of illness and to contain the spread of the virus COVID-19. Specifically, regulatory emotional self-efficacy beliefs partially mediated the relations between positivity and anxiety and depressive symptoms and fully mediated the effect of positivity on perceived self-efficacy beliefs in complying with the containment measures. These paths were equal across ages. The results of the present study appear relevant to implementing psychological interventions aimed to reduce the deleterious effects of the COVID-19 pandemic on mental health through the promotion of individuals’ optimistic orientation and emotion regulation

Pur-alpha functionally interacts with FUS carrying ALS-associated mutations

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function

Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS

Development and characterization of iron-pectin beads as a novel system for iron delivery to intestinal cells

Iron deficiency is the most common nutritional deficit worldwide. The goal of this work was to obtain iron-pectin beads by ionic gelation and evaluate their physiological behavior to support their potential application in the food industry. The beads were firstly analyzed by scanning electronic microscopy, and then physical-chemically characterized by performing swelling, thermogravimetric, porosimetry, Mössbauer spectroscopy and X-ray fluorescence analyses, as well as by determining the particle size. Then, physiological assays were carried out by exposing the beads to simulated gastric and intestinal environments, and determining the iron absorption and transepithelial transport into Caco-2/TC7 cells. Iron-pectin beads were spherical (diameter 1-2 mm), with high density (1.29 g/mL) and porosity (93.28%) at low pressure, indicating their high permeability even when exposed to low pressure. Swelling in simulated intestinal medium (pH 8) was higher than in simulated gastric medium. The source of iron [FeSO4 (control) or iron-pectin beads] did not have any significant effect on the mineral absorption. Regarding transport, the iron added to the apical pole of Caco-2/TC7 monolayers was recovered in the basal compartment, and this was proportional with the exposure time. After 4 h of incubation, the transport of iron arising from the beads was significantly higher than that of the iron from the control (FeSO4). For this reason, iron-pectin beads appear as an interesting system to overcome the low efficiency of iron transport, being a potential strategy to enrich food products with iron, without altering the sensory properties.Centro de Investigación y Desarrollo en Criotecnología de Alimento