Dynamic DNA methylation in the brain: a new epigenetic mark for experience-dependent plasticity

Experience-dependent plasticity is the ability of brain circuits to undergo molecular, structural and functional changes as a function of neural activity. Neural activity continuously shapes our brain during all the stages of our life, from infancy through adulthood and beyond. Epigenetic modifications of histone proteins and DNA seem to be a leading molecular mechanism to modulate the transcriptional changes underlying the fine-tuning of synaptic connections and circuitry rewiring during activity-dependent plasticity. The recent discovery that cytosine methylation is an epigenetic mark particularly dynamic in brain cells has strongly increased the interest of neuroscientists in understanding the role of covalent modifications of DNA in activity-induced remodeling of neuronal circuits. Here, we provide an overview of the role of DNA methylation and hydroxylmethylation in brain plasticity both during adulthood, with emphasis on learning and memory related processes, and during postnatal development, focusing specifically on experience-dependent plasticity in the visual cortex

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations

Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma

Patients with metastatic melanoma bearing V600 mutations in BRAF oncogene clinically benefit from the treatment with BRAF inhibitors alone or in combination with MEK inhibitors. However, a limitation to such treatment is the occurrence of resistance. Tackling the adaptive changes helping cells survive from drug treatment may offer new therapeutic opportunities. Very recently the ErbB3 receptor has been shown to act as a central node promoting survival of BRAF mutated melanoma. In this paper we first demonstrate that ErbB3/AKT hyperphosphorylation occurs in BRAF mutated melanoma cell lines following exposure to BRAF and/or MEK inhibitors. This strongly correlates with increased transcriptional activation of its ligand neuregulin. Anti-ErbB3 antibodies impair the establishment of de novo cell resistance to BRAF inhibition in vitro. In order to more potently ablate ErbB3 activity we used a combination of two anti-ErbB3 antibodies directed against distinct epitopes of its extracellular domain. These two antibodies in combo with BRAF/MEK inhibitors potently inhibit in vitro cell growth and tumor regrowth after drug withdrawal in an in vivo xenograft model. Importantly, residual tumor masses from mice treated by the antibodies and BRAF/ERK inhibitors combo are characterized almost exclusively by large necrotic areas with limited residual areas of tumor growth. Taken together, our findings support the concept that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma

Pediatric Obesity and Eating Disorders Symptoms: The Role of the Multidisciplinary Treatment. A Systematic Review

The prevalence of obesity in children/adolescents has increased worldwide during the past 30 years, becoming a significant public health concern; prevention, and management of pediatric obesity onset is one of the most critical public health goals for both industrialized and developing countries. Pediatric obesity has been identified as a risk factor for various psychopathologies, including eating disorders (ED). Although it has been demonstrated that a comprehensive multidisciplinary treatment (MT), with small steps and practical approaches to lifestyle change, can be an effective treatment for children and adolescents with obesity, to the best of our knowledge, this is the first systematic review investigating the effect of MT on the development, progression or decrease of ED symptoms (EDS) in this target population. PubMed and Web of Science databases were searched (last search on 18 February 2019) according to a predetermined search strategy, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines and Statement. Original studies published in English examining the effect of MT on pediatric overweight/obesity, paying particularly attention at the development of EDS, were eligible for inclusion. Seven hundred and forty-four records have been identified; nine articles with study quality ranging from weak to moderate have been included. MTs were heterogeneous in nature including length, number, frequency and type of sessions, parent-involvement and use of technology, besides several psychometric questionnaires were used to screen for EDS, since there are no standardized criteria. In 3 studies there was a significant decrease in external and emotional eating and in four studies a significant increase in restraint eating post MT. Two studies found a significant decrease of binge eating symptoms and other two studies showed an improvement of self-perception, weight, and shape concern. A statistical significant decrease in BMI, BMIz, BMISDS, and adjusted BMI was observed after all MTs, except one. A narrative summary of the evidences reported highlighted the positive impact of MT on the EDS. Moreover, since weight loss post MTs was not necessarily related to EDS, clinicians should also look for the presence of EDS and treat them accordingly

Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury

The liver is susceptible to such oxidative and metabolic stresses as ischemia-reperfusion (I/R) and fatty acid accumulation. Probiotics are viable microorganisms that restore the gut microbiota and exert a beneficial effect on the liver by inhibiting bacterial enzymes, stimulating immunity, and protecting intestinal permeability. We evaluated Lactobacillus paracasei F19 (LP-F19), for its potential protective effect, in an experimental model of I/R (30 min ischemia and 60 min reperfusion) in rats fed a standard diet or a steatogen [methionine/choline-deficient (MCD)] diet. Both groups consisted of 7 sham-operated rats, 10 rats that underwent I/R, and 10 that underwent I/R plus 8 wk of probiotic dietary supplementation. In rats fed a standard diet, I/R induced a decrease in sinusoid perfusion (P < 0.001), severe liver inflammation, and necrosis besides an increase of tissue levels of malondialdehyde (P < 0.001), tumor necrosis factor-alpha (P < 0.001), interleukin (IL)-1beta (P < 0.001), and IL-6 (P < 0.001) and of serum levels of transaminase (P < 0.001) and lipopolysaccharides (P < 0.001) vs. sham-operated rats. I/R also induced a decrease in Bacterioides, Bifidobacterium, and Lactobacillus spps (P < 0.01, P < 0.001, and P < 0.001, respectively) and an increase in Enterococcus and Enterobacteriaceae (P < 0.01 and P < 0.001, respectively) on intestinal mucosa. The severity of liver and gut microbiota alterations induced by I/R was even greater in rats with liver inflammation and steatosis, i.e., MCD-fed animals. LP-F19 supplementation significantly reduced the harmful effects of I/R on the liver and on gut microbiota in both groups of rats, although the effect was slightly less in MCD-fed animals. In conclusion, LP-F19 supplementation, by restoring gut microbiota, attenuated I/R-related liver injury, particularly in the absence of steatosis

Aleitamento materno: benefícios e fatores associados

RESUMO: O aleitamento materno consiste no contato direto entre a mãe e o bebê para o exercício da amamentação e configura-se como um fator importante para o desenvolvimento saudável do lactente. Este trabalho tem como objetivo abordar os benefícios da amamentação para a criança e para a nutriz, bem como alguns fatores relacionados ao aleitamento materno. A metodologia utilizada foi um levantamento de cinco artigos em língua portuguesa e inglesa, publicados entre os anos de 2012 a 2015 no banco de dados SciELO, PubMED e Google Acadêmico. Os resultados demonstram inúmeros benefícios do aleitamento materno à saúde do lactente, bem como para a saúde da nutriz. Para a criança, a amamentação contribuiu para o desenvolvimento neurológico, nutricional, metabólico, orofacial adequados e à prevenção de doenças gastrointestinais, distúrbios nutricionais e alergias. Nas mães, os benefícios mais comuns foram prevenção de câncer de ovário, mama, prevenção de osteoporose e diminuição do risco de hemorragia pós-parto. Os resultados sobre os fatores secundários que se relacionam à prática do aleitamento estão relacionados a aspectos culturais, biológicos e psicossociais. Conclui-se, portanto, que a amamentação é essencial para o desenvolvimento imunológico e craniofacial do lactente, prevenção da obesidade e é relacionado com a redução da mortalidade neonatal. No entanto, é possível evidenciar barreiras biológicas, psicossociais e culturais que interferem na prática da amamentação. Posto isso, é necessário a ação conjunta de programas públicos e profissionais de saúde para ampliar o conhecimento da sociedade em geral acerca dos pontos positivos da amamentação.Palavras-chave:Aleitamento Materno. Benefícios. Amamentação

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.</p

DNA methylation and its role in cortical plasticity.

During brain development there are periods, called critical or sensitive period, in which specific regions are highly plastic and learning occurs more readily and more permanently than during adulthood. If during this period abnormal stimulation causes altered circuits development, there are permanent damage to the brain as is the case of amblyopia. Understanding the molecular and genetic mechanisms underlying sensitive period plasticity could lead to clinical therapies for such disorders through reopening sensitive periods and allowing plasticity to reoccur. Ocular dominance plasticity is the most used paradigm of experience-dependent plasticity and occurs in primary visual cortex, when one eye is closed (monocular deprivation) for several days during critical period. Since the first investigation of critical period by Hubel and Wiesel, much work has been done to discover which factors are involved. A flurry of studies demonstrate that experience-dependent plasticity is initiated when neuronal activation triggers intracellular signalling pathways, from the synapse to the nucleus, that modulate gene expression. The gene expression products modelling the neuronal circuits. But how is the gene expression molecular modulates? Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the regulation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood. In this work, I analyzed whether, similarly to the establishment of cellular identity during development, epigenetic DNA modifications are used by experience-dependent plasticity to permanently modulate the neuronal gene expression and neuronal circuit formation. I first analyzed DNA methyltransferases (DNMTs) expression after 3 days of monocular deprivation, a protocol resulting in a reduction of neurons responding to the deprived eye in the binocular visual cortex . I found that monocular deprivation induced a significant increase of all the three DNMTs. The block of these enzymes with a pharmacological inhibitor (RG108) prevented the effects of monocular deprivation as demonstrated by using electrophysiological recordings. At molecular level, I analyzed the promoters of two plasticity genes previously known to be downregulated during monocular deprivation containing CpG sites, Bdnf exIV and miR132-212. I found that methylation at CpG sites upstream Bdnf exIV and some in the locus miR212-132 was significant increased during monocular deprivation and RG108 contrasted the downregulation of Bdnf exIV and mR132-212 genes. I showed that visual experience regulation of plasticity-related genes involves mechanisms of DNA methylation. These mechanisms are indispensable for cortical plasticity tested using a classical model of developmental plasticity i.e. ocular dominance plasticity in monocularly deprived juvenile mice