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1.
Epigenomics ; 12(5): 455-469, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32267165

RESUMO

Epigenetics regulate gene function without any alteration in the DNA sequence. The epigenetics represent one of the most important regulators in different cellular processes and have initially been developed in microorganisms as a protective strategy. The evaluation of the epigenetic mechanisms is also important in achieving an efficient control strategy in tuberculosis (TB). TB is one of the most significant epidemiological concerns in human history. Despite several in vivo and in vitro studies that have evaluated different epigenetic modifications in TB, many aspects of the association between epigenetics and TB are not fully understood. The current paper is aimed at reviewing our knowledge on histone modifications and DNA methylation modifications, as well as miRNAs regulation in TB.

2.
Epigenetics ; 15(8): 781-799, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32019393

RESUMO

The Presenilin1 (PSEN1) gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-ß protein precursor (AßPP), to generate the amyloid-ß (Aß) peptides, involved in Alzheimer's Disease (AD). Other substrates of the γ-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences PSEN1 expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the PSEN1 5'-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. PSEN1 expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher PSEN1 expression during brain development and in disease progression. PSEN1 methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in PSEN1 CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of γ-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that PSEN1 DNA methylation in peripheral blood may provide a biomarker for AD.

3.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023814

RESUMO

Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid-ß (Aß) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aß across the blood-brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aß load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aß transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aß transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aß clearance. Finally, the combined use of KBs promotes Aß efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aß clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

4.
Biochimie ; 173: 12-16, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32061806

RESUMO

The short, non-coding RNAs, also called microRNAs (miRNAs) can bind complementary sequences on cellular mRNAs. The consequence of this binding is generally the degradation of mRNA and the inhibition of its translation. For this reason, miRNAs are included among the epigenetic factors acting as a modulator of gene expression. How miRNAs expression is, in turn, regulated is still the object of active investigation, but DNA methylation, another epigenetic modification, seems to play a central role in this sense. The "one-carbon" metabolism is responsible for the metabolic regulation of trans-methylation reactions and, therefore, DNA methylation. For this reason, to investigate the possible correlations between alterations of the one-carbon metabolism and differential DNA methylation sounds interesting. Moreover, recent evidence indicates that, vice-versa, miRNAs are associated with DNA methylation modulation, in a mutual cross-talk. The present review will discuss the interplay between miRNAs and DNA methylation and its fall-out on gene expression regulation.

5.
Sci Total Environ ; 709: 136209, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31884276

RESUMO

Most of the leftovers from agricultural productions and industrial processing of vegetables are currently discarded as waste, augmenting production costs and environmental impacts. Black soldier flies (BSF) are non-pest insects that can grow on various types of organic materials. The larvae initially act as fast and efficient bioconverters, before being further valorized as biomass rich in proteins, fats and chitin. The aim of the present study was to exploit the potential of BSF prepupae reared on vegetable leftovers with high seasonality, and to obtain compounds with high added value and further industrial and agronomic uses such as food/feed, soil improver or fuel. The optimization of BSF rearing substrates based on different leftovers combinations was performed through a Mixture Design approach. Initially, a database was built detailing the availability, seasonality and nutrient composition of the vegetable by-products. According to the seasonal availability of the agri-food leftovers, three main groups were identified: annual, summer and autumn mixtures, in order to promote the exploitation of the highest quantity of leftovers. This approach allowed the obtainment of statistically reliable correlations (R2 > 0.75) between the employed leftovers and the content of lipid and nitrogen compounds (protein and chitin) of the BSF prepupae. In particular, a mixture of vegetable leftovers available in autumn that included legume (25 wt%), cereal (20 wt%) and vegetable (25 wt%) wastes proved to be the best combination in terms of insect growth (-25% development time compared to the control group) and nutritional composition. The chemical composition of the insect biomass allowed the identification of potential applications with high added value, such as food ingredients (protein and fats) or nutraceuticals (chitin). The identification of the optimal parameters to ensure the greatest possible efficiency would promote the scale-up of BSF rearing to an industrial level.


Assuntos
Simuliidae , Animais , Biomassa , Larva , Estações do Ano , Verduras
6.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842376

RESUMO

The functional role of cytosine methylation in the CpG moieties of DNA, is well established in several biological functions. The interplay between CpG methylation and hypomethylation is a well-known mechanism of modulation of gene expression. However, the role of non-CpG methylation and active dynamics of demethylation is not clearly recognized. Although some evidence exists of a role of active non-CpG demethylation in the fast dynamics of transcriptional activation in animals, few studies deal with this topic. At present, active demethylation of non-CpG moieties is a neglected research area, in spite of the promise of significant novelties.


Assuntos
Ilhas de CpG , Metilação de DNA , Epigênese Genética , Animais , Desmetilação , Regulação da Expressão Gênica
7.
Artigo em Inglês | MEDLINE | ID: mdl-31202182

RESUMO

The multifactorial nature of Late Onset Alzheimer's Disease (LOAD), the AD form of major relevance on epidemiological and social aspects, has driven the original investigation by LC-MS and top-down proteomics approach of the protein repertoire of the brain tissue of TgCRND8 model mice fed with a diet deficient in B vitamins. The analysis of the acid-soluble fraction of brain tissue homogenates identified a list of proteins and peptides, proteoforms and PTMs. In order to disclose possible modulations, their relative quantification in wild type and AD model mice under both B vitamin deficient and control diets was performed. The levels of metallothionein III, guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 and brain acid soluble protein 1 showed statistically significant alterations depending on genotype, diet or both effects, respectively. Particularly, metallothionein III exhibited increased levels in TgCRND8 mice under B vitamin deficient diet with respect to wild type mice under both diets. Brain acid soluble protein 1 showed the opposite, revealing decreased levels in all diet groups of AD model mice with respect to wild type mice in control diet. Lower levels of brain acid soluble protein 1 were also observed in wild type mice under deficiency of B vitamins. These results, besides contributing to increase the knowledge of AD at molecular level, give new suggestions for deeply investigating metallothionein III and brain acid soluble protein 1 in AD.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , Proteoma/metabolismo , Complexo Vitamínico B/análise , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Química Encefálica , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Cromatografia Líquida , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/genética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteoma/química , Proteoma/genética , Complexo Vitamínico B/metabolismo
8.
Neuropharmacology ; 160: 107664, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175878

RESUMO

Post-traumatic stress disorder (PTSD) is a mental disorder characterized by symptoms of persistent anxiety arising after exposure to traumatic events. Stress susceptibility due to a complex interplay between genetic and environmental factors plays a major role in the disease etiology, although biological underpinnings have not been clarified. We hypothesized that aberrant functionality of the methyl-CpG binding protein 2 (MECP2), a master regulator of experience-dependent epigenetic programming, confers susceptibility to develop PTSD-like symptomatology in the aftermath of traumatic events. Transgenic male mice expressing a truncated form of MeCP2 protein (MeCP2-308) were exposed at adulthood to a trauma in the form of high-intensity footshocks. The presence and duration of PTSD-like symptoms were assessed and compared to those of trauma-exposed wild type littermates and MeCP2-308 mice subjected to a mild stressor. The effects of fluoxetine, a prime pharmacological PTSD treatment, on PTSD-like symptomatology were also explored. Trauma-exposed MeCP2-308 mice showed long-lasting hyperresponsiveness to both correct and incorrect predictors of the trauma and persistent increased avoidance of trauma-related cues. Traumatized MeCP2-308 mice also displayed abnormal post-traumatic plasma levels of the stress hormone corticosterone and altered peripheral gene expression mirroring that of PTSD patients. Fluoxetine improved PTSD-like symptoms in trauma-exposed MeCP2-308 mice. These findings provide evidence that MeCP2 dysfunction results in increased susceptibility to develop PTSD-like symptoms after trauma exposure, and identify trauma-exposed MeCP2-308 mice as a new tool to investigate the underpinnings of PTSD vulnerability.

9.
Curr Nutr Rep ; 8(2): 74-82, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30887425

RESUMO

PURPOSE OF REVIEW: Unraveling the diet-epigenetics-neurodegeneration connection may disclose associated mechanisms and novel approaches to the neurodegenerative diseases. This review summarizes the basic concepts and the innovative results in this field focusing on the relevance of non-CpG methylation. RECENT FINDINGS: Many multifactorial neurodegenerative diseases are associated with epigenetic changes, and the brain seems more prone to epigenetic changes than other tissues. Several environmental factors induce epigenetic modulation in the organisms: diet and nutrition retain a high capacity to modulate the epigenetic traits. Finally, unexpected, specific, and functional non-CpG methylation in the brain was identified. Non-CpG methylation modulates brain expression of genes especially in promoters characterized by low-density CpGs distribution. These genes appear more prone to the epigenetic effect of environmental factors, i.e., diet, possibly inducing neurodegenerative processes. Understanding these processes could help in setting nutritional intervention aimed at contrasting neurodegenerative diseases.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Dieta/efeitos adversos , Epigênese Genética/genética , Doenças Neurodegenerativas/genética , Encéfalo , Epigenômica , Regulação da Expressão Gênica , Humanos , Estado Nutricional , Regiões Promotoras Genéticas
10.
Reprod Sci ; 26(1): 128-138, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29631479

RESUMO

α-Lipoic acid (ALA) is a safe natural molecule involved in the immunomodulation of many physiological processes. Orally administered ALA has been reported to treat several inflammatory pathologies and support pregnancy. Our study aimed at testing ALA vaginal administration in female Wistar rats evaluating its tissue distribution (experiment I), impact on implantation process (experiment II), and effectiveness in contrasting induced preterm birth (experiment III). In experiment I, rats were intravaginally treated with 50 mg/kg or 500 mg/kg ALA, or with a physiologic solution, for 4 days. α-Lipoic acid distribution in uterus and cervical tissues was evaluated by immunohistochemical analyses. In experiment II, rats received intravaginally the above treatments for 5 days, then they were mated and, if pregnant, included in the experiment to evaluate both implantation rate and the content of implantation mediators in uterus tissues. In experiment III, pregnant rats were pretreated with placebo or with vaginal ALA for 4 days and then induced to delivery with mifepristone plus PGE2 on the 19th day of pregnancy. The delivery time was recorded, and the messenger RNA (mRNA) levels of pro-inflammatory cytokines were detected in the uterine tissues by real-time polymerase chain reaction. Immunohistochemistry was also performed. Results showed that vaginal ALA was well absorbed and distributed. The treatment did not affect the implantation process and was able to significantly revert mifepristone plus prostaglandin E2 effects, delaying the timing of delivery and significantly decreasing mRNA synthesis and release of pro-inflammatory cytokines. We provide for the first time new information on vaginal ALA use, even during pregnancy, opening a perspective for further studies.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Implantação do Embrião/efeitos dos fármacos , Inflamação/tratamento farmacológico , Nascimento Prematuro/tratamento farmacológico , Ácido Tióctico/administração & dosagem , Administração Intravaginal , Animais , Colo do Útero/efeitos dos fármacos , Feminino , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Gravidez , Ratos Wistar , Distribuição Tecidual , Útero/efeitos dos fármacos
11.
J Cell Physiol ; 233(4): 3093-3104, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28802016

RESUMO

We previously demonstrated that the nuclear form of Glutathione peroxidase 4 (nGPx4) has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome and that sperm lacking nGPx4 are more prone to decondensation in vitro. In this study we have hypothesized that sperm retained acetylated histones and nGPx4 are implicated in paternal chromatin decondensation and male pronucleus formation at fertilization. Indeed, significant higher amounts of acetylated histone H4 and acetylated histone H3 were observed by both immunofluorescence and western blotting in nGPx4-KO sperm vs WT ones. In vitro fertilization of zona pellucida-deprived oocytes by WT sperm in the presence of trichostatin (TSA) also demonstrated that paternal histone acetylation was inversely related to the timing of sperm nucleus decondensation at fertilization. In contrast, TSA had no effect on nGPx4-KO sperm, indicating they had a maximal level of histone acetylation. Moreover the paternally imprinted gene Igf2/H19 was hypomethylated in KO sperm compared to WT ones. The lack of nGPx4 negatively affected male fertility, causing a marked decrease in total pups and pregnancies with delivery, a significant reduction in pronuclei (PN) embryos in in vitro fertilization assays and an approximately 2 h delay in egg fertilization in vivo. Because the zona pellucida binding and fusion to oolemma of nGPx4-KO and WT sperm were similar, the subfertility of nGPx4 sperm reflected a decreased sperm progression through egg cumulus/zona pellucida, pinpointing a defective acrosome in line with acrosomal nGPx4 localization. We conclude that paternal acetylated histones and acrosomal nGPx4 are directly involved in fertilization.


Assuntos
Núcleo Celular/metabolismo , Fertilização , Glutationa Peroxidase/metabolismo , Histonas/metabolismo , Espermatozoides/metabolismo , Acetilação , Animais , Cromatina/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Epididimo/metabolismo , Fertilidade , Fertilização In Vitro , Impressão Genômica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Isoformas de Proteínas/metabolismo , Zona Pelúcida/metabolismo
12.
Antioxidants (Basel) ; 6(4)2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28973985

RESUMO

Recent evidence emphasizes the role of dysregulated one-carbon metabolism in Alzheimer's Disease (AD). Exploiting a nutritional B-vitamin deficiency paradigm, we have previously shown that PSEN1 and BACE1 activity is modulated by one-carbon metabolism, leading to increased amyloid production. We have also demonstrated that S-adenosylmethionine (SAM) supplementation contrasted the AD-like features, induced by B-vitamin deficiency. In the present study, we expanded these observations by investigating the effects of SAM and SOD (Superoxide dismutase) association. TgCRND8 AD mice were fed either with a control or B-vitamin deficient diet, with or without oral supplementation of SAM + SOD. We measured oxidative stress by lipid peroxidation assay, PSEN1 and BACE1 expression by Real-Time Polymerase Chain Reaction (PCR), amyloid deposition by ELISA assays and immunohistochemistry. We found that SAM + SOD supplementation prevents the exacerbation of AD-like features induced by B vitamin deficiency, showing synergistic effects compared to either SAM or SOD alone. SAM + SOD supplementation also contrasts the amyloid deposition typically observed in TgCRND8 mice. Although the mechanisms underlying the beneficial effect of exogenous SOD remain to be elucidated, our findings identify that the combination of SAM + SOD could be carefully considered as co-adjuvant of current AD therapies.

13.
Antioxidants (Basel) ; 6(4)2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28954414

RESUMO

Alpha-lipoic acid (ALA) is a pleiotropic molecule with antioxidant and anti-inflammatory properties, of which the effects are exerted through the modulation of NF-kB. This nuclear factor, in fact, modulates different inflammatory cytokines, including IL-1b and IL-6, in different tissues and cell types. We recently showed that IL-1b and IL-6 DNA methylation is modulated in the brain of Alzheimer's disease patients, and that IL-1b expression is associated to DNA methylation in the brain of patients with tuberous sclerosis complex. These results prompted us to ask whether ALA-induced repression of IL-1b and IL-6 was dependent on DNA methylation. Therefore, we profiled DNA methylation in the 5'-flanking region of the two aforementioned genes in SK-N-BE human neuroblastoma cells cultured in presence of ALA 0.5 mM. Our experimental data pointed out that the two promoters are hypermethylated in cells supplemented with ALA, both at CpG and non-CpG sites. Moreover, the observed hypermethylation is associated with decreased mRNA expression and decreased cytokine release. These results reinforce previous findings indicating that IL-1b and IL-6 undergo DNA methylation-dependent modulation in neural models and pave the road to study the epigenetic mechanisms triggered by ALA.

14.
Curr Alzheimer Res ; 14(7): 753-759, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28176663

RESUMO

BACKGROUND: The GSK3ß has been associated to pathological functions in neurodegenerative diseases. This kinase is involved in hyperphosphorylation of microtubule-associated tau protein, leading to aggregation andformation of NFTs. It has clearly been shown that GSK3ß is regulated at posttranslational level: phosphorylation at Tyr216 activates kinase, while phosphorylation at Ser9 is essential to inhibit its activity. OBJECTIVES: At present, there are contradictory findings about the possibility that GSK3ß may be regulated at gene level. Previous data showed overexpression of GSK3ß mRNA in hypomethylating conditions, pointing out to the existence of epigenetic mechanisms responsible for GSK3ß gene regulation. Analysis of human GSK3ß promoter through bisulphite modification, both in neuroblastoma cells and in postmortem frontal cortex from AD patients (AD patients both at Braak stages I-II and at stages V-VI) , allowed us to characterize the methylation pattern of a putative CpG islands in human GSK3ß 5'- flanking region. RESULTS: The analysis evidenced overall hypomethylation of CpG and non-CpG cytosine residues both in cells and in human brain (AD patients and control subjects). We found that GSK3ß mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3ß in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. CONCLUSIONS: These results point out that GSK3ß hyperactivity, and then NFTs formation, could come into function at an early stage of the disease and then turn off at the last stages.


Assuntos
Doença de Alzheimer/patologia , Metilação de DNA/fisiologia , Lobo Frontal/enzimologia , Glicogênio Sintase Quinase 3 beta/genética , Proteínas 14-3-3/metabolismo , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Linhagem Celular Tumoral , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neuroblastoma/patologia , Emaranhados Neurofibrilares/patologia , Fosforilação , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Serina/metabolismo
15.
J Neuropathol Exp Neurol ; 76(1): 27-31, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053004

RESUMO

By means of functional genomics analysis, we recently described the mRNA expression profiles of various genes involved in the neuroinflammatory response in the brains of subjects with late-onset Alzheimer Disease (LOAD). Some of these genes, namely interleukin (IL)-1ß and IL-6, showed distinct expression profiles with peak expression during the first stages of the disease and control-like levels at later stages. IL-1ß and IL-6 genes are modulated by DNA methylation in different chronic and degenerative diseases; it is also well known that LOAD may have an epigenetic basis. Indeed, we and others have previously reported gene-specific DNA methylation alterations in LOAD and in related animal models. Based on these data, we studied the DNA methylation profiles, at single cytosine resolution, of IL-1ß and IL-6 5'-flanking region by bisulphite modification in the cortex of healthy controls and LOAD patients at 2 different disease stages: Braak I-II/A and Braak V-VI/C. Our analysis provides evidence that neuroinflammation in LOAD is associated with (and possibly mediated by) epigenetic modifications.


Assuntos
Doença de Alzheimer/metabolismo , Citocinas/metabolismo , Metilação de DNA/fisiologia , Perfilação da Expressão Gênica/métodos , Mediadores da Inflamação/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Citocinas/genética , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/fisiologia
16.
J Mol Neurosci ; 61(3): 359-367, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27866325

RESUMO

Recent evidence highlights the protective role of reelin against amyloid ß (Aß)-induced synaptic dysfunction and cognitive impairment in Alzheimer disease (AD). In this study, exploiting TgCRND8 mice that overexpress a mutant form of amyloid ß precursor protein (AßPP) and display an early onset of AD neuropathological signs, we addressed the question whether changes of reelin expression eventually precede the appearance of Aß-plaques in a sex-dependent manner. We show that sex-associated and brain region-specific differences in reelin expression appear long before Aß-plaque formation. However, in spite of a downregulation of reelin expression compared to males, TgCRND8 females display fewer Aß-plaques, suggesting that additional factors, other than sex and reelin level, influence amyloidosis in this mouse model.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Moléculas de Adesão Celular Neuronais/genética , Regulação para Baixo , Proteínas da Matriz Extracelular/genética , Feminino , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos , Serina Endopeptidases/genética , Fatores Sexuais
17.
J Alzheimers Dis ; 54(1): 307-24, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27567805

RESUMO

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Fármacos Neuroprotetores/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Citrato (si)-Sintase/metabolismo , Cricetulus , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/metabolismo , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Láctico/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NAD/metabolismo , Fragmentos de Peptídeos/toxicidade , Poli(ADP-Ribose) Polimerase-1/metabolismo
18.
Expert Opin Drug Metab Toxicol ; 12(10): 1181-96, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27351907

RESUMO

INTRODUCTION: Inositol and its derivatives comprise a huge field of biology. Myo-inositol is not only a prominent component of membrane-incorporated phosphatidylinositol, but participates in its free form, with its isomers or its phosphate derivatives, to a multitude of cellular processes, including ion channel permeability, metabolic homeostasis, mRNA export and translation, cytoskeleton remodeling, stress response. AREAS COVERED: Bioavailability, safety, uptake and metabolism of inositol is discussed emphasizing the complexity of interconnected pathways leading to phosphoinositides, inositol phosphates and more complex molecules, like glycosyl-phosphatidylinositols. EXPERT OPINION: Besides being a structural element, myo-inositol exerts unexpected functions, mostly unknown. However, several reports indicate that inositol plays a key role during phenotypic transitions and developmental phases. Furthermore, dysfunctions in the regulation of inositol metabolism have been implicated in several chronic diseases. Clinical trials using inositol in pharmacological doses provide amazing results in the management of gynecological diseases, respiratory stress syndrome, Alzheimer's disease, metabolic syndrome, and cancer, for which conventional treatments are disappointing. However, despite the widespread studies carried out to identify inositol-based effects, no comprehensive understanding of inositol-based mechanisms has been achieved. An integrated metabolomics-genomic study to identify the cellular fate of therapeutically administered myo-inositol and its genomic/enzymatic targets is urgently warranted.


Assuntos
Fosfatos de Inositol/metabolismo , Inositol/administração & dosagem , Fosfatidilinositóis/metabolismo , Animais , Disponibilidade Biológica , Genômica/métodos , Humanos , Inositol/metabolismo , Inositol/farmacocinética , Metabolômica/métodos , Transdução de Sinais/fisiologia
19.
J Neuroinflammation ; 13: 2, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26728085

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease which affects 1 in 88 children. Its etiology remains basically unknown, but it is apparent that neuroinflammation is involved in disease development. Great attention has been focused on pro-inflammatory cytokines, and several studies have reported their dysfunction unbalance in serum as well as in the brain. The present work aimed at evaluating putative dysregulation of interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family in the sera of patients with ASD of different grades, compared to healthy controls, as well as in postmortem brain samples obtained from patients with tuberous sclerosis as well as acute inflammatory diseases. Moreover, quantitative analysis of IL-18 was performed in the sera and brain obtained from Reeler mice, an experimental model of autism. METHODS: Serum IL-18 levels were measured by ELISA. IL-18 was localized by immunohistochemical analysis in brain sections obtained from tuberous sclerosis and encephalitis patients, as well as from gender- and age-matched controls, and in the brain sections of both Reeler and wild-type mice. IL-18 was also quantified by Western blots in homogenates of Reeler and wild-type mice brains. IL-18 binding protein (IL-18BP) was evaluated in Reeler and wild-type mice plasma as well as in their brains (sections and homogenates). RESULTS: IL-18 content decreased in the sera of patients with autism compared to healthy subjects and in Reeler sera compared to wild-type controls. IL-18 was detected within glial cells and neurons in the brain of subjects affected by tuberous sclerosis and encephalitis whereas in healthy subjects, only a weak IL-18 positivity was detected at the level of glial cells. Western blot identified higher amounts of IL-18 in Reeler brain homogenates compared to wild-type littermates. IL-18BP was expressed in higher amounts in Reeler brain compared to the brain of wild-type mice, whereas no significant difference was detected comparing IL-18BP plasma levels. CONCLUSIONS: IL-18 is dysregulated in ASD patients. Further studies seemed necessary to clarify the molecular details behind IL-18 increase in the brain and IL-18 decrease in the sera of patients. An increase in the size of the patient cohort seems necessary to ascertain whether decreased IL-18 content in the sera can become a predictive biomarker of ASD and whether its measure, in combination with other markers (e.g., increased levels of brain-derived neurotrophic factor (BDNF)), may be included in a diagnostic panel.


Assuntos
Transtorno do Espectro Autista/patologia , Encéfalo/metabolismo , Interleucina-18/metabolismo , Adolescente , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Inquéritos e Questionários , Adulto Jovem
20.
Front Behav Neurosci ; 9: 86, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25926782

RESUMO

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to 2 months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.

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