Gilbert syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The mutation, A(TA)7TAA, is thought to be the ...sole cause of the syndrome in Caucasians, but an enhancer polymorphism (T-3279G) that lowers transcriptional activity has recently been reported. We have tested the linkage of the two mutations in 11 Caucasians and 12 Japanese patients who were homozygous for A(TA)7TAA. All 23 patients were also homozygous for T-3279G, indicating that T-3279G and A(TA)7TAA were linked. The decrease in transcription caused by both mutations together may be essential to the syndrome.
Endocannabinoid signaling and food addiction D'ADDARIO, C; MICIONI DI BONAVENTURA, M. V; PUCCI, M ...
Neuroscience and biobehavioral reviews,
11/2014, Letnik:
47
Journal Article
Recenzirano
Overeating, frequently linked to an increasing incidence of overweight and obesity, has become epidemic and one of the leading global health problems. To explain the development of this eating ...behavior, new hypotheses involve the concept that many people might be addicted to food by losing control over their ability to regulate food intake. Among the different neurotransmitter networks that partake in the reward circuitry within the brain, a large body of evidence supports the involvement of the endocannabinoid system. Indeed, its dysfunctions might contribute to food addiction, by regulating appetite and food preference through central and peripheral mechanisms. Here, we review and discuss the role of endocannabinoid signaling in the reward circuitry, and the possible therapeutic exploitation of strategies based on its fine regulation.
Animal models have suggested that prenatal ethanol exposure (PEE) alters the κ opioid receptor system. The present study investigated the brain expression of dynorphin and nociceptin/orphanin FQ ...related genes and assessed anxiety-like behavior in the light-dark box (LDB), shelter-seeking and risk-taking behaviors in the concentric square field (CSF) test, and ethanol-induced locomotion in the open field (OF), in infant or adolescent Wistar rats that were exposed to PEE (0.0 or 2.0 g/kg, intragastrically, gestational days 17–20). We measured brain mRNA levels of prodynorphin (PDYN), κ opioid receptors (KOR), the nociceptin/orphanin FQ opioid peptide precursor prepronociceptin (ppN/OFQ) and nociceptine/orphanin FQ receptors (NOR). Prenatal ethanol exposure upregulated PDYN and KOR mRNA levels in the ventral tegmental area (VTA) in infant and adolescent rats and KOR mRNA levels in the prefrontal cortex in infant rats. The changes in gene expression in the VTA were accompanied by a reduction of DNA methylation at the PDYN gene promoter, and by a reduction of DNA methylation at the KOR gene promoter. The PEE-induced upregulation of PDYN/KOR in the VTA was accompanied by lower NOR gene expression in the VTA, and lower PDYN gene expression in the nucleus accumbens. PEE rats exhibited hypolocomotion in the OF, greater avoidance of the white and brightly lit areas in the LDB and CSF, and greater preference for the sheltered area in the CSF test. These results suggest that PEE upregulates the dynorphin system, resulting in an anxiety-prone phenotype and triggering compensatory responses in the nociceptin/orphanin FQ system. These findings may help elucidate the mechanisms that underlie the effects of PEE and suggest that the dynorphin and nociceptin/orphanin FQ systems may be possible targets for the prevention and treatment of PEE-induced alterations.
•Prenatal ethanol exposure (PEE) induced an anxiety-prone phenotype.•PEE upregulated PDYN and KOR mRNA levels in the VTA.•PEE upregulated KOR mRNA levels in the prefrontal cortex.•PEE reduced the DNA methylation at the PDYN and KOR gene promoter, in VTA.•Prenatal ethanol lowered NOR gene expression in the VTA.
Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the ...transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n=99), as well as of healthy controls (CT, n=42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures.
•Selective target genes expression alterations in BD•Role of DNA methylation in mediating PDYN mRNA level changes in BD•Correlation between PDYN and BDNF epigenetic mark in BD
Evidence suggests that binge eating may be caused by a unique interaction between dieting and stress. We developed a binge‐eating model in which female rats with a history of intermittent food ...restriction show binge‐like palatable food consumption after a 15‐minute exposure to the sight of the palatable food (frustration stress). The aim of the present study was to investigate the regulation of the stress neurohormone corticotropin‐releasing factor (CRF) system and of the nociceptin/orphanin FQ (N/OFQ) system genes in selective rat brain regions, using our animal model. Food restriction by itself seems to be responsible in the hypothalamus for the downregulation on messenger RNA levels of CRF‐1 receptor, N/OFQ and its receptor (NOP). For the latter, this alteration might be due to selective histone modification changes. Instead, CRF gene appears to be upregulated in the hypothalamus as well as in the ventral tegmental area only when rats are food restricted and exposed to frustration stress, and, of relevance, these changes appear to be due to a reduction in DNA methylation at gene promoters. Moreover, also CRF‐1 receptor gene resulted to be differentially regulated in these two brain regions. Epigenetic changes may be viewed as adaptive mechanisms to environmental perturbations concurring to facilitate food consumption in adverse conditions, that is, in this study, under food restriction and stressful conditions. Our data on N/OFQ and CRF signaling provide insight on the use of this binge‐eating model for the study of epigenetic modifications in controlled genetic and environmental backgrounds.
Binge eating is triggered by a unique interaction between dieting and stress. We observed that rats subjected to cycles of food restriction and then exposed to frustration stress showed binge eating. We provide data on target gene expression regulation (CRF and N/OFQ system genes) via epigenetic mechanisms, suggesting differential roles in selected brain regions. In the VTA, CRF system gene upregulation in response to stress might lead to the increase of high palatable food consumption through modulation of reward mechanisms.
Abstract The development of multiple sclerosis, a major neurodegenerative disease, is due to both genetic and environmental factors that might trigger aberrant epigenetic changes of the genome. In ...this study, we analysed global DNA methylation in the brain of mice upon induction of experimental autoimmune encephalomyelitis (EAE), and the effect of environmental enrichment (EE). We demonstrate that global DNA methylation decreased in the striatum, but not in the cortex, of EAE mice compared to healthy controls, in particular in neuronal nitric oxide synthase (nNOS)-positive interneurons of this brain area. Also, in the striatum but again not in the cortex, decreased DNA methylation of the nNOS downstream effector, dexamethasone-induced Ras protein 1 (Dexras 1), was observed in EAE mice, and was paralleled by an increase in its mRNA. Interestingly, EE was able to revert EAE effects on mRNA expression and DNA methylation levels of Dexras 1 and reduced gene expression of nNOS and 5-lipoxygenase (Alox5). Conversely, interleukin-1β (IL-1β) gene expression was found up-regulated in EAE mice compared to controls and was not affected by EE. Taken together, these data demonstrate an unprecedented epigenetic modulation of nNOS-signaling in the pathogenesis of multiple sclerosis, and show that EE can specifically revert EAE effects on Dexras 1 along this pathway.
ABSTRACT
Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically ...administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1‐ and 5‐day groups) or 1, 3 or 7 days after the last administration for the three other 5‐day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up‐regulation of prodynorphin and pronociceptin was observed in the 1‐day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5‐day group and both peptide precursors in the 1‐day withdrawal group were also up‐regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1‐day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.
Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 ...acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing.
In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT).
Gene and protein expression, promoter methylation, Ser(16) phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT.
In LOAD subjects, there was a statistically significant reduction in Ser(16) phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018).
The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.
μ-Opioid receptor activation in live cells Vukojević, Vladana; Ming, Yu; D'Addario, Claudio ...
The FASEB journal,
October 2008, Letnik:
22, Številka:
10
Journal Article
Recenzirano
Interaction of the μ-opioid receptor (MOP) with selected ligands was investigated in live cells using advanced imaging by confocal laser scanning microscopy integrated with fluorescence correlation ...spectroscopy and fluorescence cross-correlation spectroscopy. In PC12 cells stably transformed to express the fluorescently labeled MOP-enhanced green fluorescent protein construct, two pools of MOP were identified that could be discriminated by differences in their lateral mobility in the cell membrane. The majority of MOP receptors (80±10%) were characterized by a diffusion coefficient DMOP,₁ = (4±2) x 10⁻¹¹ m² s⁻¹, compared with the slowly moving fraction, DMOP,₂ = (4±2) x 10⁻¹² m² s⁻¹. On stimulation with selected agonists (D-Ala²,N-MePhe⁴,Gly-ol⁵enkephalin, enkephalin-heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe, morphine, and methadone), surface density of the MOP decreased, whereas the lateral mobility increased. In contrast, antagonists (naloxone and naltrexone) "froze" the receptor in the membrane, i.e., increased MOP surface density and decreased lateral mobility. Agonist activation was also accompanied by pronounced changes in the dynamics of plasma membrane lipids, as revealed by the general lipid marker 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate dye. The results provide new information about MOP activation in live cells at the molecular level, with a special focus on the dynamics of the intricate interplay between this receptor and the surrounding lipids.--Vukojević, V., Ming, Y., D'Addario, C., Hansen, M., Langel, Ü., Schulz, R., Johansson, B., Rigler, R., Terenius, L. μ-Opioid receptor activation in live cells.
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