Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.

Currently, there is a lack of effective medicines capable of halting or reversing the progression of neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, or Alzheimer's disease. Given the unmet medical need, it is necessary to reevaluate the existing paradigms of how to target these diseases. When considering neurodegenerative diseases from a systemic neurometabolic perspective, it becomes possible to explain the shared pathological features.

Maternal Separation Followed by Chronic Mild Stress in Adulthood Is Associated with Concerted Epigenetic Regulation of AP-1 Complex Genes.

Depression is one of the most prevalent mental diseases worldwide. Patients with psychiatric diseases often have a history of childhood neglect, indicating that early-life experiences predispose to psychiatric diseases in adulthood. Two strong models were used in the present study: the maternal separation/early deprivation model (MS) and the chronic mild stress model (CMS).

Preoperative serum circulating microRNAs as potential biomarkers for chronic postoperative pain after total knee replacement.

Background: Chronic postoperative pain affects approximately 20% of patients with knee osteoarthritis after total knee replacement. Circulating microRNAs can be found in serum and might act as biomarkers in a variety of diseases. The current study aimed to investigate the preoperative expression of circulating microRNAs as potential predictive biomarkers for the development of chronic postoperative pain in the year following total knee replacement.

Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models.

The etiology of CNS diseases including multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1 and rotenone models, mimicking these CNS diseases in humans.

Epigenetic Regulation of Ferroportin in Primary Cultures of the Rat Blood-Brain Barrier.

Ferroportin plays an essential role for iron transport through the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). To maintain the integrity of the BBB, the BCECs gain support from pericytes and astrocytes, which together with neurons form the neurovascular unit (NVU). The objectives of the present study were to investigate ferroportin expression in primary cells of the NVU and to determine if ferroportin mRNA (Fpn) expression is epigenetically regulated.

DNA methylation regulates CHRNA7 transcription and can be modulated by valproate.

The CHRNA7 gene encoding the α7 nicotinic acetylcholine receptor (nAChR) has repeatedly been linked with schizophrenia and the P50 sensory gating deficit. The α7 nAChR is considered a promising drug target for treatment of cognitive dysfunction in schizophrenia and improves memory and executive functions in patients and healthy individuals. However, clinical trials with pro-cognitive drugs are challenged by large inter-individual response variations and these have been linked to genotypic variations reducing CHRNA7 expression and α7 nAChR function.

Correction to: Hepcidin Mediates Transcriptional Changes in Ferroportin mRNA in Differentiated Neuronal-like PC12 Cells Subjected to Iron Challenge.

The original version of this article unfortunately contained mistakes on Figs. 1, 2, and 7 as some of the data were not visible. With this, the correct images are hereby published.

Hepcidin Mediates Transcriptional Changes in Ferroportin mRNA in Differentiated Neuronal-Like PC12 Cells Subjected to Iron Challenge.

Ferroportin is the only known iron exporter, and its regulation seems to be controlled at both transcriptional, post-transcriptional, and post-translational levels. The objective of the current work was to investigate how cellular iron status affects the expression of the ferroportin gene Fpn under the influence of hepcidin, known to post-translational lower the available ferroportin protein. Nerve growth factor-beta (NGF-β)-differentiated PC12 cells, used as a model of neuronal cells, were evaluated in terms of their viability and expression of ferroportin after inducing cellular iron overload with ferric ammonium citrate (FAC) or hepcidin, iron deficiency with deferoxamine (DFO), or hepcidin in combination with FAC or DFO.

DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele.

The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression.

Transfection of brain capillary endothelial cells in primary culture with defined blood-brain barrier properties.

Background: Primary brain capillary endothelial cells (BCECs) are a promising tool to study the blood-brain barrier (BBB) in vitro, as they maintain many important characteristics of the BBB in vivo, especially when co-cultured with pericytes and/or astrocytes. A novel strategy for drug delivery to the brain is to transform BCECs into protein factories by genetic modifications leading to secretion of otherwise BBB impermeable proteins into the central nervous system. However, a huge challenge underlying this strategy is to enable transfection of non-mitotic BCECs, taking a non-viral approach.

Epigenetic regulation of Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat.

Electroconvulsive therapy (ECT) remains one of the most effective treatments of major depression. Unfortunately, some patients report side effects, of which the most prominent are memory deficits. The immediate early gene Arc plays a critical role in the maintenance phase of long-term potentiation and consolidation of memory in the rat brain.

Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons.

Chronic inflammation in the substantia nigra (SN) accompanies conditions with progressive neurodegeneration. This inflammatory process contributes to gradual iron deposition that may catalyze formation of free-radical mediated damage, hence exacerbating the neurodegeneration. This study examined proteins related to iron-storage (ferritin) and iron-export (ferroportin) (aka metal transporter protein 1, MTP1) in a model of neurodegeneration.

Temporal gene expression profile after acute electroconvulsive stimulation in the rat.

Electroconvulsive therapy (ECT) remains one of the most effective treatments of major depression. It has been suggested that the mechanisms of action involve gene expression. In recent decades there have been several investigations of gene expression following both acute and chronic electroconvulsive stimulation (ECS).

Development of a novel lipophilic, magnetic nanoparticle for in vivo drug delivery.

The aim of the present study was to evaluate the transfection potential of chitosan-coated, green-fluorescent magnetic nanoparticles (MNPs) (chi-MNPs) after encapsulation inside polyethylglycol (PEG)ylated liposomes that produced lipid-encapsulated chitosan-coated MNPs (lip-MNPs), and also to evaluate how these particles would distribute in vivo after systemic injection. The transfection potential of both chi-MNPs and lip-MNPs was evaluated in vitro in rat brain endothelial 4 (RBE4) cells with and without applying a magnetic field. Subsequently, the MNPs were evaluated in vivo in young rats.

Low maternal care exacerbates adult stress susceptibility in the chronic mild stress rat model of depression.

In the present study we report the finding that the quality of maternal care, in early life, increased the susceptibility to stress exposure in adulthood, when rats were exposed to the chronic mild stress paradigm. Our results indicate that high, as opposed to low maternal care, predisposed rats to a differential stress-coping ability. Thus rats fostered by low maternal care dams became more prone to adopt a stress-susceptible phenotype developing an anhedonic-like condition.

Brain delivery systems via mechanism independent of receptor-mediated endocytosis and adsorptive-mediated endocytosis.

The endothelial cells of the brain form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain. Traditional attempts to bypass the BBB have been by formulation of drugs with lipophilicity or low molecular weight designed to enable transport via solute nutrient transporters. The identification of many new targets in the brain cells form new ways of thinking drug design as modern therapeutics could be proteins and molecules of genetic origins like siRNA and cDNA that are prevented from entry into the brain unless encapsulated in drug carriers.

Epigenetic regulation of Arc and c-Fos in the hippocampus after acute electroconvulsive stimulation in the rat.

Electroconvulsive stimulation (ECS) remains one of the most effective treatments of major depression. However, the underlying molecular changes still remain to be elucidated. Since ECS causes rapid and significant changes in gene expression we have looked at epigenetic regulation of two important immediate early genes that are both induced after ECS: c-Fos and Arc.

Gene delivery by pullulan derivatives in brain capillary endothelial cells for protein secretion.

The blood-brain barrier (BBB) formed by brain capillary endothelial cells protects the brain against potentially harmful substances present in the circulation, but also restricts exogenous substances such as pharmacologically acting drugs or proteins from entering the brain. A novel and rather unchallenged approach to allow proteins to enter the brain is gene therapy based on delivery of genetic material into brain capillary endothelial cells. In theory in vivo transfection will allow protein expression and secretion from brain capillary endothelial cells and further into the brain.

Heterogenous distribution of ferroportin-containing neurons in mouse brain.

Iron is crucial for a variety of cellular functions in neuronal cells. Neuronal iron uptake is reflected in a robust and consistent expression of transferrin receptors and divalent metal transporter 1 (DMT 1). Conversely, the mechanisms by which neurons neutralize and possibly excrete iron are less clear.

Use of biomarkers in the discovery of novel anti-schizophrenia drugs.

Schizophrenia is characterized by a diverse symptomatology that often includes positive, cognitive and negative symptoms. Current anti-schizophrenic drugs act at multiple receptors, but little is known about how each of these receptors contributes to their mechanisms of action. Screening of novel anti-schizophrenic drug candidates targeting single receptors will be based on biomarker assays that measure signalling pathways, transcriptional factors, epigenetic mechanisms and synaptic function and translate these effects to behavioural effects in animals and humans.

Macromolecular drug transport into the brain using targeted therapy.

The brain forms a vascular barrier system comprised of the blood-brain barrier (BBB) and the blood-CSF barriers. Together they prevent the passage of a number of drugs from the bloodstream into the brain parenchyma, because their molecules are either hydrophilic, too large or both. In many disorders affecting the CNS, these barriers are physically intact, which limits the entry of large molecules with potentially important therapeutic implications.

Arabidopsis MAP kinase 4 regulates gene expression through transcription factor release in the nucleus.

Plant and animal perception of microbes through pathogen surveillance proteins leads to MAP kinase signalling and the expression of defence genes. However, little is known about how plant MAP kinases regulate specific gene expression. We report that, in the absence of pathogens, Arabidopsis MAP kinase 4 (MPK4) exists in nuclear complexes with the WRKY33 transcription factor.

Functionality of the beta/six site-specific recombination system in tobacco and Arabidopsis: a novel tool for genetic engineering of plant genomes.

The beta recombinase is a member of the prokaryotic site-specific serine recombinases (invertase/resolvase family), which in the presence of a DNA bending cofactor can catalyse DNA deletions between two directly oriented 90-bp six recombination sites. We have examined here whether the beta recombinase can be expressed in plants and whether it displays in planta its specific catalytic activity excising DNA sequences that are flanked by six sites. In plant protoplasts, the enzyme could be expressed as a GFP-beta recombinase fusion which can localise to the cell nucleus.

The Arabidopsis genome encodes structurally and functionally diverse HMGB-type proteins.

The high mobility group (HMG) proteins of the HMGB family are chromatin-associated proteins that act as architectural factors in nucleoprotein structures, which regulate DNA-dependent processes including transcription and recombination. In addition to the previously identified HMGB1-HMGB6 proteins, the Arabidopsis genome encodes at least two other candidate family members (encoded by the loci At2g34450 and At5g23405) having the typical overall structure of a central domain displaying sequence similarity to HMG-box DNA binding domains, which is flanked by basic N-terminal and acidic C-terminal regions. Subcellular localisation experiments demonstrate that the At2g34450 protein is a nuclear protein, whereas the At5g23405 protein is found mainly in the cytoplasm.

Ectopic expression of the maize chromosomal HMGB1 protein causes defects in root development of tobacco seedlings.

Chromatin-associated high mobility group (HMG) proteins of the HMGB family are versatile architectural factors assisting various DNA-dependent processes such as transcription and recombination. Here, transgenic tobacco lines were generated that ectopically express the maize HMGB1 protein, as detected by immunoblot analyses. The shoot morphology of HMGB1 expressing plants does not differ from that of control plants.