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1

Gene expression profiling of psychotropic drugs effects in the brain

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Korostynski M., Piechota M., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr 1
Psychotropic drugs activate synchronized patterns of gene expression in the brain. These patterns are connected to biological processes involved in therapeutic as well as adverse drug effects. To reveal the transcriptional networks activated by different classes of psychotropic drugs we compared the effects of antidepressants (e.g. mianserine, fluoxetine), analgesics (e.g. morphine, heroin), psychostimulants (e.g. methamphetamine, cocaine) and antipsychotics (e.g. clozapine, haloperidol) on genomic profile in mouse (C57BL/6J) striatum. We applied a whole-genome microarray (Illumina WG-6) profiling to characterize time-course of transcriptome alterations following acute drug administration (1, 2, 4 and 8h after injection). We identified major drug-regulated expression patterns that are formed by inducible transcriptional networks, as for example: (1) CREB/SRF-dependent genes that appears to be related to dopaminergic activity the striatum, (2) the group of genes controlled at least in part via release of steroid hormones. The data were stored as raw values, fold of change versus saline and P value of drug versus saline comparison in the database (available at www. genes2mind.org). The database interface allows for multidimensional data analysis (PCA), search for drug using genomic signatures and visualize drug-regulated gene transcription patterns. Our results elucidates the networks of drug-induced genes that share common regulatory elements, functional relations and may provide novel diagnostic tools for prediction of drug effectiveness. This work was supported by EU grant LSHM-CT-2004-005166, POIG DeMeTer 3.1 and NN405 274137 grants.
2

Analysis of regulatory elements in promoters of genes regulated by morphine in mouse brain

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Piechota M., Korostynski M., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
3

Global analysis of drug-regulated alternative expression of genes in mouse brain

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Korostynski M., Piechota M., Golda S., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
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nr Suppl.1
Genomic response of neuronal cell to external stimuli includes expression of specific transcript isoforms, that use alternative transcription start sites and polyadenylation signals. We applied microarray profiling (Illumina Mouse WG-6) and next-generation sequencing (SOLID 5500xl) to screen for drug-induced activitydependent transcriptional events in the C57BL/6J mouse striatum. We compared effects on gene expression induced by psychoactive drugs with diverse neuropharmacological mechanisms of action (antidepressants, antipsychotics, anxiolytics, psychostimulants and opiods). Using whole-genome approach we identified a pool of transcripts that are regulated by the psychotropic drugs in mouse striatum (317 transcripts). We found that drug-responsive transcripts are organized into three main co-regulated gene expression networks. Furthermore, using Bowtie read aligner and Cufflinks algorithm we identified specific gene isoforms responsive to drug treatment. 58% among the drug-regulated transcripts were defined as alternative transcription events. To search for transcriptional factors that control alternative gene transcription in the brain we developed seqinterpreter web-based tool (http:// seqinterpreter.cremag.org). We found SRF, NPAS4 and GR as candidate regulatory factors. The complex program of regulation in gene transcription may further impact long-lasting alterations in brain function.
4

Effects of morphine on gene expression in the striatum

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Korostynski M., Piechota M., Kaminska D., Solecki W., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
5

Regulation of the immediate-early gene expression in the mouse forebrain by acute administration of antidepressants

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Ziolkowska B., Wrobel J., Bargiela A., Korostynski M., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
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nr Suppl.1
The sites of action of antidepressants in the brain responsible for their psychotropic effects are not fully elucidated. Our study was undertaken to compare acute effects of antidepressants representing diverse modes of molecular action on regional brain activity, reflected by expression of immediate-early genes (IEG). In situ hybridization was used to analyze expression of the IEG Fos, Egr1 and Arc in the mouse forebrain after a single injection of tranylcypromine (MAO inhibitor), mianserin (acting on 5-HT, NA and histamine receptors but not on monoamine levels) and tianeptine (with unknown molecular targets). Tranylcypromine and tianeptine produced a widespread IEG induction in the neocortex and striatum (where mianserin down-regulated IEG). The similarity of the tianeptine and tranylcypromine effects suggests that elevation of monoamine levels is an important mechanism by which tianeptine affects forebrain function. Moreover, all three drugs elicited IEG induction in several brain regions implicated in the regulation of mood in humans: anterior cingulate and insular cortex, basolateral amygdala and paraventricular thalamic nucleus. The common activation of these regions by different types of antidepressants suggests that they may be the sites where neuroplastic changes take place upon chronic drug treatment, leading to the long-term psychotropic effect.
6

Effects of morphine on immediate-early gene expression in CS7BL/6 and DBA/2 strains of mice

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Ziolkowska B., Korostynski M., Piechota M., Kaminska D., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
7

Modulation of the expression of opioid inducible genes using RNA interference

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Ligeza A., Wawrzczak-Bargiela A., Kaminska D., Korostynski M., Przewlocki M.
Acta Neurobiologiae Experimentalis
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2005
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tom 65
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nr 3
8

Regulation of alternative gene expression in the mouse striatum in response to cocaine

76%
Zygmunt M., Rodriguez-Parkitna J., Golda S., Piechota M., Ficek J., Korostynski M.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: Cocaine is a potent psychostimulant that increases levels of striatal dopamine and activates neuronal circuits controlling motivation and reward-based learning. Transcriptional response to cocaine includes expression of alternative gene isoforms and splicing variants. Unraveling the regulatory mechanisms that are involved in selection of active transcription start and termination sites provides novel insight into molecular basis of drug-induced brain plasticity. METHODS: We used next-generation sequencing (RNA-seq) to comprehensively map expression of genesin the mouse striatum. Total RNA and small RNA resequencing was performed in samples collected 1 h after acute treatment with 25 mg/kg cocaine. To identify transcripts responsive to drug treatment we used Tophat read-mapper and Cufflinks algorithm for FPKM quantification. The seqinterpreter online tool was used to search for key regulatory factors that control alternative gene transcription in the brain (http://seqinterpreter.cremag.org). RESULTS: In addition to increased expression of activity-regulated genes, different types of cocaine-inducible splicing variants and transcript biotypes were identified. Examples of different modalities of gene expression include alternative first exon (e.g. Stxbp1), alternative last exon (Hsph1), intron retention (Dnajb5), long noncoding RNA (Gm13889) and small RNA (Mir92b and Mir130a). In order to investigate neuron-type specificity of gene expression we have used fluorescence-activated cell sorting to isolate genetically labeled dopamine receptor 1 expressing neurons. CONCLUSIONS: Our results provide a comprehensive assessment of neuronal activity-induced gene expression at the level of individual transcriptional units rather than whole genes. Further experiments will explore differences in activity-regulated gene expression in discrete neuron types, i.e. the D1 or D2 expressing medium spiny neurons of the striatum. This work was supported by NCN grant SONATA 2011/03/D/ NZ3/01686.
9

Molecular biomarkers of addiction in a model of long-term morphine self-administration in mice

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Skupio U., Sikora M., Korostynski M., Wawrzczak-Bargiela A., Piechota M., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Chronic exposure to opioids induces various adaptations in brain physiology that lead to formation of dependence and addiction. Commonly used approaches for modeling morphine dependence, such as conditioned place preference and morphine self-administration typically last less than two weeks, which is presumably too short to observe long-lasting alterations in the brain that accompany drug addiction. AIM(S): In the present study, we aimed to establish a novel model of long-term morphine self-administration in C57BL/6J mice. Our second goal was to identify molecular biomarkers, specific transcriptional patterns and signs of genetic predispositions to opiate addiction. METHOD(S): We used automated IntelliCage system to observe the animals in groups. The animals in two separate cages were allowed access to morphine or saccharin solutions for 3 months. We tested animals for symptoms of addiction using paradigms like progressive ratio schedule and intermittent access. Gene expression profiles were evaluated in the striatum using whole-genome microarrays and qPCR. RESULTS: The animals drinking morphine showed addiction-related behavioral pattern when compared with control animals. The analysis of molecular changes revealed long-lasting alterations in gene expression profiles between the analyzed groups of animals. Interestingly, correlation analyses between individual gene expression levels and motivation allowed to identify genes (Epha5, Ncam) that possibly indicate predisposition to addiction-like behaviors. CONCLUSIONS: Our model represents a novel approach for investigating both behavioral and molecular mechanisms of addiction. Mice drinking morphine exhibit many of the addiction-like symptoms compared to control animals. Prolonged morphine intake resulted in adaptive processes in the brain that manifested as altered transcriptional sensitivity to opioids. FINANCIAL SUPPORT: Supported by Polish National Science Centre Grant no. 2013/08/A/NZ3/00848.
10

Molecular and behavioral patterns associated to stress responsivity and PTSD risk

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Szklarczyk K., Smutek M., Korostynski M., Solecki W., Golda S., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Post-traumatic stress disorder (PTSD) is a chronic anxiety condition that develops as a result of a terrifying event. Clinical studies show that only about 10% of trauma-exposed people suffer from PTSD. Our research was focused on endophenotypes and molecular biomarkers of PTSD in an animal model. Differences in response to stress among inbred mouse strains (C57BL/6J, DBA/2J, SWR/J and 129P3/J) were compared: a single intense footshock was applied and ultrasonic vocalization during/after the stress was measured. Long-lasting effects were assessed 4-6 weeks after the traumatic event: conditioned and sensitized fear, social withdrawal, depressive-like behavior and susceptibility to drug addiction. SWR/J strain displayed the lowest conditioned fear, whereas sensitized fear was increased over time in C57BL/6J mice. Moreover, C57BL/6J strain exhibited increase in depressive-like behavior, while DBA/2J strain displayed increased social withdrawal. In addition, it was observed that exposition to traumatic stress increased sensitivity to rewarding properties of morphine in 129P3/J mice. Diverse long-lasting behavioral consequences of exposition to stress were associated with changes in basal and stress-induced profile of glucocorticoid receptor-dependent (GR) genes (e.g., Fkbp5 and Tsc22d3) in amygdala. Furthermore, our research showed that administration of GR antagonist disrupted reconsolidation of the traumatic event memory. Our research supports a model in which genetic factors are important for phenotypic variation in responsivity to stress. These genes may provide novel insight into mechanisms of stress-related disorders. This work was supported by Polish MSHE grants NN405 274137, N405 143238, IUVENTUS Plus and POIG De-Me-Ter 3.1
11

Expression of opioid genes in neuropathie and inflammatory pain

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Korostynski M., Kaminska D., Rodriguez Parkitna J. M., Obara I., Makuch W., Przewlocka B., Przewlocki R.
Acta Neurobiologiae Experimentalis
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2005
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tom 65
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nr 3
12

Let genes talk: transcriptomic changes in the PFC induced by L-DOPA in hemiparkinsonian rats

76%
Radlicka A., Kaminska K., Piechota M., Korostynski M., Lorenc-Koci E., Pera J., Parkitna J. R.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: The hallmark symptoms of Parkinson’s disease (PD) are progressive motor impairments. Nevertheless, PD is also associated with altered executive function and other cognitive impairments. While treatments of PD provide at least temporary relief from the motor symptoms, the effects of L-DOPA on the cognitive impairments may provide mixed effects and require further investigation. AIM(S): Here we assess changes in gene expression in the prefrontal cortex (PFC) of rats with unilateral lesion of midbrain dopamine neurons. METHOD(S): Male Wistar Han rats were infused with 6‑hydroxydopamine (6‑OHDA, 8 µg/4 µl) into the left medial forebrain bundle. The experimental animals were treated i.p. with L‑DOPA (12.5 mg/kg) supplemented with benserazide hydrochloride (6.25 mg/kg) daily for 14 days. An hour after the last dose, the rats were killed, and the left and right PFC were isolated separately. Analysis of gene expression was performed by RNA‑seq (Illumina PE 150, 20M pair reads per sample). Reads were aligned to rn6 rat reference genome using hisat2 2.1.0. RESULTS: We identified 12,459 genes with FPKM > 1 after L‑DOPA treatment in both ipsi‑ and contralateral portions of the PFC of rats lesioned with 6‑OHDA. Two‑way ANOVA revealed 48 genes with differential expression profiles. The effect of treatment was the most pronounced, and included transcripts linked to activity-regulated expression in neurons and metabolism in the glia. Ontology analysis of the genes with altered expression indicated over-representation of terms associated with cytokine and glucocorticoid signalling. The involvement of altered glucocorticoid signalling induced by L-DOPA treatment was also confirmed by analysis of the promoter regions of the regulated genes. CONCLUSIONS: Unilateral lesions of dopamine neurons lead to enhanced sensitization of neurons in PFC to L‑DOPA action. We show that, to a large extent, these changes appear to bilaterally affect the molecular profile of PFC.
13
Content available remote

Comparison of gene expression profiles in neuropathic and inflammatory pain

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Rodriguez Parkitna J., Korostynski M., Kaminska-Chowaniec D., Obara I., Mika J., Przewlocka B., Przewlocki R.
Journal of Physiology and Pharmacology
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2006
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tom 57
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nr 3
Molecular mechanisms underlying the differences between chronic neuropathic and inflammatory pain are still poorly understood. Identifying those differences should provide insight into the molecular mechanism underlying features unique for neuropathic pain, such as allodynia. We have performed screening for differentially expressed genes in the spinal cord in the rat models of neuropathic and inflammatory pain. Using BD Atlas Rat 4K arrays we found several differences in expression of secretion-related genes between inflammatory and neuropathic pain. Development of the latter was characterized by up-regulated expression of genes associated with immune response and microglia activation and also, to a lesser extent, with cytoskeleton rearrangement. The relative increase in abundance of four genes, intercellular adhesion molecule 1 (ICAM-1), calcitonin gene related peptide (CGRP), tissue inhibitor of metalloproteinase 1 (TIMP-1), chemokine-like receptor 1 was confirmed by reverse transcription Real-Time PCR (qPCR) validation in the spinal cord in neuropathic pain. Levels of transcripts corresponding to ICAM-1 and TIMP-1 were also increased in the dorsal root ganglia (DRG) of neuropathic rats. Our data point at the importance of immune response- and microglia activation-related genes in the development of chronic neuropathic pain, and suggest that expression of CGRP gene in the dorsal horn of the spinal cord could be involved in persistence of its symptoms.
14

FKRP gene mutations and candidate disease-modifying genes in Polish patients with limb-girdle muscular dystrophy – results of whole exome sequencing study

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Macias A., Fichna J., Korostynski M., Piechota M., Potulska-Chromik A., Redowicz M. J., Zekanowski C., Kaminska A. M., Kostera-Pruszczyk A.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Limb-girdle muscular dystrophies (LGMD) are hereditary progressive disorders of skeletal muscles. Currently 33 LGMD types are recognized. For up to 50% of LGMD patients the causal genetic defect remains unknown. There is considerable phenotypic variability, even among patients with identical causal mutation. Mutations in fukutin-related protein (FKRP) gene are responsible for an autosomal recessive type 2 I of LGMD, which is a relatively frequent type of LGMD in Europe. AIM(S): The aim of this work was to assess frequency of LGMD2I in Polish LGMD patients, characterize the pathogenic mutations, clinical phenotype and possible disease modifying genes. METHOD(S): The study involved 85 patients with LGMD diagnosis based on clinical assessment and muscle biopsy. Whole exome sequencing of peripheral blood DNA was performed. Filtering of the identified variants was based on allele frequency, association with Human Phenotype Ontology terms and predicted pathogenicity. Selected variants were confirmed using a direct fluorescence‑based sequencing. RESULTS: Homozygous or compound heterozygous mutations in FKRP gene were found in 7/85 patients. L276I mutation was the most common one – found in 6/7 LGMD2I patients, 3 of them were homozygous. We could observe considerable phenotypic variability. Candidate disease-modifying genes were COL6A3, COL12A1, PLEC, SYNE1. In 2 patients with particularly severe course of the disease, heterozygous mutation in genes involved In glycosylation process was found (LARGE, ISPD, ITGA7). Two patients were found to be heterozygous for mutations in DYSF gene. CONCLUSIONS: LGMD2I is a common type of LGMD in Polish population. The most common mutation in FKRP gene is L276I. Heterozygocity for mutations in other LGMD genes is high in this group of patients. New generation sequencing methods are a valuable tool for identifying causal mutations, but also for finding candidate disease‑modifying genes, which can help to elucidate mechanisms of LGMD.
15

Regulation on spinal nociceptive TRPV1/CB1 processing as therapeutic opportunities in a rat model of neuropathic pain

64%
Starowicz K., Zychowska M., Mrugala M., Makuch W., Korostynski M., Slezak M., Petrosino S., Di Marzo V., Przewlocka B.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Anandamide (AEA) has emerged as a multifunctional lipid mediator of various stimuli. Latest reports suggest a role for AEA as an endovanilloid ligand, however, no data exist on the potential role of endogenous AEA upregulation in the spinal cord in neuropathic pain model. Rats chronically implanted with intrathecal (i.t.) catheters underwent sciatic nerve ligation (CCI model). The effect of selective inhibitor of AEA enzymatic hydrolysis, URB597 and the involvement of TRPV1 or cannabinoid CB1 receptors, were investigated. Measurements of allodynia and hyperalgesia were made 7 days after CCI and the levels of AEA in the spinal cord of CCI rats were determined. The spinal endovanilloid/endocannabinoid system was studied by means of qRT-PCR and western blott analysis in CCI rats. Finally, the distribution of TRPV1 and endovanilloid degradation enzymes were compared in the rat lumbar spinal cord. Depending on the administered dose, URB597 (10 – 200 μg/rat) reduced pain via CB1 or TRPV1 receptors. URB597 (10 – 100 μg) dose-dependently enhanced spinal AEA levels. Surprisingly those were reduced by 200 μg of URB597 suggesting an indirect effect of an endovanilloid/endocannabinoid AEA action at TRPV1. Alterations in lypoxygenases (LOX) mRNA support the idea of alternative ways of AEA metabolism. LOX-mediated production of hydroperoxides was associated with increased phospholipase A2 acitvity. Finally, baicalein by blocking the 12-LOX activity reduced the URB597 (200 μg) analgesic effect in CCI rats. We suggest that i.t. AEA reduces neuropathic pain by acting as an endovanilloid, on the he spinal cord TRPV1/ CB1 neurons. When endogenously up-regulated with URB597, AEA exerts analgesia via both receptors. Dependent on efficiency of FAAH a secondary route of AEA metabolism plays a role in CCI model. Moreover spinal lipoxygenase metabolites contribute to the AEA-mediated nociception in CCI model suggesting a complex interplay these systems in vivo. Supported by 0152/B/2008/35.
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