oru.sePublications
Change search
Refine search result
1 - 40 of 40
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Ahmad, Abrar
    et al.
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Venizelos, Nikolaos
    Department of Clinical Research, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hahn-Strömberg, Victoria
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden; ; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Prognostic Effect of Vascular Endothelial Growth Factor +936C/T Polymorphism on Tumor Growth Pattern and Survival in Patients Diagnosed with Colon Carcinoma2016In: Journal of Tumor Research, Vol. 2, no 1, p. 1-6, article id 1000108Article in journal (Refereed)
    Abstract [en]

    Introduction: Vascular endothelial growth factor (VEGF) is considered as endothelial cell-specific mitogen that plays an important role in the process of angiogenesis, thereby affecting the prognosis of tumor as angiogenesis is a crucial phase in tumor growth and metastasis. Accordingly, we carried out a case-control study to assess whether VEGF rs3025039 polymorphism affects the growth pattern and susceptibility to colon carcinoma.

    Materials and methods: One hundred and fifty, formalin fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with colon carcinoma and the same number of blood controls were used in the present study. VEGF +936 C>T (rs3025039) polymorphism was evaluated by pyrosequencing. Computer image analysis was used to analyse the growth pattern of the colon carcinoma tumor by using cytokeratin-8 stained slides.

    Results: A heterozygous genotype TC in rs3025039 polymorphism was found as a significantly protective genotype as compared to homozygous genotypes (CC and TT). However we found no significant correlation between investigated polymorphisms, tumor growth pattern, 5 years survival and other clinicopathological parameters.

    Conclusion: We concluded that the heterogenous genotype of VEGF rs3025039 polymorphism appears to be a protective factor for colon carcinoma that could be a useful marker in follow-up studies and may be a genetic determinant for colon carcinoma.

    Download full text (pdf)
    fulltext
  • 2. Bjerkenstedt, Lars
    et al.
    Farde, Lars
    Terenius, Lars
    Edman, Gunnar
    Venizelos, Nikolaos
    Örebro University, Department of Clinical Medicine.
    Wiesel, Frits-Axel
    Support for limited brain availability of tyrosine in patients with schizophrenia2006In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 9, no 2, p. 247-255Article in journal (Refereed)
    Abstract [en]

    Several mechanisms have been suggested to account for altered dopaminergic neurotransmission in schizophrenia. The brain is the only organ for which amino-acid transport is limited and competition for transport over the blood-brain barrier (BBB) occurs at physiological plasma concentrations. One line of research suggests that patients with schizophrenia have altered brain levels of the essential amino acid tyrosine, the precursor for the synthesis of dopamine. The most common hypothesis is that less tyrosine is available because of competition with elevated levels of other amino acids. By consequence, the synthesis of dopamine in the brain will decrease. In contrast, another line of evidence suggests a change in the affinity for one of the transport proteins. A limitation of this research has been that the systems for amino-acid transport across the BBB have not been fully characterized at a molecular or functional level. The L system is the major system for transport of tyrosine across cell membranes including the BBB. The A system is also involved in this transport. Earlier in-vitro studies using fibroblasts have demonstrated a normal L system in schizophrenia but nevertheless reduced tyrosine transport. The combination of molecular research, fibroblast techniques, and brain imaging provides a new basis for clinical research on the role of amino-acid membrane transport in schizophrenia.

  • 3.
    Comasco, Erika
    et al.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Vumma, Ravi
    Department of Chemistry and Biomedical Sciences, Faculty of Health and Life Sciences, Linnaeus University, Kalmar, Sweden.
    Toffoletto, R.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Johansson, Jessica
    Örebro University, School of Health Sciences. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Flyckt, Lena
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
    Lewander, Tommy
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Oreland, Lars
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Bjerkenstedt, Lars
    Strömstad Academy, Strömstad, Sweden.
    Andreou, Dimitrios
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
    Söderman, Erik
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
    Terenius, Lars
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
    Agartz, Ingrid
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway .
    Jönsson, Erik G.
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Venizelos, Nikolaos
    Örebro University, School of Health Sciences.
    Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia2017In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 74, no 2, p. 96-103Article in journal (Refereed)
    Abstract [en]

    Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

  • 4.
    Engwall, Magnus
    et al.
    Örebro University, School of Science and Technology.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Westman, Ola
    Örebro University, School of Science and Technology.
    Larsson, Maria
    Örebro University, School of Science and Technology.
    Nordén, Marcus
    Örebro University, School of Science and Technology.
    Hollert, Henner
    Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Polycyclic aromatic hydrocarbons (PAHs) reduce hepatic beta-oxidation of fatty acids in chick embryos2013In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 20, no 3, p. 1881-1888Article in journal (Refereed)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAHs) are widespread fused-ring contaminants formed during incomplete combustion of almost all kind of organic materials from both natural and anthropogenic sources. Some PAHs have been shown to be carcinogenic to humans, and a wide range of PAHs are found in wildlife all around the globe including avian species. The purpose of this project was to assess the effects of a standard mixture of 16 PAHs (United States Environmental Protection Agency) on the hepatic fatty acid beta-oxidation in chicken embryos (Gallus gallus domesticus) exposed in ovo. The hepatic beta-oxidation was measured using a tritium release assay with [9,10-H-3]-palmitic acid (16:0) as substrate. Treated groups were divided into groups of 0.05, 0.1, 0.3, 0.5, and 0.8 mg PAHs/kg egg weight. The hepatic beta-oxidation was reduced after exposure in ovo to the 16 PAHs mixture compared to control. The mechanisms causing reduced fatty acid oxidation in the present study are unclear, however may be due to deficient membrane structure, the functionality of enzymes controlling the rate of fatty acid entering into the mitochondria, or complex pathways connected to endocrine disruption. To the best of our knowledge, this is the first time a PAH-caused reduction of hepatic beta-oxidation of fatty acids in avian embryos has been observed. The implication of this finding on risk assessment of PAH exposure in avian wildlife remains to be determined.

  • 5. Fernell, Elisabeth
    et al.
    Karagiannakis, Aristea
    Örebro University, Department of Clinical Medicine.
    Edman, Gunnar
    Bjerkenstedt, Lars
    Wiesel, Frits-Axel
    Venizelos, Nikolaos
    Örebro University, Department of Clinical Medicine.
    Aberrant amino acid transport in fibroblasts from children with autism2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 418, no 1, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Autism is a developmental, cognitive disorder clinically characterized by impaired social interaction, communication and restricted behaviours. The present study was designed to explore whether an abnormality in transport of tyrosine and/or alanine is present in children with autism. Skin biopsies were obtained from 11 children with autism (9 boys and 2 girls) fulfilling the DSM-IV diagnostic criteria for autistic disorder and 11 healthy male control children. Transport of amino acids tyrosine and alanine across the cell membrane of cultured fibroblasts was studied by the cluster tray method. The maximal transport capacity, Vmax and the affinity constant of the amino acid binding sites, Km, were determined. Significantly increased Vmax for alanine (p = 0.014) and increased Km for tyrosine (p = 0.007) were found in children with autism. The increased transport capacity of alanine across the cell membrane and decreased affinity for transport sites of tyrosine indicates the involvement of two major amino acid transport systems (L- and A-system) in children with autism. This may influence the transport of several other amino acids across the blood–brain-barrier. The significance of the findings has to be further explored. © 2007 Elsevier Ireland Ltd. All rights reserved

  • 6. Flyckt, Lena
    et al.
    Edman, Gunnar
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Borg, Kristian
    Aberrant tyrosine transport across the fibroblast membrane in patients with schizophrenia: indications of maternal inheritance2011In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 45, no 4, p. 519-525Article in journal (Refereed)
    Abstract [en]

    Background: In previous studies of the present patients with schizophrenia, aberrant tyrosine transport across the fibroblast membrane was found. A low K(m), a kinetic factor indicating high affinity between tyrosine and the binding site at the cell membrane, was found to be associated with poor cognitive functions in patients. The present study aimed at investigating possible relationships between patients with schizophrenia and their first-degree relatives in aberrant tyrosine transport indicating that it may be a biological marker for the genetic susceptibility. Methods: Thirty-three parents, 13 fathers and 20 mothers, from 23 families with a schizophrenic patient agreed to enter the study. They underwent skin biopsies for fibroblast cultivation, neuropsychological and psychiatric investigations and were classified as family history positive or negative. Tyrosine transport kinetics (K(m) and V(max)) were calculated from in vitro trials of gradients of extracellular tyrosine concentrations in fibroblast cultures. Results: An association between patients with schizophrenia and their mothers were found for a low K(m) indicating maternal inheritance. Mothers displaying a low K(m) performed worse on the neuropsychological tests compared to mothers with normal K(m). Corresponding relationships between a low K(m) and neurocognitive dysfunction had previously been found for the patients. Conclusions: An aberrant tyrosine transport across plasma membrane may constitute a biological marker for an endophenotype within the schizophrenia spectrum with low cognitive functioning. A plausible mode for genetic transmission is maternal inheritance. (C) 2010 Elsevier Ltd. All rights reserved.

  • 7.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Landgren, Magnus
    Unit of Neurodevelopmental Disorders, Department of Paediatrics, Skaraborg Hospital, Mariestad, Sweden.
    Fernell, Elisabeth
    Unit of Neurodevelopmental Disorders, Department of Paediatrics, Skaraborg Hospital, Mariestad, Sweden; The Research and Development Centre, Skaraborg Hospital, Skövde, Sweden; The Gillberg Neuoropsychiatry Centre, Sahlgrenska Academy, Gothenburg, Sweden.
    Lewander, Tommy
    Department of Neuroscience, Psychiatry, Uppsala University Hospital, Uppsala, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Decreased binding capacity (Bmax) of muscarinic acetylcholine receptors in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD)2013In: ADHD Attention Deficit and Hyperactivity Disorders, ISSN 1866-6116, E-ISSN 1866-6647, Vol. 5, no 3, p. 267-271Article in journal (Refereed)
    Abstract [en]

    Monoaminergic dysregulation is implicated in attention-deficit/hyperactivity disorder (ADHD), and methylphenidate and amphetamines are the most frequently prescribed pharmacological agents for treating ADHD. However, it has recently been proposed that the core symptoms of the disorder might be due to an imbalance between monoaminergic and cholinergic systems. In this study, we used fibroblast cell homogenates from boys with and without ADHD as an extraneural cell model to examine the cholinergic receptor density, that is, muscarinic acetylcholine receptors (mAChRs). We found that the binding capacity (Bmax) of [³H] Quinuclidinyl benzilate (³H-QNB) to mAChRs was decreased by almost 50 % in the children with ADHD (mean = 30.6 fmol/mg protein, SD = 25.6) in comparison with controls [mean = 63.1 fmol/mg protein, SD = 20.5, p ≤ 0.01 (Student's unpaired t test)]. The decreased Bmax indicates a reduced cholinergic receptor density, which might constitute a biomarker for ADHD. However, these preliminary findings need to be replicated in larger ADHD and comparison cohorts

    Download full text (pdf)
    fulltext
  • 8.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Landgren, Magnus
    Fernell, Elisabeth
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences.
    Ahlin, Arne
    Bjerkenstedt, Lars
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study2011In: Behavioral and Brain Functions, ISSN 1744-9081, E-ISSN 1744-9081, Vol. 7, p. 40-Article in journal (Refereed)
    Abstract [en]

    Background: The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. Methods: Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (V(max)) and affinity constant (K(m)) were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test. Results: The ADHD group had significantly decreased V(max) (p = 0.039) and K(m) (increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher V(max) of alanine transport (p = 0.031), but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group. Conclusions: Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

  • 9.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Landgren, Magnus
    Fernell, Elisabeth
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences.
    Åhlin, Arne
    Bjerkenstedt, Lars
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Altered tryptophan and alanine transport in fibroblasts from boys with Attention Deficit/Hyperactivity Disorder (ADHD): an in vitro studyManuscript (preprint) (Other academic)
  • 10.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Larsson, Christer
    Landgren, Magnus
    Fernell, Elisabeth
    Lewander, Tommy
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Decreased density of muscarinic acetylcholine receptors in fibroblasts from children with Attention Deficit/Hyperactivity Disorder (ADHD)Manuscript (preprint) (Other academic)
  • 11.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Persson, M-L
    Karolinska Institutet, Stockholm, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Aberrant tyrosine transport in fibroblasts from patients with bipolar type-1 disorder2010In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 3, p. 364-365Article in journal (Refereed)
  • 12.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Interleukin-1beta inhibits tyrosine transport in fibroblasts from patients with schizophrenia and healthy controls2010In: Abstracts of, International Institute of Anticancer Research, 2010, no 3, p. 365-367, article id 45Conference paper (Refereed)
  • 13.
    Kolisis, Fragiskos
    et al.
    National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBRB), Athens, Greece.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    ABSTRACTS OF THE 3rd SWEDISH-HELLENIC LIFE SCIENCES RESEARCH CONFERENCE Athens, March 25-27, 2010 Preface2010In: In Vivo, ISSN 0258-851X, Vol. 24, no 3, p. 35p. 343-343Article in journal (Refereed)
  • 14.
    Logotheti, Marianthi
    et al.
    e-NIOS Applications PC, Kallithea, Greece; Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    e-NIOS Applications PC, Kallithea, Greece; Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Venizelos, Nikolaos
    Örebro University, School of Medical Sciences.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Recent Advancements in Bipolar Disorder studies through Genomic, Epigenomic and Metagenomic Approaches2019In: Journal of Psychiatry and Psychology Research, ISSN 2640-6136, Vol. 2, no 1, p. 56-66Article, review/survey (Refereed)
    Abstract [en]

    Bipolar disorder is a complex and highly heritable psychiatric disorder characterized by severe mood alterations. The precise geneticunderpinnings of the disease have not been identified so far, despite numerous genome-wide association findings. This review describes thecurrent state of genetic studies based on next generation sequencing technologies including whole exome and whole genome sequencing, aswell as RNA-sequencing and highlights the fact that the integration of these studies can reveal novel knowledge such as the functional roleof gene variants. However, due to the complexity of bipolar disorder, it is a compelling candidate for studies beyond DNA and RNAsequencing. Epigenetic alterations, defined as heritable but reversible modifications including DNA methylation, DNAhydroxymethylation, histone modifications and non-coding RNAs may be the link between genome and environment interactions.Additionally, a possible source of the reported immune activation in bipolar disorder is the micro biome of gastrointestinal tract, due torecent studies that indicate its pivotal role in brain function through the ‘gut-brain’ axis. The identification of methods able to modulate themicro biome emerges as a promising path for novel diagnostic and treatment options in bipolar disorder, thus the number of metagenomicstudies in bipolar disorder has substantially increased the last years. Overall, the paper aims to review the most recent literature ongenomic, epigenomic and metagenomic studies that have contributed to our understanding of the pathophysiology of bipolar disorder sofar. The paper also focuses on the exploitation of recent advancements in high-throughput technologies for the elucidation of bipolardisorder through different approaches that may provide complementary knowledge and concludes to the need for merging the gap betweenall the gathered knowledge from the analysis of high-throughput data.

    Download full text (pdf)
    Recent Advancements in Bipolar Disorder studies through Genomic, Epigenomic and Metagenomic Approaches
  • 15.
    Logotheti, Marianthi
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Metabolic Engineering and Bioinformatics Group, National Hellenic Research Foundation, Athens, Greece; Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Papadodima, Olga
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Gene Expression Analysis of Fibroblasts from Patients with Bipolar Disorder2015In: Journal of Neuropsychopharmacology & Mental Health, ISSN 2472-095X, Vol. 1, no 1, p. 1-9, article id 1000103Article in journal (Refereed)
    Abstract [en]

    Bipolar disorder is a severe, lifelong psychiatric disease. The main underlying pathophysiology of the disease is still incomprehensible. Various studies have suggested that many genes of small impact in combination with environmental factors contribute to the expression of the disease. In this study comparative transcriptomic profiling to characterize skin fibroblasts’ gene expression of bipolar disorder patients compared to healthy controls has been performed. Skin fibroblast cells from bipolar disorder patients (n=10) and marched healthy controls (n=5) have been cultured. RNA was extracted and then hybridized onto Illumina Human HT-12 v4 Expression BeadChips. Differentially expressed genes between bipolar disorder samples and healthy controls were identified by performing unequal t-test on log 2 transformed expression values. The resulting gene list was obtained by setting the p-value threshold to 0.05 and by removing genes that presented a fold change ≥ |0.5| (in log 2 scale). We concluded to 457 differentially expressed genes. Among them 127 showed an upregulation and 330 were downregulated. Τhe expression alterations of selected genes were validated by quantitative real-time polymerase chain reaction. In order to derive better insight into the biological mechanisms related to the differentially expressed genes, the lists of significant genes were subjected to pathway analysis and target prioritization indicating various processes such as calcium ion homeostasis, positive regulation of apoptotic process and cellular response to retinoic acid.

    Download full text (pdf)
    fulltext
  • 16.
    Logotheti, Marianthi
    et al.
    Neuropsychiatric Research Laboratory, Department of Clinical Medicine, Örebro University, Örebro, Sweden; Metabolic Engineering and Bioinformatics Program, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Papadodima, Olga
    Metabolic Engineering and Bioinformatics Program, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Venizelos, Nikolaos
    Neuropsychiatric Research Laboratory, Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Chatziioannou, Aristitelis
    Metabolic Engineering and Bioinformatics Program, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    A Comparative Genomic Study in Schizophrenic and in Bipolar Disorder Patients, Based on Microarray Expression Profiling Meta-Analysis2013In: Scientific World Journal, ISSN 1537-744X, E-ISSN 1537-744X, Vol. 2013, no 685917, p. 1-14, article id 685917Article in journal (Refereed)
    Abstract [en]

    Schizophrenia affecting almost 1% and bipolar disorder affecting almost 3%-5% of the global population constitute two severe mental disorders. The catecholaminergic and the serotonergic pathways have been proved to play an important role in the development of schizophrenia, bipolar disorder, and other related psychiatric disorders. The aim of the study was to perform and interpret the results of a comparative genomic profiling study in schizophrenic patients as well as in healthy controls and in patients with bipolar disorder and try to relate and integrate our results with an aberrant amino acid transport through cell membranes. In particular we have focused on genes and mechanisms involved in amino acid transport through cell membranes from whole genome expression profiling data. We performed bioinformatic analysis on raw data derived from four different published studies. In two studies postmortem samples from prefrontal cortices, derived from patients with bipolar disorder, schizophrenia, and control subjects, have been used. In another study we used samples from postmortem orbitofrontal cortex of bipolar subjects while the final study was performed based on raw data from a gene expression profiling dataset in the postmortem superior temporal cortex of schizophrenics. The data were downloaded from NCBI's GEO datasets

    Download full text (pdf)
    fulltext
  • 17.
    Logotheti, Marianthi
    et al.
    Örebro University, School of Medical Sciences. Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Pilalis, Eleftherios
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Venizelos, Nikolaos
    Örebro University, School of Health Sciences.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Development and validation of a skin fibroblast biomarker profile for schizophrenic patientsManuscript (preprint) (Other academic)
  • 18.
    Logotheti, Marianthi
    et al.
    Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Pilalis, Eleftherios
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Venizelos, Nikolaos
    Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden .
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece.
    Development and validation of a skin fibroblast biomarker profile for schizophrenic patients2016In: AIMS Bioengineering, ISSN 2375-1487, Vol. 3, no 4, p. 552-565Article in journal (Refereed)
    Abstract [en]

    Gene expression profiles of non-neural tissues through microarray technology could be used in schizophrenia studies, adding more information to the results from similar studies on postmortem brain tissue. The ultimate goal of such studies is to develop accessible biomarkers. Supervised machine learning methodologies were used, in order to examine if the gene expression from skin fibroblast cells could be exploited for the classification of schizophrenic subjects. A dataset of skin fibroblasts gene expression of schizophrenia patients was obtained from Gene Expression Omnibus database. After applying statistical criteria, we concluded to genes that present a differential expression between the schizophrenic patients and the healthy controls. Based on those genes, functional profiling was performed with the BioInfoMiner web tool. After the statistical analysis, 63 genes were identified as differentially expressed. The functional profiling revealed interesting terms and pathways, such as mitogen activated protein kinase and cyclic adenosine monophosphate signaling pathways, as well as immune-related mechanisms. A subset of 16 differentially expressed genes from fibroblast gene expression profiling that occurred after Support Vector Machines Recursive Feature Elimination could efficiently separate schizophrenic from healthy controls subjects. These findings suggest that through the analysis of fibroblast based gene 553 expression signature and with the application of machine learning methodologies we might conclude to a diagnostic classification model in schizophrenia.

    Download full text (pdf)
    Development and validation of a skin fibroblast biomarker profile for schizophrenic patients
  • 19.
    Logotheti, Marianthi
    et al.
    Örebro University, School of Medical Sciences. Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Pilalis, Eleftherios
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Venizelos, Nikolaos
    Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Studying Microarray Gene Expression Data of Schizophrenic Patients for Derivation of a Diagnostic Signature through the Aid of Machine Learning2016In: Biometrics & Biostatistics International Journal, ISSN 2378-315X, Vol. 4, no 5, article id 00106Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a complex psychiatric disease that is affected by multiple genes, some of which could be used as biomarkers for specific diagnosis of the disease. In this work, we explore the power of machine learning methodologies for predicting schizophrenia, through the derivation of a biomarker gene signature for robust diagnostic classification purposes. Postmortem brain gene expression data from the anterior prefrontal cortex of schizophrenia patients were used as training data for the construction of the classifiers. Several machine learning algorithms, such as support vector machines, random forests, and extremely randomized trees classifiers were developed and their performance was tested. After applying the feature selection method of support vector machines recursive feature elimination a 21-gene model was derived. Using these genes for developing classification models, the random forests algorithm outperformed all examined algorithms achieving an area under the curve of 0.98 and sensitivity of 0.89, discriminating schizophrenia from healthy control samples with high efficiency. The 21-gene model that was derived from the feature selection is suggested for classifying schizophrenic patients, as it was successfully applied on an independent dataset of postmortem brain samples from the superior temporal cortex, and resulted in a classification model that achieved an area under the curve score of 0.91. Additionally, the functional analysis of the statistically significant genes indicated many mechanisms related to the immune system.

  • 20.
    Nordén, Marcus
    et al.
    Örebro University, School of Science and Technology.
    Westman, Ola
    Örebro University, School of Science and Technology.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Perfluorooctane sulfonate increases β-oxidation of palmitic acid in chicken liver2012In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 19, no 5, p. 1859-1863Article in journal (Refereed)
    Abstract [en]

    Purpose: Perfluorooctane sulfonate (PFOS) belongs to a group of chemicals called perfluoroalkyl acids that have been extensively used in various applications such as stain and oil resistant treatments for fabrics, fire-fighting foams, and insecticides. These chemicals present an environmental and health risk being present in many samples both in wildlife and humans. In this study, we investigate the effect of PFOS on fatty acid β-oxidation in developing chicken embryos.

    Methods: Fertilized chicken eggs were exposed in ovo to PFOS at day 4 of incubation. On day 10, the eggs were dissected and livers were incubated in vitro with (3)H-palmitic acid for 2 h. The media were collected, and after clean up, the amount of tritiated water was measured with liquid scintillation counting to determine the rate of palmitic acid β-oxidation.

    Results: PFOS was found to induce fatty acid β-oxidation at doses starting from a lowest observed effect level (LOEL) of 0.1 μg/g egg weight. Maximum induction of 77 % compared to control was seen at 0.3 μg/g.

    Conclusions: The administered doses in which effects are seen are around and even lower than the levels that can be found in wild populations of birds. General population human levels are a factor of two to three times lower than the LOEL value of this study. The environmental contamination of PFOS therefore presents a possibility of effects in wild populations of birds.

  • 21. Olsson, Emma
    et al.
    Friberg, Örjan
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Koskela, Anita
    Örebro University, School of Health and Medical Sciences.
    Källman, Jan
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences.
    Coagulase-negative staphylococci isolated from sternal wound infections after cardiac surgery: attachment to and accumulation on sternal fixation stainless steel wires2007In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 115, no 2, p. 142-151Article in journal (Refereed)
    Abstract [en]

    Sternal wound infection (SWI) is a serious complication after cardiac surgery. Coagulase-negative staphylococci (CoNS) have been found to be the most common pathogen involved in this postoperative infection related to implanted foreign materials, i.e. sternal fixation wires made from stainless steel. In this study a rapid and simple assay was developed for studying attachment and accumulation of CoNS on stainless steel wires in vitro using [(3)H] thymidine. The method showed a potential to detect differences in the dynamics of the adherence patterns among various CoNS isolates. However, no differences in attachment and accumulation were found between isolates causing deep SWI after cardiac surgery and contaminant isolates. In addition, there were no differences in the distribution of the ica operon between the two groups, as determined by polymerase chain reaction (PCR). Nevertheless, the ability to produce biofilm was found to be present significantly more frequently among SWI isolates than among contaminants.

  • 22.
    Pernow, Ylva
    et al.
    Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Shahror, Rami
    Nutrition-Gut-Brain Interactions Research Centre (NGBI), Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Acharya, Shikha
    Nutrition-Gut-Brain Interactions Research Centre (NGBI), Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Jahnson, Lena
    Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.
    Vumma, Ravi
    Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Medical Sciences.
    Aberrant tryptophan transport in cultured fibroblast from patients with Male Idiopathic Osteoporosis: An in vitro study2018In: Bone Reports, ISSN 2352-1872, Vol. 8, p. 25-28Article in journal (Refereed)
    Abstract [en]

    It has been demonstrated, that long-term chronic tryptophan deficiency, results in decreased serotonin synthesis, which may lead to low bone mass and low bone formation. Findings from studies in male patients with idiopathic osteoporosis suggested a decreased transport of tryptophan in erythrocytes of osteoporotic patients, indicating that serotonin system defects may be involved in the etiology of low bone mass. Tryptophan is the precursor of serotonin, and a disturbed transport of tryptophan is implicated in altered serotonin synthesis. However, no study has investigated the tryptophan transport kinetics in MIO patients. The aim of this study is to investigate the kinetic parameters of tryptophan transport in fibroblasts derived from MIO patients compared to age and sex matched controls. Fibroblast cells were cultured from skin biopsies obtained from 14 patients diagnosed with Male Idiopathic Osteoporosis and from 13 healthy age-sex matched controls, without a diagnosis of osteoporosis. Transport of the amino acid tryptophan across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined by using the Lineweaver-Burke plot equation. The results of this study have shown a significantly lower mean value for Vmax (p = 0.0138) and lower Km mean value (p = 0.0009) of tryptophan transport in fibroblasts of MIO patients compared to the control group. A lower Vmax implied a decreased tryptophan transport availability in MIO patients. In conclusion, reduced cellular tryptophan availability in MIO patients might result in reduced brain serotonin synthesis and its endogenous levels in peripheral tissues, and this may contribute to low bone mass/formation. The findings of the present study could contribute to the etiology of idiopathic osteoporosis and for the development of novel approaches for diagnosis, treatment and management strategies of MIO.

    Download full text (pdf)
    Aberrant tryptophan transport in cultured fibroblast from patients with Male Idiopathic Osteoporosis: An in vitro study
  • 23.
    Persson, Maj-Liz
    et al.
    Stockholm County Council, Center for Dependency Disorder, Karolinska University Hospital Huddinge.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences.
    Raita, Jani
    Stockholm County Council, Center for Dependency Disorder, Karolinska University Hospital Huddinge.
    Bjerkenstedt, Lars
    Psychiatry Section, Dept of Clinical and Experimental Medicine, Linköping University.
    Wiesel, Frits-Axel
    Department of Neuroscience, Psychiatry, University Hospital, Uppsala University.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Aberrant amino acid transport in fibroblasts from patients with bipolar disorder2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 457, no 1, p. 49-52Article in journal (Refereed)
    Abstract [en]

    Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n = 10) and healthy controls (n = 10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (Vmax) and affinity constant (Km) were determined. A significantly lower Vmax for tyrosine (p = 0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in Km for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low Vmax) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.

  • 24.
    Tobe, Brian T. D.
    et al.
    Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Psychiatry, Veterans Administration Medical Center, La Jolla CA, USA .
    Venizelos, Nikolaos
    Örebro University, School of Health Sciences. Department of Cinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Snyder, Evan Y.
    Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA, USA.
    Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. E4462-E4471, article id 1700111114Article in journal (Refereed)
    Abstract [en]

    The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active non-phosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2: CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the " lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.

    Download full text (pdf)
    fulltext
  • 25.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Aberrant Amino Acid Transport in Patients with Schizophrenia, Bipolar-I Disorders and Autism2011In: Psychiatry and the neurosciences: international perspectives, Bologna, Italy: Medimond, 2011, p. 155-161Conference paper (Other academic)
    Abstract [en]

    Tyrosine and tryptophan are precursors to dopamine and serotonin and are involved in partial regulation of dopamine and serotonin synthesis. Changes in tyrosine and or tryptophan availability may influence dopamine-serotonin function that may cause widespread changes both in neurotransmission and psychopathology in patients with schizophrenia, bipolar-I and related CNS disorders. Competitive transport with other amino acids or aberrant transport of these precursors, across the cell membranes/blood brain barrier (BBB), can cause a limited availability of tyrosine and/or tryptophan to the brain. Transport of neutral amino acids including tyrosine, tryptophan and alanine, mainly occurs through L and A system and its isoforms. Evidence from different investigations of an aberrant amino acid transport in fibroblast cell obtain from patients with schizophrenia, bipolar-I disorders and autism, as well as the functionality and the relationship between tyrosine, tryptophan and alanine transport are touched on in this article

  • 26.
    Venizelos, Nikolaos
    Örebro University, School of Medical Sciences.
    Amino acids and cognition in schizophrenia and bipolar-I disorders2008In: Book of Abstracs, 3rd dual INA-WFSBPcongress on “Psychiatry and the Neurosciences” Athens, Greece, 2008, p. 25-26Conference paper (Other academic)
  • 27.
    Venizelos, Nikolaos
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bjerkenstedt, Lars
    Strömstad Academy, Strömstad, Sweden.
    Amino acids and psychiatric disorders: a historical background2011In: Psychiatry and the Neurosciences: International Perspectives / [ed] C.R. Soldatos & D.G. Dikeos, Bologna, Italy: Medimond, 2011, p. 23-30Chapter in book (Other academic)
    Abstract [en]

    The brain is the only organ for which amino acid transport is limited, so that competition occurs at physiological plasma concentrations. Amino acids are building stones in the synthesis of the monoamines dopamine, noradrenaline, and serotonin. Central monoamine turnover is mainly regulated by the availability of the precursor amino acids tyrosine and tryptophan in plasma. New and extended knowledge in the 21st century about the membrane bound amino acid transporters has revolutionized earlier facts about their affinity and capacity. Accordingly there are now four isoforms of system L (LAT 1-LAT 4) and three isoforms of system A (ATA1-ATA3). Each one has its own kinetic definition and can be tested by the fibroblast technique using blockers for one or more systems. Using this in vitro technique it has been found that there is a competition between the amino acids tyrosine and alanine with the major tyrosine transporter LAT 1 coded by a gene on chromosome 16. This fact has made possible a new interpretation and in all probability new understanding of earlier performed studies in patients with schizophrenia, bipolar disorder and autism.

  • 28.
    Venizelos, Nikolaos
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Landgren, Magnus
    Dept Pediatrics, Skaraborg Hosp, Mariestad, Sweden.
    Fernell, Elisabeth
    Gillberg Neuoropsychiat Center, Sahlgrenska Academy, Gothenburg, Sweden.
    Lewander, T
    Uppsala University, Uppsala, Sweden.
    Decreased density of muscarinic acetylcholine receptors in fibroblast from boys with attention deficit/hyperactivity disorder (ADHD): An in vitro study2012In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 15, no s1, p. 224-224, article id P-17-015Article in journal (Refereed)
    Abstract [en]

    Background: It is believed that the neurotransmitters, dopamine and norepinephrine are involved in the pathophysiology of the neurobehavioral disorder Attention Deficit/Hyperactivity Disorder (ADHD). Moreover, it is known that cholinergic activity can modulate dopaminergic activity in the brain. The aim of this study was to measure the density and affinity of muscarinic acetylcholine receptors (mAChRs) in children with ADHD, by using the fibroblast cell model.

    Methods: Fibroblast cell homogenates from 11 boys with ADHD, fulfilling the DSM-IV diagnostic criteria and from 9 matching controls were used in the study. Radioligand binding assay was used to determine the maximal binding capacity (Bmax) and the equilibrium dissociation constant (KD) of mAChRs, using the mAChR antagonist 3H-QNB. Due to non-normally distribution of the calculated data, three outliers were identified by the MADE method (two in the ADHD group, both with a non-hereditary ADHD and one in the comparison group), and were therefore excluded from the statistical analyses.

    Results: A significantly lower Bmax for the binding of the muscarinic antagonist 3H-QNB was observed in the fibroblasts from the children with ADHD (n=9) when compared to controls (n=8) (p=0.01), but the KD did not differ between the two groups (p=0.40).

    Conclusions:The present results indicate a reduced density of mAChR in fibroblasts from children with a hereditary ADHD, which might be an indicator of the disorder. However, further studies are needed to confirm these observations.

  • 29.
    Venizelos, Nikolaos
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Landgren, Magnus
    Dept Pediatrics, Skaraborg Hosp, Mariestad, Sweden.
    Fernell, Elisabeth
    Gillberg Neuoropsychiat Center, Sahlgrenska Academy, Gothenburg, Sweden.
    Vumma, R
    Altered tryptophan and alanine transport in cultured fibroblast from boys with attention deficit/hyperactivity disorder (ADHD)2012In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 15, no s1, p. 224-224, article id P-17-014Article in journal (Refereed)
    Abstract [en]

    Background: The amino acid tyrosine is the precursor for the synthesis of the neurotransmitters dopamine and norepinephrine, while tryptophan is the precursor of serotonin. These neurotransmitters are implicated in the pathophysiology of Attention Deficit/Hyperactivity Disorder (ADHD). A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other neuropsychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. 

    Materials and Methods: Skin biopsies from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder were obtained, and from the biopsies were primary fibroblast cell lines derived. The transport of the amino acids tyrosine, tryptophan and alanine across the fibroblast cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined. Student’s unpaired t-test or the Mann Whitney U test was used to analyze any difference between the two groups.

    Results: The tryptophan transport (Vmax) was significantly decreased in the ADHD group in comparison to controls (p=0.039), while the alanine transport (Vmax) was significantly increased in the ADHD group (p=0.031). There was no significant difference regarding the tyrosine transport between the two groups.

    Conclusions: A decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group, since tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

  • 30.
    Venizelos, Nikolaos
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Venizelos, Frans
    The Stockholm Centre for Dependency Disorders, Stockholm County Council, Stockholm, Sweden.
    Availability Of Tyrosine And Tryptophan, Precursors Of Dopamine And Serotonin And Neuropsychiatric Disorders: A Review2015In: Pluralism in psychiatry: II. Multidimensional conciderations / [ed] Constantin Soldatos, Dimitris Dikeos, Pedro Ruiz, Dinesh Bhugna, Michelle Riba, Bologna, Italy: Medimond, 2015, p. 49-54Chapter in book (Refereed)
    Abstract [en]

    The large neutral amino acids tyrosine and tryptophan are precursors of the neurotransmitters dopamine and serotonin and their availability in the brain may influence neurotransmission. Disturbed neurotransmitter systems, such as the dopaminergic, noradrenergic and serotoninergic systems are implicated in the pathogenesis of neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism and attention deficit hyperactivity disorder (ADHD).

    The primary aim of this study is to outline the findings/evidence from different investigations in vitro, concerning aberrant amino acid (tyrosine, tryptophan and alanine) transport in fibroblasts obtained from patients with schizophrenia and their relatives, bipolar-I disorder, autism and ADHD disorders.

    The outlines of the findings presented in this study provide evidence that amino acids, tyrosine and tryptophan are strongly involved in schizophrenia, bipolar disorder, autism and ADHD.

  • 31.
    Vumma, Ravi
    et al.
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Lewander, Tommy
    Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University Hospital.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Functional characterization of tryptophan transport in human fibroblast cellsManuscript (Other (popular science, discussion, etc.))
  • 32.
    Vumma, Ravi
    et al.
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Lewander, Tommy
    Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University Hospital, Uppsala, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Tryptophan transport in human fibroblast cells: a functional characterization2011In: International Journal of Tryptophan Research, ISSN 1178-6469, no 4, p. 19-27Article in journal (Refereed)
    Abstract [en]

    There are indications that serotonergic neurotransmission is disturbed in several psychiatric disorders. One explanation may be disturbed transport of tryptophan (precursor for serotonin synthesis) across cell membranes. Human fibroblast cells offer an advantageous model to study the transport of amino acids across cell membranes, since they are easy to propagate and the environmental factors can be controlled. The aim of this study was to functionally characterize tryptophan transport and to identify the main transporters of tryptophan in fibroblast cell lines from healthy controls.

    Tryptophan kinetic parameters (Vmax and Km) at low and high concentrations were measured in fibroblasts using the cluster tray method. Uptake of 3H (5)-L-tryptophan at different concentrations in the presence and absence of excess concentrations of inhibitors or combinations of inhibitors of amino acid transporters were also measured. Tryptophan transport at high concentration (0.5 mM) had low affinity and high Vmax and the LAT1 isoform of system-L was responsible for approximately 40% of the total uptake of tryptophan. In comparison, tryptophan transport at low concentration (50 nM) had higher affinity, lower Vmax and approximately 80% of tryptophan uptake was transported by system-L with LAT1 as the major isoform. The uptake of tryptophan at the low concentration was mainly sodium (Na+) dependent, while uptake at high substrate concentration was mainly Na+ independent. A series of different transporter inhibitors had varying inhibitory effects on tryptophan uptake.

    This study indicates that tryptophan is transported by multiple transporters that are active at different substrate concentrations in human fibroblast cells. The tryptophan transport trough system-L was mainly facilitated by the LAT1 isoform, at both low and high substrate concentrations of tryptophan.

    Download full text (pdf)
    fulltext
  • 33.
    Vumma, Ravi
    et al.
    Department of Chemistry and Biomedical Sciences, Faculty of Health and Life Sciences, Linnaeus University, Kalmar, Sweden.
    Johansson, Jessica
    Örebro University, School of Health Sciences.
    Venizelos, Nikolaos
    Örebro University, School of Medical Sciences.
    Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts2017In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 75, no 4, p. 178-184Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated.

    AIMS: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts.

    METHODS: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls.

    RESULTS AND CONCLUSION: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

  • 34.
    Vumma, Ravi
    et al.
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Wiesel, F-A
    Bjerkenstedt, L.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Tyrosine transport through LAT1 transport system in fibroblasts of schizophrenic patients and healthy controlsManuscript (Other academic)
  • 35.
    Vumma, Ravi
    et al.
    Örebro University, School of Health and Medical Sciences.
    Wiesel, Frits-Axel
    Flyckt, Lena
    Bjerkenstedt, Lars
    Venizelos, Nikolaos
    Functional characterization of tyrosine transport in fibroblast cells from healthy controls2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 434, no 1, p. 56-60Article in journal (Refereed)
    Abstract [en]

    Human fibroblast cells are an advantageous model to study the transport of amino acids across cell membranes, since one can control the environmental factors. A major problem in all earlier studies is the lack of precise and detailed knowledge regarding the expression and functionality of tyrosine transporters in human fibroblasts. This motivated us to perform a systematic functional characterization of the tyrosine transport in fibroblast cells with respect to the isoforms of system-L (LAT1, LAT2, LAT3, LAT4), which is the major transporter of tyrosine. Ten (n = 10) fibroblast cell lines from healthy volunteers were included in the study. Uptake of L-[U-14C] tyrosine in fibroblasts was measured using the cluster tray method in the presence and absence of excess concentrations of various combinations of inhibitors. This study demonstrated that LAT1 is involved in 90% of total uptake of tyrosine and also around 51% of alanine. Not more than 10% can be accounted for by LAT2, LAT3 and LAT4 isoforms. LAT2 seems to be functionally weak in uptake of tyrosine while LAT3 and LAT4 contributed around 7%. 10% could be contributed by system-A (ATA2 isoform). Alanine consequently inhibited the tyrosine transport by up to 60%. Tyrosine transport through the LAT1 isoform has a higher affinity compared to system-L. In conclusion, the LAT1 isoform is the major transporter of tyrosine in human fibroblast cells. Competition between tyrosine and alanine for transport is shown to exist, probably between LAT1 and LAT2 isoforms. This study established fibroblast cells as a suitable experimental model for studying amino acid transport defects in humans.

  • 36.
    Westman, Ola
    et al.
    Örebro University, School of Science and Technology. Structor Miljöteknik AB, Örebro, Sweden.
    Larsson, Maria
    Örebro University, School of Science and Technology.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hollert, Henner
    Institute for Environmental Research, Department of Ecosystem Analysis, RWTH Aachen University, Aachen, Germany.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    An oxygenated metabolite of benzo[a]pyrene increases hepatic beta-oxidation of fatty acids in chick embryos2014In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 21, no 9, p. 6243-6251Article in journal (Refereed)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAHs) are well-known carcinogens to humans and ecotoxicological effects have been shown in several studies. However, PAHs can also be oxidized into more water soluble-oxygenated metabolites (Oxy-PAHs). The first purpose of the present project was to (1) assess the effects of a mixture containing three parent PAHs: anthracene, benz[a]anthracene, and benzo[a]pyrene versus a mixture of their oxygenated metabolites, namely: anthracene-9,10-dione, benz[a]anthracene-7,12-dione, and 9,10-dihydrobenzo[a]pyrene-7-(8H)-one on the hepatic fatty acid beta-oxidation in chicken embryos (Gallus gallus domesticus) exposed in ovo. The second and also main purpose of the project was to (2) assess the effects of the parent PAHs versus their oxy-PAHs analogues when injected individually, followed by (3) additional testing of the individual oxy-PAHs. The hepatic beta-oxidation was measured using a tritium release assay with [9,10-H-3]-palmitic acid (16:0) as substrate. The result from the first part (1) showed reduced hepatic beta-oxidation after exposure in ovo to a mixture of three PAHs, however, increased after exposure to the mixture of three oxy-PAHs compared to control. The result from the second part (2) and also the follow-up experiment (3) showed that 9,10-dihydrobenzo[a]pyrene-7-(8H)-one was the causative oxy-PAH. The implication of this finding on the risk assessment of PAH metabolite exposure in avian wildlife remains to be determined. To the best of our knowledge, no similar studies have been reported.

  • 37.
    Westman, Ola
    et al.
    Örebro University, School of Science and Technology.
    Larsson, Maria
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hollert, Henner
    3RWTH Aachen University, Inst. For Environmental Research, Department of Ecosystem Analysis, Aachen, Germany.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    An oxygenated metabolite of benzo[a]pyrene increases hepatic β-oxidation of fatty acids in chick embryosManuscript (preprint) (Other academic)
  • 38.
    Westman, Ola
    et al.
    Örebro University, School of Science and Technology.
    Nordén, Marcus
    Örebro University, School of Science and Technology.
    Larsson, Maria
    Örebro University, School of Science and Technology.
    Venizelos, Nikolaos
    Örebro University, School of Science and Technology.
    Hollert, Henner
    RWTH Aachen University, Aachen, Germany.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Reduced beta-oxidation in avian following exposure of polycyclic aromatic hydrocarbons2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Supplement, p. s86-s87Article in journal (Refereed)
  • 39.
    Westman, Ola
    et al.
    Örebro University, School of Science and Technology.
    Nordén, Marcus
    Örebro University, School of Science and Technology.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Effects of perfluorinated compounds on hepatic fatty acid oxidation in avian embryos using a tritium release assay2010In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 3, p. 363-364Article in journal (Refereed)
    Abstract [en]

    Objective: Due to high persistence and bioaccumulationperfluorinated compounds (PFCs) are found globally in varioustypes of wildlife samples and also human samples¹. Accordingto our laboratory studies, perfluorooctane sulfonate (PFOS) hascaused early mortality in chicken embryos at doses close toconcentrations found in eggs of the Baltic guillemot². We havedesigned a method in which hepatic embryonic tissue fromchicken (Gallus domesticus) is used to investigate the effectsof PFCs on the β-oxidation of fatty acids.Materials and Methods: The embryos were exposed inovo to PFCs. On day 10 embryo livers were incubated invitro with tritiated fatty acids. Fatty acid oxidation was thencalculated from the tritium released into water, using ascintillation counter.Results: Our studies suggest a small but significant increaseof the β-oxidation of fatty acids in chicken embryonic livertissue in vitro after in ovo exposure to PFOS. The β-oxidationwas significantly induced after embryo exposure to 1 mg/kgPFOS (p=0.003) and 10 mg/kg PFOS (p=0.04), being 39%and 34% higher, respectively compared to control.Conclusion: The results show that in ovo exposure incombination with an in vitro method using a tritium releaseassay to detect effects on the β-oxidation of fatty acids inavian embryo hepatic tissue could be a useful method inelucidating possible mechanisms behind avian developmental toxicity.

  • 40.
    Wiesel, F.-A.
    et al.
    Department of Neuroscience Psychiatry, Uppsala University Hospital, Uppsala, Sweden.
    Bjerkenstedt, L.
    Department of Clinical Neuroscience, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
    Edman, G.
    Department of Psychiatry, R&D Section, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Flyckt, L.
    Department of Psychiatry, R&D Section, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Venizelos, Nikolaos
    Örebro University, Department of Clinical Medicine.
    The complexity of using D2-dopamine antagonists in the treatment of patients with schizophrenia2007In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 22, p. S5-S6Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a complex disorder and the view that schizophrenia is caused by hyperdopaminergic activity is an oversimplification. In fact, there are clinical evidence in accordance with a hypodopaminergic condition. Thus, untreated patients show motor disturbances in line with a decreased dopamine activity in the extrapyramidal system, likewise cognitive deficits and negative symptoms.

     

    In our research we have explored the evidence of schizophrenia as a hyper- or hypodopaminergic condition. With Positron Emission Tomography (PET) we have not seen any evidence of increased D2-dopamine receptors in the brain of never medicated patients. The major dopamine metabolite homovanillic acid (HVA) was lowered in CSF in line with a decreased dopamine turnover in the brain. Tyrosine is precursor to the synthesis of dopamine and for that aim we have made transport studies in an in vitro model with fibroblasts to determine tyrosine kinetics.

     

    The results demonstrated that tyrosine transport is lower in patients with schizophrenia in comparison to healthy controls. Tyrosine kinetics measured with PET demonstrated dysregulation of tyrosine transport into the brain.

    We have found evidence of schizophrenia as a hypodopaminergic condition. This fact is a problem realizing that our antipsychotics are D2-dopamine antagonists, thus decreasing dopamine activity even further.

    The concept of schizophrenia as both a hypo- and hyperdopaminergic condition may explain why clozapine, a week D2-antagonist, works more efficiently than other antipsychotic compounds. It should be recognized that positive symptoms are, at least partly, related to changes in dopamine activity and therefore respond very efficiently to D2-dopamine antagonists.

1 - 40 of 40
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf