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  • 1.
    Adori, Csaba
    et al.
    Karolinska Inst, Sweden.
    Daraio, Teresa
    Karolinska Inst, Sweden.
    Kuiper, Raoul
    Karolinska Inst, Sweden.
    Barde, Swapnali
    Karolinska Inst, Sweden.
    Horvathova, Lubica
    Slovak Acad Sci, Slovakia.
    Yoshitake, Takashi
    Karolinska Inst, Sweden.
    Ihnatko, Robert
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Georg August Univ Gottingen, Germany.
    Valladolid-Acebes, Ismael
    Karolinska Inst, Sweden.
    Vercruysse, Pauline
    Karolinska Inst, Sweden.
    Wellendorf, Ashley M.
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA.
    Gramignoli, Roberto
    Karolinska Inst, Sweden.
    Bozoky, Bela
    Karolinska Univ Hosp, Sweden.
    Kehr, Jan
    Karolinska Inst, Sweden.
    Theodorsson, Elvar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Cancelas, Jose A.
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA; Univ Cincinnati, OH 45267 USA.
    Mravec, Boris
    Slovak Acad Sci, Slovakia; Comenius Univ, Slovakia.
    Jorns, Carl
    Karolinska Univ Hosp Huddinge, Sweden.
    Ellis, Ewa
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Mulder, Jan
    Karolinska Inst, Sweden.
    Uhlen, Mathias
    Karolinska Inst, Sweden; Royal Inst Technol, Sweden.
    Bark, Christina
    Karolinska Inst, Sweden.
    Hökfelt, Tomas
    Karolinska Inst, Sweden.
    Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging2021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 30, article id eabg5733Article in journal (Refereed)
    Abstract [en]

    Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.

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  • 2.
    Barde, Swapnali
    et al.
    Karolinska Institute, Sweden.
    Ruegg, Joelle
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden; Swedish Toxicol Science Research Centre Swetox, Sweden.
    Prudhomme, Jose
    Douglas Mental Health University of Institute, Canada.
    Ekström, Tomas J.
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Palkovits, Miklos
    Semmelweis University, Hungary.
    Turecki, Gustavo
    Douglas Mental Health University of Institute, Canada; McGill University, Canada.
    Bagdy, Gyorgy
    Semmelweis University, Hungary.
    Ihnatko, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Juhasz, Gabriella
    Semmelweis University, Hungary; University of Manchester, England.
    Diaz-Heijtz, Rochellys
    Karolinska Institute, Sweden.
    Mechawar, Naguib
    Douglas Mental Health University of Institute, Canada; McGill University, Canada.
    Hokfelt, Tomas G. M.
    Karolinska Institute, Sweden.
    Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide2016In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN 0027-8424, Vol. 113, no 52, p. E8472-E8481Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL(1-3), are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL(3) antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.

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  • 3.
    Cholujová, Dana
    et al.
    Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Jakubíková, Jana
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Kubeš, Miroslav
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Arendacká, Barbora
    Institute of Measurement Science, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sapák, Michal
    Institute of Immunology, Medical Faculty of Comenius University, Sasinkova 4, Bratislava, Slovakia.
    Ihnatko, Robert
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sedlák, Ján
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays2008In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 213, no 8, p. 629-640Article in journal (Refereed)
    Abstract [en]

    Cytotoxicity is one of the major defence mechanisms against both virus-infected and tumor cells. Radioactive 51chromium (51Cr) release assay is a “gold standard” for assessment of natural killer (NK) cytolytic activity in vitro. Several disadvantages of this assay led us to design alternative tools based on flow cytometry analysis. Four different fluorescent dyes, calcein acetoxymethyl ester (CAM), carboxyfluorescein succinimidyl ester (CFSE), Vybrant DiO (DiO) and MitoTracker Green (MTG) were tested for labeling of NK target K-562 cells. Target staining stability, spontaneous release of fluorochromes and subsequent accumulation in bystander unstained cells were measured using fluorimetry and flow cytometry. Healthy donor peripheral blood mononuclear cells and affinity column purified NK cells were used as effectors coincubated with target K-562 cells at different E:T ratios for 3h and 90min, respectively. Fluorescent probe 7-amino-actinomycin D was used for live and dead cell discrimination. Bland–Altman statistical method was applied to measure true agreement for all CAM–51Cr, CFSE–51Cr, DiO–51Cr and MTG–51Cr pairs analyzed. Based on the data, none of the four proposed methods can be stated equivalent to the standard 51Cr release assay. Considering linear relationships between data obtained with four fluorochromes and 51Cr release assay as well as linear regression analysis with R2=0.9393 value for CAM–51Cr pair, we found the CAM assay to be the most closely related to the 51Cr assay.

  • 4.
    Hokfelt, Tomas
    et al.
    Karolinska Inst, Sweden.
    Barde, Swapnali
    Karolinska Inst, Sweden.
    Xu, Zhi-Qing David
    Karolinska Inst, Sweden; Capital Med Univ, Peoples R China.
    Kuteeva, Eugenia
    Karolinska Inst, Sweden; Atlas Antibodies AB, Sweden.
    Ruegg, Joelle
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden; Swetox, Sweden.
    Le Maitre, Erwan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Risling, Marten
    Karolinska Inst, Sweden.
    Kehr, Jan
    Pronexus Analyt AB, Sweden; Karolinska Inst, Sweden.
    Ihnatko, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Palkovits, Miklos
    Semmelweis Univ, Hungary.
    Deakin, William
    Univ Manchester, England.
    Bagdy, Gyorgy
    Semmelweis Univ, Hungary; Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Juhasz, Gabriella
    Univ Manchester, England; Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Prudhomme, H. Josee
    Douglas Hosp, Canada.
    Mechawar, Naguib
    Douglas Hosp, Canada; McGill Univ, Canada.
    Diaz-Heijtz, Rochellys
    Karolinska Inst, Sweden.
    Ogren, Sven Ove
    Karolinska Inst, Sweden.
    Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness2018In: Frontiers in Neural Circuits, E-ISSN 1662-5110, Vol. 12, article id 106Article, review/survey (Refereed)
    Abstract [en]

    Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanins role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression-like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a brake to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting - a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.

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  • 5.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Edén, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Congenital Aniridia and the Ocular Surface2016In: OCULAR SURFACE, ISSN 1542-0124, Vol. 14, no 2, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface, in particular, can be severely affected by a progressive pathology termed aniridia-associated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micro-morphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition.

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  • 6.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Edén, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Dellby, Anette
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Analysis of protein composition and protein expression in the tear fluid of patients with congenital aniridia2013In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, p. 78-88Article in journal (Refereed)
    Abstract [en]

    Aniridia is a rare congenital genetic disorder caused by haploinsuffiency of the PAX6 gene, the master gene for development of the eye. The expression of tear proteins in aniridia is unknown. To screen for proteins involved in the aniridia pathophysiology, the tear fluid of patients with diagnosed congenital aniridia was examined using two-dimensional electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two-dimensional map of tear proteins in aniridia has been established and 7 proteins were differentially expressed with P less than 0.01 between aniridia patients and control subjects. Five of them were more abundant in healthy subjects, particularly alpha-enolase, peroxiredoxin 6, cystatin S, gelsolin, apolipoprotein A-1 and two other proteins, zinc-alpha 2-glycoprotein and lactoferrin were more expressed in the tears of aniridia patients. Moreover, immunoblot analysis revealed elevated levels of vascular endothelial growth factor (VEGF) in aniridia tears which is in concordance with clinical finding of pathological blood and lymph vessels in the central and peripheral cornea of aniridia patients. The proteins with different expression in patients tears may be new candidate molecules involved in the pathophysiology of aniridia and thus may be helpful for development of novel treatment strategies for the symptomatic therapy of this vision threatening condition. Biological significance This study is first to demonstrate protein composition and protein expression in aniridic tears and identifies proteins with different abundance in tear fluid from patients with congenital aniridia vs. healthy tears.

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  • 7.
    Ihnatko, Robert
    et al.
    Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, 842 45 Bratislava, Slovakia.
    Kubes, M
    Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, 842 45 Bratislava, Slovakia.
    TNF signaling: early events and phosphorylation.2007In: General Physiology and Biophysics, ISSN 0231-5882, E-ISSN 1338-4325, Vol. 26, no 3, p. 159-67Article in journal (Refereed)
    Abstract [en]

    Tumor necrosis factor-alpha (TNF) is a major mediator of apoptosis as well as immunity and inflammation. Inappropriate production of TNF or sustained activation of TNF signaling has been implicated in the pathogenesis of a wide spectrum of human diseases, including cancer, osteoporosis, sepsis, diabetes, and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TNF binds to two specific receptors, TNF-receptor type I (TNF-R1, CD120a, p55/60) and TNF-receptor type II (TNF-R2, CD120b, p75/80). Signaling through TNF-R1 is extremely complex, leading to both cell death and survival signals. Many findings suggest an important role of phosphorylation of the TNF-R1 by number of protein kinases. Role of TNF-R2 phosphorylation on its signaling properties is understood less than TNF-R1. Other cellular substrates as TRADD adaptor protein, TRAF protein family and RIP kinases are reviewed in relation to TNF receptor-mediated apoptosis or survival pathways and regulation of their actions by phosphorylation.

  • 8.
    Ihnatko, Robert
    et al.
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Kubes, Miroslav
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Takacova, Martina
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Sedlakova, Olga
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Sedlak, Jan
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Pastorek, Jaromir
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Kopacek, Juraj
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Pastorekova, Silvia
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia2006In: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 29, no 4, p. 1025-33Article in journal (Refereed)
    Abstract [en]

    Most solid tumors display extracellular acidosis, which only partially overlaps with hypoxia and induces distinct adaptive changes leading to aggressive phenotype. Although acidosis is mainly attributable to excessive production of lactic acid, it also involves carbonic anhydrase (CA) IX-mediated conversion of CO(2) to an extracellular proton and a bicarbonate ion transported to cytoplasm. CA IX is pre-dominantly expressed in tumors with poor prognosis and its transcription and activity are induced by hypoxia. Here we investigated whether low extracellular pH in absence of hypoxia can influence CA IX expression in cell lines derived from glioblastoma, a tumor type particularly linked with acidosis. Our data show that extracellular acidosis increased the level of CA IX protein, mRNA and the activity of minimal CA9 promoter that contains binding sites for HIF-1 and SP-1 transcription factors. Mutation within each of these two biding sites reduced the promoter activity, but did not eliminate the increase by acidosis. Transfection of HIF-1alpha cDNA produced additive inducing effect with acidosis. Normoxic acidosis was accompanied by HIF-1alpha protein accumulation and transiently increased phosphorylation of ERK1/2. Expression of a dominant-negative mutant of ERK2 reduced the CA9 promoter activity in both standard and acidic conditions. Similar result was obtained by inhibitors of MAPK and PI3K pathways, whose combination completely suppressed CA IX expression and abolished induction by acidosis. Altogether, our results suggest that acidosis increases the CA IX expression via a hypoxia-independent mechanism that operates through modulation of the basic CA9 transcriptional machinery.

  • 9.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Post, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 109, no 7, p. 1867-1875Article in journal (Refereed)
    Abstract [en]

    Background:

    Anorexia-cachexia is a common and severe cancer-related complication but the underlying mechanisms are largely unknown. Here, using a mouse model for tumour-induced anorexia-cachexia, we screened for proteins that are differentially expressed in the hypothalamus, the brain’s metabolic control centre.

    Methods:

    The hypothalamus of tumour-bearing mice with implanted methylcholanthrene-induced sarcoma (MCG 101) displaying anorexia and their sham-implanted pair-fed or free-fed littermates was examined using two-dimensional electrophoresis (2-DE)-based comparative proteomics. Differentially expressed proteins were identified by liquid chromatography-tandem mass spectrometry.

    Results:

    The 2-DE data showed an increased expression of dynamin 1, hexokinase, pyruvate carboxylase, oxoglutarate dehydrogenase, and N-ethylmaleimide-sensitive factor in tumour-bearing mice, whereas heat-shock 70 kDa cognate protein, selenium-binding protein 1, and guanine nucleotide-binding protein Gα0 were downregulated. The expression of several of the identified proteins was similarly altered also in the caloric-restricted pair-fed mice, suggesting an involvement of these proteins in brain metabolic adaptation to restricted nutrient availability. However, the expression of dynamin 1, which is required for receptor internalisation, and of hexokinase, and pyruvate carboxylase were specifically changed in tumour-bearing mice with anorexia.

    Conclusion:

    The identified differentially expressed proteins may be new candidate molecules involved in the pathophysiology of tumour-induced anorexia-cachexia.

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  • 10.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Shaw, Edward
    Dep. Microbiology and Molecular Genetics, Oklahoma State University, USA.
    Toman, Rudolf
    Institute of Virology, Slovak Academy of Science, Bratislava, Slovakia.
    Proteome of Coxiella burnetii2012In: Coxiella burnetii: Recent Advances and New Perspectives in Research of the Q Fever Bacterium / [ed] Rudolf Toman, Robert A. Heinzen, James E. Samuel and Jean-Louis Mege, Springer-Verlag New York, 2012, Vol. 984, p. 105-130Chapter in book (Refereed)
    Abstract [en]

    Recent proteomic studies of C. burnetii, the etiological agent of Q fever, have brought a deeper insight into the pathogens physiology and offered new possibilities in investigations of inter- or intra-species relatedness. The data generated from these studies in conjunction with the current genomic sequence databases may reveal additional identities for conserved and unique C. burnetii biomarkers and aid in creating algorithms and/or databases that could develop into diagnostic and detection tools for the pathogen. Moreover, wide scale screening and further characterization of potential C. burnetii protein antigens along with a comprehensive evaluation of the humoral immune response will be of fundamental importance towards research and development of a safe and efficacious vaccine as well as improved serodiagnostic tests for rapid and sensitive detection of the Q fever pathogen. Given these advances, proteomics may make marked contributions to the improvement of human health protection against C. burnetii in the coming years.

  • 11.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Short N-terminal galanin fragments are occurring naturally in vivo2017In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 63Article in journal (Refereed)
    Abstract [en]

    The galanin family currently consists of four peptides, namely galanin, galanin-message associated peptide, galanin-like peptide and alarin. Unlike galanin that signals through three different G protein-coupled receptors; GALL, GAL(2), and GAL(3), binding at its N-terminal end, the cognate receptors for other members of the galanin family are currently unknown. Research using short N-terminal galanin fragments generated either by enzymatic cleavage or solid-phase synthesis has revealed differences in their receptor binding properties exerting numerous biological effects distinct from galanin(1-29) itself. Our studies on tissue extracts derived from rat small intestine and bovine gut using chromatographic techniques and sensitive galanin(1-16)-specific radioimmunoassay revealed the presence of immunoreactive compounds reacting with antiserum against galanin(1-16) distributed in distinct elution volumes. These results suggested a possible presence of short N-terminal galanin fragments also in vivo. Moreover, employing immunoaffinity chromatography and reverse-phase high performance liquid chromatography (HPLC) followed by mass spectrometry allowed specific enrichment of these immunoreactive compounds from rat tissues and identification of their molecular structure. Indeed, our study revealed presence of several distinct short N-terminal galanin sequences in rat tissue. To prove their receptor binding, four of the identified sequences were synthetized, namely, galanin(1-13), galanin(1-16), galanin(1.20), galanin(6-20), and tested on coronal rat brain sections competing with I-125-labeled galanin(1-29). Our autoradiographs confirmed that galanin(1-13), galanin(1-16), and galanin(1-20) comprehensively displaced I-125-galanin(1-29) but galanin (6-20) did not. Here we show, for the first time, that short N-terminal galanin fragments occur naturally in rat tissues and that similar or identical galanin sequences can be present also in tissues of other species. Biological significance: This study is first to provide an evidence of the presence of short N-terminal galanin fragments in vivo in a biological system and provides further foundations for the previous studies using synthetized short N-terminal galanin fragments.

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  • 12.
    Ihnatko, Robert
    et al.
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Vadovič, Pavol
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Toman, Rudolf
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Proteins of Coxiella Burnetii and Analysis of their Function2011In: BSL3 and BSL4 Agents: Proteomics, Glycomics, and Antigenicity / [ed] Jiri Stulik, Rudolf Toman, Patrick Butaye and Robert G. Ulrich, Wiley-VCH Verlag GmbH & Co. KGaA , 2011, p. 145-151Chapter in book (Refereed)
  • 13.
    Kubes, M.
    et al.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Kuzmová, Z.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Gajdosová, E.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Ihnatko, Robert
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Mucha, V.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Toman, R.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Kovácová, E.
    Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
    Induction of tumor necrosis factor alpha in murine macrophages with various strains of Coxiella burnetii and their lipopolysaccharides2006In: Acta virologica, ISSN 0001-723X, E-ISSN 1336-2305, Vol. 50, no 2, p. 93-9Article in journal (Refereed)
    Abstract [en]

    The ability of various strains of Coxiella burnetii (C.b.) and their phase I and II lipopolysaccharides (LPSs) to induce tumor necrosis factor alpha (TNF-alpha) in peritoneal Balb/c mouse macrophages in vitro was investigated. Considerable differences in the induction ability were observed in dependence on the strain applied. In a TNF-alpha bioassay, the most effective inducers were both corpuscles and LPSs of the strains Priscilla and Scurry, followed by Nine Mile, Luga, and Henzerling I. In contrast, in ELISA, the most effective inducers were LPSs of the strains Luga and Henzerling, followed by Nine Mile, Priscilla, and Scurry. The role of toll-like receptor 4 (TLR4) in the induction was confirmed by the use of C3H/HeJ mouse macrophages. Thus, the induction of TNF-alpha was much higher in Balb/c mouse macrophages than that in TLR4-deficient C3H/HeJ mouse macrophages. Differences in the results of the bioassay and those of ELISA suggest a role of another secreted factor(s) induced with C.b. in murine macrophages that could act synergically with TNF-alpha in L929 cells in the bioassay. The observed differences in TNF-alpha induction might play a role in the pathobiology of Q fever.

  • 14.
    Matsuwaki, Takashi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. University of Tokyo, Japan.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ihnatko, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Kakuta, Shigeru
    University of Tokyo, Japan.
    Dufour, Sylvie
    CNRS, France.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Waisman, Ari
    Johannes Gutenberg University of Mainz, Germany.
    Mueller, Werner
    University of Manchester, England.
    Pinteaux, Emmanuel
    University of Manchester, England.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 66, p. 165-176Article in journal (Refereed)
    Abstract [en]

    Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (1(0) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120 mu g/kg; HPA-axis: 120 mu g/kg), but showed attenuated but not extinguished fever (120 g/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-alpha (TNF alpha) inhibitor etanercept nor the IL -6 receptor antibody tocilizumab abolished the LPS induced fever in IL -1R1 KO mice. Deletion of IL -1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFa, but by some yet unidentified pyrogenic factor. 

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  • 15.
    Palkovicova, K.
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Vadovic, P.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Betinova, E.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Skultety, L.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Frangoulidis, D.
    undeswehr Institute of Microbiology, Neuherbergstr. 11, Munich, Germany.
    Toman, R.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    A monoclonal antibody specific for a unique biomarker, virenose, in a lipopolysaccharide of Coxiella burnetii2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15 Suppl 2, p. 183-4Article in journal (Refereed)
    Abstract [en]

    Q fever is a zoonotic disease caused by Coxiella burnetii. Easy aerosol dissemination, strong environmental persistence and high infectivity make the bacterium a serious threat for humans and animals. A rapid, sensitive and specific test for the infectious agent is still a challenge in the field. C. burnetii expresses a spectrum of amphophilic macromolecules on its surface. Among them, a lipopolysaccharide (LPS) is of particular biological, immunological and medical significance [1]. Upon serial laboratory passages in yolk sacs of embryonated hen eggs, C.

  • 16.
    Toman, Rudolf
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Skultety, Ludovit
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Coxiella burnetii glycomics and proteomics--tools for linking structure to function2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1166, p. 67-78Article in journal (Refereed)
    Abstract [en]

    Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterium and a highly infectious pathogen. The disease is a widespread zoonosis and is endemic throughout the world. An easy aerosol dissemination, environmental persistence, and high infectivity make the bacterium a serious threat for humans and animals. Lipopolysaccharide is considered one of the major factors of virulence expression and infection of the bacterium. Detailed glycomic studies enabled to better understand structural and functional peculiarities of this biopolymer and its role in pathogenesis and immunity of Q fever. Recent proteomic studies of C. burnetii have brought new approaches in accurate detection of the infectious agent and offered new insights into the inter- or intra-species relatedness. Thus, structure/function relationship studies are currently of utmost importance in the field. This paper will focus on glycomic and proteomic approaches providing information on unique glycan and protein species of the microorganism as the candidate molecules for the use in detection/diagnosis, therapy, and prophylaxis.

  • 17.
    Vadovic, P.
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, SAS, Bratislava, Slovakia, Czech Republic.
    Fuleova, A.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, SAS, Bratislava, Slovakia, Czech Republic.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, SAS, Bratislava, Slovakia, Czech Republic.
    Skultety, L.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, SAS, Bratislava, Slovakia, Czech Republic.
    Halada, P.
    Institute of Microbiology, v.v.i, CAS, Prague, Czech Republic.
    Toman, R.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, SAS, Bratislava, Slovakia, Czech Republic.
    Structural studies of lipid A from a lipopolysaccharide of the Coxiella burnetii isolate RSA 514 (Crazy)2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, p. 198-199Article in journal (Refereed)
    Abstract [en]

    Coxiella burnetii is the aetiological agent of Q fever. LPS is a major factor of virulence of the bacterium, and therefore studies of its structure/function relationship studies are of potential interest. In virulent phase I, C. burnetii biosynthesises smooth LPS I with an O-specific chain, whereas in avirulent phase II, it synthesises rough LPS II [1]. Both LPSs were isolated [1] from the C. burnetii isolates RSA 493, clone 7, and RSA 439, clone 4, respectively. We investigated an LPS from the C. burnetii clonal derivative RSA 514 named ‘Crazy’ (Cr), which was isolated from the placental tissue of a guinea pig infected with the RSA 493 isolate for 343 days [2]. The major emphasis was put on the lipid A as no data on its structure have been available thus far. It has been recognised recently that variation of the lipid A domain of LPS serves as one strategy utilised [3] by Gram-negative bacteria to promote survival by providing resistance to components of the innate immune system and helping to evade recognition by Toll-like receptor 4. Thus, it was of interest to see if the long-term survival of the microorganism in the host led to modifications in its lipid A in comparison with the known structures for lipid A from the C. burnetii isolate Priscilla [4] and also those established most recently in the LPS I and LPS II (P.V. Vadovic and R.T. Toman, unpublished results).

  • 18.
    Vadovič, Pavol
    et al.
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Ihnatko, Robert
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Toman, Rudolf
    Slovak Academy of Sciences, Institute of Virology, Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Slovak Republic.
    Composition and Structure of Lipid A of the Intracellular Bacteria Piscirickettsia Salmonis and Coxiella Burnetii2011In: BSL3 and BSL4 Agents: Proteomics, Glycomics, and Antigenicity / [ed] Jiri Stulik, Rudolf Toman, Patrick Butaye and Robert G. Ulrich, Wiley-VCH Verlag GmbH & Co. KGaA , 2011, p. 139-144Chapter in book (Refereed)
1 - 18 of 18
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