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Laitera T.,Kuopio University Hospital | Kurki M.I.,Kuopio University Hospital | Pursiheimo J.-P.,University of Turku | Zetterberg H.,Gothenburg University | And 11 more authors.
Journal of Alzheimer's Disease | Year: 2015

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPα, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and AβPP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of AβPP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of β-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPα, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients. © 2015 - IOS Press and the authors.


Haghighi Poodeh S.,University of Oulu | Alhonen L.,Ai Virtanen Institute For Molecular Science | Alhonen L.,University of Eastern Finland | Salonurmi T.,University of Oulu | Savolainen M.J.,University of Oulu
Biochemical and Biophysical Research Communications | Year: 2014

Introduction: Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting. Methods: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined. Results: No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction. Discussion: Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome. © 2014 Elsevier Inc. All rights reserved.


Hyvonen M.T.,Ai Virtanen Institute For Molecular Science | Sinervirta R.,Ai Virtanen Institute For Molecular Science | Keinanen T.A.,Ai Virtanen Institute For Molecular Science | Fashe T.,Ai Virtanen Institute For Molecular Science | And 4 more authors.
Pancreatology | Year: 2010

Background/Aims: Polyamines are ubiquitous organic cations essential for cellular proliferation and tissue integrity. We have previously shown that pancreatic polyamine depletion in rats overexpressing the catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), results in the development of severe acute pancreatitis, and that therapeutic administration of metabolically stable α-methylated polyamine analogs protects the animals from pancreatitis-associated mortality. Our aim was to elucidate the therapeutic mechanism(s) of α-methylspermidine (MeSpd). Methods: The effect of MeSpd on hemostasis and the extent of organ failure were studied in SSAT transgenic rats with either induced pancreatitis or lipopolysaccharide (LPS)-induced coagulopathy. The effect of polyamines on fibrinolysis and coagulation was also studied in vitro.Results: Pancreatitis caused a rapid development of intravascular coagulopathy, as assessed by prolonged coagulation times, decreased plasma fibrinogen level and antithrombin activity, enhanced fibrinolysis, reduced platelet count and presence of schistocytes. Therapeutic administration of MeSpd restored these parameters to almost control levels within 24 h. In vitro, polyamines dose-dependently inhibited fibrinolysis and intrinsic coagulation pathway. In LPS-induced coagulopathy, SSAT transgenic rats were more sensitive to the drug than their syngeneic littermates, and MeSpd-ameliorated LPS-induced coagulation disorders. Conclusion: Pancreatitis-associated mortality in SSAT rats is due to coagulopathy that is alleviated by treatment with MeSpd. Copyright © 2010 S. Karger AG, Basel and IAP.


Salminen A.,University of Eastern Finland | Jouhten P.,VTT Technical Research Center of Finland | Jouhten P.,EMBL European Molecular Biology Laboratory | Sarajarvi T.,University of Eastern Finland | And 5 more authors.
Neurochemistry International | Year: 2016

We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis. © 2015 Elsevier Ltd. All rights reserved.


Heikkinen L.,Ai Virtanen Institute For Molecular Science | Kolehmainen M.,University of Eastern Finland | Wong G.,Ai Virtanen Institute For Molecular Science
Bioinformatics | Year: 2011

Motivation: MicroRNAs (miRNAs) are small non-coding RNAs that regulate transcriptional processes via binding to the target gene mRNA. In animals, this binding is imperfect, which makes the computational prediction of animal miRNA targets a challenging task. The accuracy of miRNA target prediction can be improved with the use of machine learning methods. Previous work has described methods using supervised learning, but they suffer from the lack of adequate training examples, a common problem in miRNA target identification, which often leads to deficient generalization ability. Results: In this work, we introduce mirSOM, a miRNA target prediction tool based on clustering of short 3′-untranslated region (3′-UTR) substrings with self-organizing map (SOM). As our method uses unsupervised learning and a large set of verified Caenorhabditis elegans 3′-UTRs, we did not need to resort to training using a known set of targets. Our method outperforms seven other methods in predicting the experimentally verified C.elegans true and false miRNA targets. © The Author 2011. Published by Oxford University Press. All rights reserved.


PubMed | Ai Virtanen Institute For Molecular Science
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2013

Vascular endothelial growth factors (VEGFs) are potential therapeutic agents for treatment of ischemic diseases. Their angiogenic effects are mainly mediated through VEGF receptor 2 (VEGFR2).Receptor binding, signaling, and biological efficacy of several VEGFR2 ligands were compared to determine their characteristics regarding angiogenic activity and vascular permeability.Tested VEGFR2 ligands induced receptor tyrosine phosphorylation with different efficacy depending on their binding affinities. However, the tyrosine phosphorylation pattern and the activation of the major downstream signaling pathways were comparable. The maximal angiogenic effect stimulated by different VEGFR2 ligands was dependent on their ability to bind to co-receptor Neuropilin (Nrp), which was shown to form complexes with VEGFR2. The ability of these VEGFR2 ligands to induce vascular permeability was dependent on their concentration and VEGFR2 affinity, but not on Nrp binding.VEGFR2 activation alone is sufficient for inducing endothelial cell proliferation, formation of tube-like structures and vascular permeability. The level of VEGFR2 activation is dependent on the binding properties of the ligand used. However, closely similar activation pattern of the receptor kinase domain is seen with all VEGFR2 ligands. Nrp binding strengthens the angiogenic potency without increasing vascular permeability.This study sheds light on how different structurally closely related VEGFR2 ligands bind to and signal via VEGFR2/Nrp complex to induce angiogenesis and vascular permeability. The knowledge of this study could be used for designing VEGFR2/Nrp ligands with improved therapeutic properties.

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