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| 6. |
- Fisher, Linda, et al.
(författare)
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Targeting cytokine expression in glial cells by cellular delivery of an NFκB decoy
- 2007
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Ingår i: Journal of Molecular Neuroscience. - 0895-8696 .- 1559-1166. ; 31:3, s. 209-219
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of nuclear factor (NF)-κB has emerged as an important strategy for design of anti-inflammatory therapies. In neurodegenerative disorders like Alzheimer’s disease, inflammatory reactions mediated by glial cells are believed to promote disease progression. Here, we report that uptake of a double-stranded oligonucleotide NF-κB decoy in rat primary glial cells is clearly facilitated by noncovalent binding to a cell-penetrating peptide, transportan 10, via a complementary peptide nucleic acid (PNA) sequence. Fluorescently labeled oligonucleotide decoy was detected in the cells within 1 h only when cells were incubated with the decoy in the presence of cell-penetrating peptide. Cellular delivery of the decoy also inhibited effects induced by a neurotoxic fragment of the Alzheimer β amyloid peptide in the presence of the inflammatory cytokine interleukin (IL) 1β. Pretreatment of the cells with the complex formed by the decoy and the cell-penetrating peptide-PNA resulted in 80% and 50% inhibition of the NF-κB binding activity and IL-6 mRNA expression, respectively.
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| 7. |
- Gutiérrez-de-Terán, Hugo, et al.
(författare)
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Inhibitor binding to the Plasmepsin IV aspartic protease from Plasmodium falciparum
- 2006
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 45:35, s. 10529-10541
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Tidskriftsartikel (refereegranskat)abstract
- Plasmepsin IV (Plm IV) is one of the aspartic proteases present in the food vacuole of the malaria parasite Plasmodium falciparum involved in host hemoglobin degradation by the parasite. Using a series of previously synthesized plasmepsin inhibitors [Ersmark, K., et al. (2005) J. Med. Chem. 48, 6090-106], we report here experimental data and theoretical analysis of their inhibitory activity toward Plm IV. All compounds share a 1,2-dihydroxyethylene unit as the transition state mimic. They possess symmetric P1 and P1' side chains and either a diacylhydrazine, a five-membered oxadiazole ring, or a retroamide at the P2 and P2' positions. Experimental binding affinities are compared to those predicted by the linear interaction energy (LIE) method and an empirical scoring function, using both a crystal structure and a homology model for the enzyme. Molecular dynamics (MD) simulations of the modeled complexes allow a rational interpretation of the structural determinants for inhibitor binding. A ligand bearing a P2 and P2' symmetric oxadiazole which is devoid of amide bonds is identified both experimentally and theoretically as the most potent inhibitor of Plm IV. For the P2 and P2' asymmetric compounds, the results are consistent with earlier predictions regarding the mode of binding of this class of inhibitors to Plm II. Theoretical estimation of selectivity for some compounds is also reported. Significant features of the Plm IV binding pocket are discussed in comparison to related enzymes, and the results obtained here should be helpful for further optimization of inhibitors.
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| 8. |
- Hellström, Ann, 1959, et al.
(författare)
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Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.
- 2016
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Ingår i: Acta paediatrica (Oslo, Norway : 1992). - : Wiley. - 1651-2227 .- 0803-5253. ; 105:6, s. 576-86
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Tidskriftsartikel (refereegranskat)abstract
- Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero, and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities.
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| 9. |
- Johansson, Jenny, 1980-
(författare)
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The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters. The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS.We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.
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| 10. |
- Köhn, Linda, 1979-, et al.
(författare)
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Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
- 2007
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Ingår i: European Journal of Human Genetics. - : Nature publishing group. - 1018-4813 .- 1476-5438. ; 15:6, s. 664-671
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.
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| 11. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 12. |
- Mahalingam, A. Kannan, et al.
(författare)
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HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol : Improved Antiviral Activity in Cells
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:2, s. 607-615
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Tidskriftsartikel (refereegranskat)abstract
- By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.
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| 14. |
- Mejtoft, Thomas, Universitetslektor, 1976-, et al.
(författare)
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Medtech innovation guide : an empiric model to support medical technology innovation
- 2022
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Ingår i: Health and Technology. - : Springer. - 2190-7188 .- 2190-7196. ; 12:5, s. 911-922
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Tidskriftsartikel (refereegranskat)abstract
- Innovation has become increasingly important for most industries to cope with rapid technological changes as well as changing societal needs. Even though there are many sectors with specific needs when it comes to supporting innovation, the medical technology sector is facing several unique challenges that both increases the lead-time from idea to finished product and decreases the number of innovations that are developed. This paper presents a proposed innovation guide that has been developed and evaluated as a support for the innovation process within medical technology research. The guide takes the unique characteristics of the medical technology sector into account and serves as a usable guide for the innovator. The complete guide contains both a structure for the process and a usable web application to support the journey from idea to finished products and services. The paper also includes a new readiness level, Sect. 4.2 to provide support both when developing and determining the readiness for clinical implementation of a medical technology innovation.
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| 15. |
- Moghadasi, Setareh, et al.
(författare)
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The BRCA1 c. 5096G > A p.Arg1699Gln (R1699Q) intermediate risk variant : breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
- 2018
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Ingår i: Journal of Medical Genetics. - : BMJ PUBLISHING GROUP. - 0022-2593 .- 1468-6244. ; 55:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: We previously showed that the BRCA1 variant c. 5096G> A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1* R1699Q carriers.Methods: Data were collected from 129 BRCA1* R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).Conclusion: O ur results confirm that BRCA1* R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingooophorectomy should be considered based on family history.
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| 16. |
- Pressler, Ronit M., et al.
(författare)
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Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO) : an open-label, dose finding, and feasibility phase 1/2 trial
- 2015
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 14:5, s. 469-477
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Tidskriftsartikel (refereegranskat)abstract
- Background Predinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. Methods In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Findings Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0.05 mg/kg, n=4; 0.1 mg/kg, n=3; 0. 2 mg/kg, n=6; 0.3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0.05 mg/kg, one on 0.1 mg/kg and three on 0.2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0.05 mg/kg and one on 0.3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Interpretation Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials.
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| 17. |
- Samuelsson, Malin, et al.
(författare)
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Transcription factors as targets to block inflammation in neurodegenerative disorder : s
- 2006
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 2:3, Supplement, s. S457-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Accumulating evidence supports the importance of inflammation in neurodegenerative disorders like Alzheimer’s disease (AD). Epidemiological studies have revealed that patients taking anti-inflammatory drugs for conditions like arthritis have a lower prevalence of Alzheimer’s than others. In addition, there are reports that show that inflammation indeed can cause neurodegeneration in vivo. “The glial loop hypothesis” describes the model where surrounding glial cells are activated and produce neurotoxic products and therefore lead to neuronal death. One of the most important transcription factors involved in the inflammatory signalling cascade is NF-κB (nuclear factor κB). Supporting a role for NF-κB in AD, this transcription factor has been shown to be upregulated in brains from patients suffering from the disease. Another transcription factor family, thought to work together with NF-κB, is CCAAT enhancer binding protein (C/EBP). C/EBPδ has also been shown to be overexpressed in brains from Alzheimer patients. Objective: Our aim was to characterize the activation of transcription factors that may be involved in AD and to investigate the possibilities to block the effects of these transcription factors. Methods: We have used a delivery system that we have previously developed with a decoy non-covalently bound to a cell-penetrating peptide (CPP). In our studies primary mixed glial cultures from rat (5-10% microglia and 90-95% astrocytes) were used as a modelsystem. Transcription factor activation and cytokine mRNA expression were analyzed by electrophoretic mobility shift assay and RT-PCR, respectively. Cellular uptake studies were performed using confocal laser scanning microscopy. Results: Our studies show that a β-amyloid peptide alone or in combination with the inflammatory cytokine interleukin-1β upregulates NF-κB binding activity as well as the mRNA expression of its downstream target gene interleukin-6 (IL-6). Using our delivery system with an NF-κB decoy resulted in inhibition of upregulated NF-κB binding activity by approx. 80% and IL-6 mRNA expression by approx. 50%. We observed a clear uptake of the CPP-coupled decoy. In parallel, we have also investigated the possibility to use C/EBP as a therapeutic target. Conclusion: Facilitated uptake of transcription factor decoys may be a promising strategy to target the inflammation in neurodegenerative disorders like AD.
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| 18. |
- Watanabe, Hiroyuki, et al.
(författare)
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Ipsilesional versus contralesional postural deficits induced by unilateral brain trauma : a side reversal by opioid mechanism
- 2020
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Ingår i: Brain Communications. - : Oxford University Press. - 2632-1297. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Unilateral traumatic brain injury and stroke result in asymmetric postural and motor deficits including contralateral hemiplegia and hemiparesis. In animals, a localized unilateral brain injury recapitulates the human upper motor neuron syndrome in formation of hindlimb postural asymmetry with contralesional limb flexion and the asymmetry of hindlimb nociceptive withdrawal reflexes. The current view is that these effects are developed due to aberrant activity of motor pathways that descend from the brain into the spinal cord. These pathways and their target spinal circuits may be regulated by local neurohormonal systems that may also mediate effects of brain injury. Here we evaluate if a unilateral traumatic brain injury induces hindlimb postural asymmetry, a model of postural deficits, and if this asymmetry is spinally encoded and mediated by the endogenous opioid system in rats. A unilateral right-sided controlled cortical impact, a model of clinical focal traumatic brain injury was centered over the sensorimotor cortex and was observed to induce hindlimb postural asymmetry with contralateral limb flexion. The asymmetry persisted after complete spinal cord transection, implicating local neurocircuitry in the development of the deficits. Administration of the general opioid antagonist naloxone and µ-antagonist β-funaltrexamine blocked formation of postural asymmetry. Surprisingly, κ-antagonists nor-binaltorphimine and LY2444296 did not affect the asymmetry magnitude but reversed the flexion side; instead of contralesional (left) hindlimb flexion the ipsilesional (right) limb was flexed. The postural effects of the right-side cortical injury were mimicked in animals with intact brain via intrathecal administration of the opioid κ-agonist U50,488 that induced hindlimb postural asymmetry with left limb flexion. The δ-antagonist naltrindole produced no effect on the contralesional (left) flexion but inhibited formation of the ipsilesional (right) limb flexion in brain-injured rats that were treated with κ-antagonist. The effects of the antagonists were evident before and after spinal cord transection. We concluded that the focal traumatic brain injury-induced postural asymmetry was encoded at the spinal level, and was blocked or its side was reversed by administration of opioid antagonists. The findings suggest that the balance in activity of the mirror symmetric spinal neural circuits regulating contraction of the left and right hindlimb muscles is controlled by receptors; and that this equilibrium is impaired after unilateral brain trauma through side-specific opioid mechanism.
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