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Fredriksson, Robert
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Publications (10 of 95) Show all publications
Philippot, G., Hallgren, S., Gordh, T., Fredriksson, A., Fredriksson, R. & Viberg, H. (2018). A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol). Toxicological Sciences, 166(1), 203-212
Open this publication in new window or tab >>A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)
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2018 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 166, no 1, p. 203-212Article in journal (Refereed) Published
Abstract [en]

Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
Keywords
developmental toxicity, acetaminophen (paracetamol), CB1R, spontaneous behavior, habituation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-372828 (URN)10.1093/toxsci/kfy199 (DOI)000453585900016 ()30165669 (PubMedID)
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Hellsten, S. V., Tripathi, R., Ceder, M. & Fredriksson, R. (2018). Nutritional Stress Induced by Amino Acid Starvation Results in Changes for Slc38 Transporters in Immortalized Hypothalamic Neuronal Cells and Primary Cortex Cells. FRONTIERS IN MOLECULAR BIOSCIENCES, 5, Article ID 45.
Open this publication in new window or tab >>Nutritional Stress Induced by Amino Acid Starvation Results in Changes for Slc38 Transporters in Immortalized Hypothalamic Neuronal Cells and Primary Cortex Cells
2018 (English)In: FRONTIERS IN MOLECULAR BIOSCIENCES, ISSN 2296-889X, Vol. 5, article id 45Article in journal (Refereed) Published
Abstract [en]

Amino acid sensing and signaling is vital for cells, and both gene expression and protein levels of amino acid transporters are regulated in response to amino acid availability. Here, the aim was to study the regulation of all members of the SLC38 amino acid transporter family, Slc38a1-11 , in mouse brain cells following amino acid starvation. We reanalyzed microarray data for the immortalized hypothalamic cell line N25/2 subjected to complete amino acid starvation for 1, 2, 3, 5, or 16 h, focusing specifically on the SLC38 family. All 11 Slc38 genes were expressed in the cell line, and Slc38a1, Slc38a2, and Slc38a 7 were significantly upregulated at 5 h and most strongly at 16 h. Here, protein level changes were measured for SLC38A7 and the orphan family member SLC38A11 which has not been studied under different amino acid starvation condition at protein level. At 5 h, no significant alteration on protein level for either SLC38A7 or SLC38A11 could be detected. In addition, primary embryonic cortex cells were deprived of nine amino acids, the most common amino acids transported by the SLC38 family members, for 3 h, 7 h or 12 h, and the gene expression was measured using qPCR. Slc38a1, Slc38a2, Slc38a5, Slc38a6, Slc38a9, and Slc38a10 were upregulated, while Slc38a3 and Slc38a7 were downregulated. Slc38a8 was upregulated at 5 h and downregulated at 12 h. In conclusion, several members from the SLC38 family are regulated depending on amino acid levels and are likely to be involved in amino acid sensing and signaling in brain.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
SLC38 transporters, amino acid starvation, gene expression, protein expression, glutamine transporters
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-375584 (URN)10.3389/fmolb.2018.00045 (DOI)000455243400001 ()29868606 (PubMedID)
Funder
Swedish Research CouncilNovo NordiskStiftelsen Olle Engkvist ByggmästareGunvor och Josef Anérs stiftelseMagnus Bergvall Foundation
Available from: 2019-01-31 Created: 2019-01-31 Last updated: 2019-01-31Bibliographically approved
Hoeber, J., König, N., Trolle, C., Lekholm, E., Zhou, C., Pankratova, S., . . . Kozlova, E. (2017). A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. Stem Cells and Development, 26(14), 1065-1077
Open this publication in new window or tab >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed) Published
Abstract [en]

Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

Keywords
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareSwedish Research Council, 20716
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Perland, E., Bagchi, S., Klaesson, A. & Fredriksson, R. (2017). Characteristics of 29 novel atypical SLCs of MFS type: evolutionary conservation, predicted structure and neuronal co-expression. Open Biology, 7(9), Article ID 170142.
Open this publication in new window or tab >>Characteristics of 29 novel atypical SLCs of MFS type: evolutionary conservation, predicted structure and neuronal co-expression
2017 (English)In: Open Biology, ISSN 2046-2441, E-ISSN 2046-2441, Vol. 7, no 9, article id 170142Article in journal (Refereed) Published
Abstract [en]

Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6L, 7, 8, 9, 10, 11, 12, 13A, 14A, 14B; SV2A, SV2B, SV2C, SVOP, SVOPL; SPNS1, SPNS2, SPNS3; UNC93A and UNC93B1, and we studied their fundamental properties. We also included CLN3, an atypical SLC not yet belonging to any Pfam clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted Atypical MFS Transporter Families (AMTF1-15). Hidden Markov models were used to identify orthologues from human to D.melanogaster and C.elegans. Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLC were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs. 

Keywords
Major facilitator superfamily, solute carrier, atypical SLC, family clustering, topology, nutrition
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-326696 (URN)10.1098/rsob.170142 (DOI)000412166300008 ()28878041 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationNovo NordiskMagnus Bergvall Foundation
Available from: 2017-07-28 Created: 2017-07-28 Last updated: 2018-01-13Bibliographically approved
Perland, E. & Fredriksson, R. (2017). Classification Systems of Secondary Active Transporters. TIPS - Trends in Pharmacological Sciences, 38(3), 305-315
Open this publication in new window or tab >>Classification Systems of Secondary Active Transporters
2017 (English)In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 38, no 3, p. 305-315Article, review/survey (Refereed) Published
Abstract [en]

Membrane-bound solute carrier (SLC) transporter proteins are vital to the human body, as they sustain homeostasis by moving soluble molecule as nutrients, drugs, and waste across lipid membranes. Of the 430 identified secondary active transporters in humans, 30% are still orphans, and systematic research has been requested to elaborate on their possible involvement in diseases and their potential as drug targets. To enable this, the various classification systems in use must be understood and used correctly. In this review, we describe how various classification systems for human SLCs are constructed, and how they overlap and differ. To facilitate communication between researchers and to avoid ambiguities, everyone must clearly state which classification system they are referring to when writing scientific articles.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE LONDON, 2017
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-321011 (URN)10.1016/j.tips.2018.11.008 (DOI)000395617000008 ()27939446 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationNovo NordiskMagnus Bergvall Foundation
Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2018-01-13Bibliographically approved
Syk, M., Ramklint, M., Fredriksson, R., Ekselius, L. & Cunningham, J. L. (2017). Elevated total plasma-adiponectin is stable over time in young women with bulimia nervosa. European psychiatry, 41, 30-36
Open this publication in new window or tab >>Elevated total plasma-adiponectin is stable over time in young women with bulimia nervosa
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2017 (English)In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 41, p. 30-36Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bulimia nervosa (BN) is characterized by dysregulated eating behaviour and present data suggest adipokines may regulate food intake. We investigated a possible association between BN and adipokine levels and hypothesized that plasma (P)-adiponectin would be elevated and P-leptin and P-leptin-adiponectin-ratio would be reduced in women with BN.

METHODS: The study was designed as a cross-sectional study with a longitudinal arm for patients with BN. Plasma-adiponectin and leptin was measured in 148 female patients seeking psychiatric ambulatory care and 45 female controls. Fifteen patients were diagnosed with BN and the remaining with other affective and anxiety disorders. P-adiponectin and P-leptin levels were compared between patients with BN, patients without BN and controls. At follow-up 1-2years later, adipokines were reassessed in patients with BN and the Eating Disorder Examination Questionnaire was used to assess symptom severity.

RESULTS: P-adiponectin was elevated in patients with BN at baseline and at follow-up when compared to patients without BN and controls (P<0.004 and <0.008 respectively). The difference remained significant after controlling for body mass index. P-adiponectin was correlated to symptom severity at follow-up in patients with BN without morbid obesity (ρ=0.72, P<0.04). P-leptin-adiponectin-ratio was significantly lower in patients with BN compared to controls (P<0.04) and P-leptin non-significantly lower.

CONCLUSIONS: Findings indicate a stable elevation of P-adiponectin in women with BN. P-adiponectin at follow-up correlates to eating disorder symptom severity in patients without morbid obesity, indicating that P-adiponectin should be further investigated as a possible potential prognostic biomarker for BN.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Adiponectin, Biomarker, Bulimia nervosa, Leptin, Prognosis
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-318532 (URN)10.1016/j.eurpsy.2016.09.006 (DOI)000397668400006 ()28049078 (PubMedID)
Funder
Swedish Society of Medicine
Available from: 2017-03-25 Created: 2017-03-25 Last updated: 2019-02-27Bibliographically approved
Lekholm, E., Perland, E., Eriksson, M. M., Hellsten, S. V., Lindberg, F. A., Rostami, J. & Fredriksson, R. (2017). Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability. Frontiers in Molecular Neuroscience, 10, Article ID 11.
Open this publication in new window or tab >>Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability
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2017 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 11Article in journal (Refereed) Published
Abstract [en]

Characterization of orphan transporters is of importance due to their involvement in cellular homeostasis but also in pharmacokinetics and pharmacodynamics. The tissue and cellular localization, as well as function, is still unknown for many of the solute carriers belonging to the major facilitator superfamily (MFS) Pfam clan. Here, we have characterized two putative novel transporters MFSD14A (HIAT1) and MFSD14B (HIATL1) in the mouse central nervous system and found protein staining throughout the adult mouse brain. Both transporters localized to neurons and MFSD14A co-localized with the Golgi marker Giantin in primary embryonic cortex cultures, while MFSD14B staining co-localized with an endoplasmic retention marker, KDEL. Based on phylogenetic clustering analyses, we predict both to have organic substrate profiles, and possible involvement in energy homeostasis. Therefore, we monitored gene regulation changes in mouse embryonic primary cultures after amino acid starvations and found both transporters to be upregulated after 3 h of starvation. Interestingly, in mice subjected to 24 h of food starvation, both transporters were downregulated in the hypothalamus, while Mfsdl4a was also downregulated in the brainstem. In addition, in mice fed a high fat diet (HFD), upregulation of both transporters was seen in the striatum. Both MFSD14A and MFSD14B were intracellular neuronal membrane bound proteins, expressed in the Golgi and Endoplasmic reticulum, affected by both starvation and HFD to varying degree in the mouse brain.

Keywords
MFSD14A, HIAT1, MFSD14B, HIATL1, SLC, MFSD, transporter protein
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-316413 (URN)10.3389/fnmol.2017.00011 (DOI)000392751300001 ()28179877 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Novo NordiskMagnus Bergvall Foundation
Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2017-11-29Bibliographically approved
Perland, E., Hellsten, S. V., Schweizer, N., Arapi, V., Rezayee, F., Bushra, M. & Fredriksson, R. (2017). Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice. PLoS ONE, 12(10), Article ID e0186325.
Open this publication in new window or tab >>Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, article id e0186325Article in journal (Refereed) Published
Abstract [en]

Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.

Keywords
MFSD4A, MFSD9, solute carrier, major facilitator superfamily, transporter, homology models, protein expression, nutrition.
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-326695 (URN)10.1371/journal.pone.0186325 (DOI)000413195900057 ()
Available from: 2017-08-01 Created: 2017-08-01 Last updated: 2018-02-08Bibliographically approved
Hellsten, S. V., Lekholm, E., Ahmad, T. & Fredriksson, R. (2017). The gene expression of numerous SLC transporters is altered in the immortalized hypothalamic cell line N25/2 following amino acid starvation. FEBS Open Bio, 7(2), 249-264
Open this publication in new window or tab >>The gene expression of numerous SLC transporters is altered in the immortalized hypothalamic cell line N25/2 following amino acid starvation
2017 (English)In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 2, p. 249-264Article in journal (Refereed) Published
Abstract [en]

Amino acids are known to play a key role in gene expression regulation,and in mammalian cells, amino acid signaling is mainly mediated via twopathways, the mammalian target of rapamycin complex 1 (mTORC1) pathwayand the amino acid responsive (AAR) pathway. It is vital for cells tohave a system to sense amino acid levels, in order to control protein andamino acid synthesis and catabolism. Amino acid transporters are crucialin these pathways, due to both their sensing and transport functions. Inthis large-scale study, an immortalized mouse hypothalamic cell line (N25/2)was used to study the gene expression changes following 1, 2, 3, 5 or 16 hof amino acid starvation. We focused on genes encoding solute carriers(SLCs) and putative SLCs, more specifically on amino acid transporters.The microarray contained 28 270 genes and 86.2% of the genes wereexpressed in the cell line. At 5 h of starvation, 1001 genes were upregulatedand 848 genes were downregulated, and among these, 47 genes from theSLC superfamily or atypical SLCs were found. Of these, 15 were genesencoding amino acid transporters and 32 were genes encoding other SLCsor atypical SLCs. Increased expression was detected for genes encodingamino acid transporters from system A, ASC, L, N, T, xc-, and y+. UsingGO annotations, genes involved in amino acid transport and amino acidtransmembrane transporter activity were found to be most upregulated at3 h and 5 h of starvation.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-331260 (URN)10.1002/2211-5463.12181 (DOI)000397220400011 ()28174690 (PubMedID)
Funder
Swedish Research CouncilNovo NordiskStiftelsen Olle Engkvist ByggmästareMagnus Bergvall Foundation
Available from: 2017-10-12 Created: 2017-10-12 Last updated: 2018-09-07Bibliographically approved
Hellsten, S. V., Eriksson, M., Lekholm, E., Arapi, V., Perland, E. & Fredriksson, R. (2017). The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet. PLoS ONE, 12(2), Article ID e0172917.
Open this publication in new window or tab >>The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0172917Article in journal (Refereed) Published
Abstract [en]

SLC38A9 is characterized as a lysosomal component of the amino acid sensing RagulatorRAG GTPase complex, controlling the mechanistic target of rapamycin complex 1 (mTORC1). Here, immunohistochemistry was used to map SLC38A9 in mouse brain and staining was detected throughout the brain, in cortex, hypothalamus, thalamus, hippocampus, brainstem and cerebellum. More specifically, immunostaining was found in areas known to be involved in amino acid sensing and signaling pathways e.g. piriform cortex and hypothalamus. SLC38A9 immunoreactivity co-localized with both GABAergic and glutamatergic neurons, but not with astrocytes. SLC38A9 play a key role in the mTORC1 pathway, and therefore we performed in vivo starvation and high-fat diet studies, to measure gene expression alterations in specific brain tissues and in larger brain regions. Following starvation, Slc38a9 was upregulated in brainstem and cortex, and in anterior parts of the brain (Bregma 3.2 to -2.1mm). After high-fat diet, Slc38a9 was specifically upregulated in hypothalamus, while overall downregulation was noticed throughout the brain (Bregma 3.2 to -8.6mm).

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-318954 (URN)10.1371/journal.pone.0172917 (DOI)000394688200168 ()
Funder
Swedish Research CouncilThe Swedish Brain FoundationNovo NordiskMagnus Bergvall Foundation
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2017-11-29Bibliographically approved
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