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Hallberg, M
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Publications (10 of 93) Show all publications
Balgoma, D., Zelleroth, S., Grönbladh, A., Hallberg, M., Pettersson, C. & Hedeland, M. (2020). Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver. Metabolomics, 16(1), Article ID 12.
Open this publication in new window or tab >>Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver
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2020 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 16, no 1, article id 12Article in journal (Refereed) Published
Abstract [en]

Introduction: The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown.

Objectives: To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver.

Methods: We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry.

Results: Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid.

Conclusion: The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

Place, publisher, year, edition, pages
SPRINGER, 2020
Keywords
Androgens, Androgen receptor, Estrogen receptors, Lipidomics, Liver X receptors
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-407500 (URN)10.1007/s11306-019-1632-0 (DOI)000516536100002 ()31925559 (PubMedID)
Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved
Isaksson, R., Casselbrant, A., Elebring, E., Hallberg, M., Larhed, M. & Fändriks, L. (2020). Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages. European Journal of Pharmacology, 868, Article ID 172855.
Open this publication in new window or tab >>Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages
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2020 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 868, article id 172855Article in journal (Refereed) Published
Abstract [en]

The angiotensin II type 2 receptor (AT2) is upregulated after tissue damage and mediates protective functions in the renin-angiotensin-aldosterone system (RAAS). One of these is to inhibit inducible nitric oxide synthase (iNOS) in activated macrophages. In the present study, we assessed the effect of AT2 receptor ligands on nitric oxide production in murine macrophages as a potential assay to determine the functional activity of an AT2 receptor ligand. Mouse macrophage J744.2 and RAW264.7 were cultivated in lipopolysaccharide (LPS) to induce M1 differentiation and increase iNOS expression. Using Griess reagent and spectrophotometric analysis, the nitric oxide levels were determined, while employing Western blot and immunocytochemistry to determine basal protein expression.

Using the first reported selective non-peptide AT2 receptor agonist, compound C21, we conclude that activation of AT2 receptor reduces nitric oxide production in M1 macrophages. Furthermore, the AT2 receptor selective ligand compound C38, a regioisomer of C21, reported as a selective AT2 receptor antagonist exhibits a similar effect on nitric oxide production. Thus, we propose C38 acts as a partial agonist in the macrophage system. Monitoring nitric oxide attenuation in M1 J744.1 and RAW264.7 macrophages provides a new method for characterizing functional activity of AT2 receptor ligands, foreseen to be valuable in future drug discovery programs.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Renin-angiotensin-aldosterone system, Bioassay, Functional activity, Antagonist, Agonist, Inducible nitric oxide synthase
National Category
Other Biological Topics Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381097 (URN)10.1016/j.ejphar.2019.172855 (DOI)000505215700004 ()31837306 (PubMedID)
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2020-01-29Bibliographically approved
Nylander, E., Zelleroth, S., Stam, F., Nyberg, F., Grönbladh, A. & Hallberg, M. (2020). Growth hormone increases dendritic spine density in primary hippocampal cell cultures. Growth Hormone & IGF Research, 50, 42-47
Open this publication in new window or tab >>Growth hormone increases dendritic spine density in primary hippocampal cell cultures
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2020 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 50, p. 42-47Article in journal (Refereed) Published
Abstract [en]

Objective: Growth hormone (GH) is widely known for its peripheral effects during growth and development. However, numerous reports also suggest that GH exert pro-cognitive, restorative, and protective properties in the brain. In in vitro studies, the detection of dendritic spines, small protrusions extending from axons, can act as a marker for cognition-related function as spine formation is considered to be associated with learning and memory. Here we show that an acute 24-hour treatment of GH can increase dendritic spine density in primary hippocampal cell cultures.

Design: Primary hippocampal cells were harvested from embryonic Wistar rats and cultured for 14 days. Cells were treated with supra-physiological doses of GH (10-1000 nM) and subjected to a high-throughput screening protocol. Images were acquired and analyzed using automated image analysis and the number of spines, spines per neurite length, neurite length, and mean area of spines, was reported.

Results: GH treatment increased dendritic spine density using the highest dose while the general health of the cells was unaffected.

Conclusion: The results from the present study further confirms a potential role of GH in the treatment of cognitive dysfunction.

Keywords
growth hormone, dendritic spines, spine formation, cognition, memory, high-throughput screening, hippocampus, cell culture, in vitro
National Category
Cell and Molecular Biology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-393938 (URN)10.1016/j.ghir.2019.12.003 (DOI)000518868300006 ()31862540 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council, 9459
Available from: 2019-09-30 Created: 2019-09-30 Last updated: 2020-04-05Bibliographically approved
Engen, K., Reddy Vanga, S., Lundbäck, T., Agalo, F., Konda, V., Jensen, A. J., . . . Rosenström, U. (2020). Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors. ChemistryOpen, 9(3), 325-337
Open this publication in new window or tab >>Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
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2020 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 9, no 3, p. 325-337Article in journal (Refereed) Published
Abstract [en]

Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP.

Place, publisher, year, edition, pages
John Wiley & Sons, Ltd, 2020
Keywords
enzymes, inhibitors, insulin, preclinical profiling, regulated aminopeptidases, spiro compounds
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-406132 (URN)10.1002/open.201900344 (DOI)
Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-07
Isaksson, R., Lindman, J., Wannberg, J., Sallander, J., Backlund, M., Baraldi, D., . . . Larhed, M. (2019). A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode. ChemistryOpen, 8(1), 114-125
Open this publication in new window or tab >>A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
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2019 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed) Published
Abstract [en]

We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-377050 (URN)10.1002/open.201800282 (DOI)000457433000017 ()30697513 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC)Swedish Research Council
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-04-04Bibliographically approved
Wallinder, C., Sköld, C., Sundholm, S., Guimond, M.-O., Yahiaoui, S., Lindeberg, G., . . . Alterman, M. (2019). High affinity rigidified AT(2) receptor ligands with indane scaffolds. MedChemComm, 10(12), 2146-2160
Open this publication in new window or tab >>High affinity rigidified AT(2) receptor ligands with indane scaffolds
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 12, p. 2146-2160Article in journal (Refereed) Published
Abstract [en]

Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-402229 (URN)10.1039/c9md00402e (DOI)000502767000012 ()
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-01-17Bibliographically approved
Zelleroth, S., Nylander, E., Nyberg, F., Grönbladh, A. & Hallberg, M. (2019). Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures. Neuroscience, 397, 172-183
Open this publication in new window or tab >>Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures
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2019 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 397, p. 172-183Article in journal (Refereed) Published
Abstract [en]

The use of anabolic androgenic steroids (AASs) among non-athletes is a public health-problem, as abusers underestimate the negative effects associated with these drugs. The present study investigated the toxic effects of testosterone, nandrolone, stanozolol, and trenbolone, and aimed to understand how AAS abuse affects the brain. Mixed cortical cultures from embryonic rats were grown in vitro for 7 days and thereafter treated with increasing concentrations of AASs for 24 h (single-dose) or 3 days (repeated exposure). Cells were co-treated with the androgen-receptor (AR) antagonist flutamide, to determine whether the potential adverse effects observed were mediated by the AR. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase (LDH) release, and caspase-3/7 activity. Nandrolone, unlike the other AASs studied, indicated an effect on mitochondrial activity after 24 h. Furthermore, single-dose exposure with testosterone, nandrolone and trenbolone increased LDH release, while no effect was detected with stanozolol. However, all of the four steroids negatively affected mitochondrial function and resulted in LDH release after repeated exposure. Testosterone, nandrolone, and trenbolone caused their toxic effects by induction of apoptosis, unlike stanozolol that seemed to induce necrosis. Flutamide almost completely prevented AAS-induced toxicity by maintaining mitochondrial function, cellular integrity, and inhibition of apoptosis. Overall, we found that supra-physiological concentrations of AASs induce cell death in mixed primary cortical cultures, but to different extents, and possibly through various mechanisms. The data presented herein suggest that the molecular interactions of the AASs with the AR are primarily responsible for the toxic outcomes observed.

Keywords
mitochondrial function membrane integrity cell death androgen-receptor flutamide
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-370111 (URN)10.1016/j.neuroscience.2018.11.035 (DOI)000454922800016 ()30500611 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain Foundation
Note

Även finansierat av Kjell och Märta Beijers stiftelse

Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-28Bibliographically approved
Wannberg, J., Isaksson, R., Bremberg, U., Backlund, M., Sävmarker, J., Hallberg, M. & Larhed, M. (2018). A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes. Bioorganic & Medicinal Chemistry Letters, 28(3), 519-522
Open this publication in new window or tab >>A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed) Published
Abstract [en]

A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
AT(2)R antagonists, Angiotensin II type 2 receptor antagonists, Liver microsomes, Sulfonyl carbamates, Transesterification
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343592 (URN)10.1016/j.bmcl.2017.11.042 (DOI)000424285600053 ()29279275 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2019-04-04Bibliographically approved
Skogh, A., Lesniak, A., Sköld, C., Karlgren, M., Gaugaz, F. Z., Svensson, R., . . . Johansson, A. (2018). An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice. Bioorganic & Medicinal Chemistry Letters, 28(14), 2446-2450
Open this publication in new window or tab >>An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 14, p. 2446-2450Article in journal (Refereed) Published
Abstract [en]

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343682 (URN)10.1016/j.bmcl.2018.06.009 (DOI)000438467200020 ()29929882 (PubMedID)
Funder
Swedish Research Council, 9459
Note

Title in dissertation reference list: An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability

Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-24Bibliographically approved
Brolin, E., Zelleroth, S., Jonsson, A., Hallberg, M., Grönbladh, A. & Nyberg, F. (2018). Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat. Pharmacology, Biochemistry and Behavior, 167, 1-8
Open this publication in new window or tab >>Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
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2018 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 167, p. 1-8Article in journal (Refereed) Published
Abstract [en]

The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Morphine, Morris water maze (MWM), Mini-osmotic pumps, Memory, Insulin-like growth factor-1 (IGF-1), N-methyl-D-aspartate (NMDA), Rats
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-352711 (URN)10.1016/j.pbb.2018.01.007 (DOI)000430033600001 ()29421366 (PubMedID)
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2019-05-28
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