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  • 1.
    Budnjo, Almir
    University of Skövde, School of Bioscience.
    Gene expression of MAP2K1 and Cyclin D1 in BDII rat model of Endometrial cancer2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Endometrial adenocarcinoma (EAC) is the most frequently diagnosed gynecological cancer of the female genital tract in the Western world. Research studies in EC is difficult to conduct on human tumor samples due to the complex nature of tumor arousal and genetic heterogeneousness in the human population. Therefore, inbred animal models can be promising tools to use in EC research due to similar histopathology and pathogenesis as humans. Studies performed on MAP2K1 and CCND1 has shown that their altered expression play a crucial role in carcinogenesis. CCND1 has been demonstrated to have oncogenic properties when overexpressed in human neoplasias.

    The aim of this study is to investigate gene expression levels of MAP2K1 and CCND1 in BDII rat model of endometrial adenocarcinoma cells. Quantitative real-time PCR was used to analyze expression levels of MAP2K1 and CCND1 genes in BDII/Han rat model of endometrial cancer cells using TaqMan approach. The differences in gene expression levels of MAP2K1 and CCND1 between pathologically EAC malignant and nonmalignant cells showed an upregulation of MAP2K1 and CCND1 in EAC malignant cells. The analyzed data presented observable mean differences between MAP2K1 and CCND1 in several endometrial cell lines that were examined.

    Although no statistical significance was reached, an alteration in gene expression levels in malignant and nonmalignant endometrial cells could be observed. Furthermore, this present study shows observable upregulation of MAP2K1 and CCND1 in endometrial carcinoma cells vs. nonmalignant endometrium cells and encourages further investigation of the role of CCND1 and MAP2K genes in endometrial carcinogenesis.

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  • 2.
    Chaudhari, Aditi
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Krumlinde, Daniel
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Lundqvist, Annika
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Akyürek, Levent M.
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Bandaru, Sashidhar
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Skålén, Kristina
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Ståhlman, Marcus
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, University of Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity2015In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed)
    Abstract [en]

    The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

  • 3.
    Ghosheh, Nidal
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Edsbagge, Josefina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    Van Giezen, Mariska
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, Annika
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Andersson, Tommy B.
    AstraZeneca R&D, CVMD DMPK, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines2016In: Stem Cells International, ISSN 1687-9678, Vol. 2016, article id 8648356Article in journal (Refereed)
    Abstract [en]

    Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.

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  • 4.
    Godoy, Patricio
    et al.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany / Department of Physiology, Faculty of Biological Sciences, University of Concepción, Chile.
    Schmidt-Heck, Wolfgang
    Leibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany.
    Natarajan, Karthick
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Lucendo-Villarin, Baltasar
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Szkolnicka, Dagmara
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Asplund, Annika
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Widera, Agata
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Stöber, Regina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Campos, Gisela
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Hammad, Seddik
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Sachinidis, Agapios
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Chaudhari, Umesh
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Damm, Georg
    Charité University Medicine Berlin, Department of General-, Visceral- and Transplantation Surgery, Berlin, Germany.
    Weiss, Thomas S.
    Center for Liver Cell Research, Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany.
    Nüssler, Andreas
    Eberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, Tübingen, Germany.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Edlund, Karolina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Küppers-Munther, Barbara
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Hay, David C.
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Hengstler, Jan G.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells2015In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 63, no 4, p. 934-942Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories.

    METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified.

    RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC.

    CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation.

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  • 5.
    Gopalan Nair, Rekha
    University of Skövde, School of Bioscience.
    Cloning and functional analysis of an arsB gene responsible for arsenic sequestration in Lysinibacillus sphaericus2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
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  • 6.
    Granéli, Cecilia
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Global Medicines Development, CVRM, AstraZeneca Gothenburg, Mölndal, Sweden.
    Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models2019In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 15, no 1, p. 13-22Article in journal (Refereed)
    Abstract [en]

    The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. 

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  • 7.
    Holmgren, Gustav
    Sahlgrenska Academy at University of Gothenburg.
    In vitro toxicity testing using human pluripotent stem cell derivatives2016Doctoral thesis, comprehensive summary (Other academic)
  • 8.
    Holmgren, Gustav
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Ulfenborg, Benjamin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Asplund, Annika
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Toet, Karin
    Department of Metabolic Health Research, TNO, Leiden, The Netherlands.
    Andersson, Christian X.
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Hammarstedt, Ann
    The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Hanemaaijer, Roeland
    Department of Metabolic Health Research, TNO, Leiden, The Netherlands.
    Küppers-Munther, Barbara
    R&D, Hepatocyte Product Development, Takara Bio Europe AB, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 2, article id E469Article in journal (Refereed)
    Abstract [en]

    There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor α (TNFα) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

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  • 9.
    Johansson, Markus
    et al.
    University of Skövde, Systems Biology Research Environment. University of Skövde, School of Bioscience. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    University of Skövde, Systems Biology Research Environment. University of Skövde, School of Bioscience.
    Andersson, Christian X.
    BioPharmaceuticals R&D Cell Therapy, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Synnergren, Jane
    University of Skövde, Systems Biology Research Environment. University of Skövde, School of Bioscience.
    Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy2022In: Life, E-ISSN 2075-1729, Vol. 12, no 2, article id 293Article in journal (Refereed)
    Abstract [en]

    Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization using a multi-omics approach. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48, and 72 h, and their transcriptome and secreted proteome were analyzed. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling. An integrated transcriptome–secretome analysis enabled the identification of multimodal biomarkers that may prove highly relevant for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on both transcriptomic- and secreted-proteomic levels. The results also shed novel insights into the underlying mechanisms of cardiac hypertrophy, and novel putative early cardiac hypertrophy biomarkers have been identified that warrant further investigation to assess their potential clinical relevance.

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  • 10.
    Jonsson, Malin K. B.
    et al.
    Genome Institute of Singapore, Genome, Singapore.
    van Veen, Toon A. B.
    Department of Medical Physiology, Division of Heart & Lungs, UMC Utrecht, Utrecht, Netherlands.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Becker, Bruno
    Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Mölndal, Sweden.
    Towards Creating the Perfect In Vitro Cell Model2016In: Stem Cells International, ISSN 1687-9678, Vol. 2016, article id 3459730Article in journal (Refereed)
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  • 11.
    Kristensson, Lisbeth
    et al.
    AstraZeneca, Mölndal, Sweden.
    Lundin, Anders
    AstraZeneca, Mölndal, Sweden / Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, David
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fryklund, Jan
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fex, Tomas
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca, Mölndal, Sweden / the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Ryberg, Erik
    AstraZeneca, Mölndal, Sweden.
    Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons2018In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 681, p. 37-43, article id S0304-3940(18)30351-3Article in journal (Refereed)
    Abstract [en]

    Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 ± 0.18 μM), glycine (EC50 11.0 ± 3.7 μM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter-screening of lead series compounds towards unwanted GABAAreceptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist.

  • 12.
    Kunze, Angelika
    et al.
    Department of Applied Physics, Chalmers University of Technology, Göteborg, Sweden / Institute of Physical Chemistry, University of Göttingen, Göttingen, Germany.
    Steel, Daniella
    Cellectis AB, Göteborg, Sweden / Abcam, Cambridge, United Kingdom.
    Dahlenborg, Kerstin
    Cellectis AB, Göteborg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Göteborg, Sweden / AstraZeneca R&D, Mölndal, Sweden.
    Svedhem, Sofia
    Department of Applied Physics, Chalmers University of Technology, Göteborg, Sweden.
    Non-Invasive Acoustical sensing of Drug-Induced Effects on the Contractile Machinery of Human Cardiomyocyte Clusters2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 5, p. 1-10, article id e0125540Article in journal (Refereed)
    Abstract [en]

    There is an urgent need for improved models for cardiotoxicity testing. Here we propose acoustic sensing applied to beating human cardiomyocyte clusters for non-invasive, surrogate measuring of the QT interval and other characteristics of the contractile machinery. In experiments with the acoustic method quartz crystal microbalance with dissipation monitoring (QCM-D), the shape of the recorded signals was very similar to the extracellular field potential detected in electrochemical experiments, and the expected changes of the QT interval in response to addition of conventional drugs (E-4031 or nifedipine) were observed. Additionally, changes in the dissipation signal upon addition of cytochalasin D were in good agreement with the known, corresponding shortening of the contraction-relaxation time. These findings suggest that QCM-D has great potential as a tool for cardiotoxicological screening, where effects of compounds on the cardiomyocyte contractile machinery can be detected independently of whether the extracellular field potential is altered or not.

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  • 13.
    Küppers-Munther, Barbara
    et al.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, A.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Abadie, A.
    Takara Bio Europe SAS, Paris, France.
    Novel human iPSC-derived hepatocytes with advanced functionality and long-term 2D cultures of human primary hepatocytes for metabolic disease studies2018In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A146-A146, article id P406Article in journal (Refereed)
  • 14.
    Lindholm, Heléne
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Szekeres, Ferenc
    University of Skövde, Digital Health Research (DHEAR). University of Skövde, School of Health Sciences.
    Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells2022In: Medicine International, ISSN 2754-3242, Vol. 2, no 5, article id 27Article in journal (Refereed)
    Abstract [en]

    The alpha subunits (ATP1A1-3) of Na+/K+-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the ATP1A1 and ATP1A3 subunits. In Panc-1 cells, ATP1A3 gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the ATP1A1 gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.

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  • 15.
    Lundin, Anders
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ricchiuto, Piero
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sanchez, José
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sabirsh, Alan
    Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ding, Mei
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK / UK Dementia Research Institute at UCL, London, UK.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Department of Micro and Nanosystems KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models2018In: Stem Cell Reports, ISSN 2213-6711, Vol. 10, no 3, p. 1030-1045Article in journal (Refereed)
    Abstract [en]

    In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.

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  • 16.
    Nawaz, Muhammad
    et al.
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Tangruksa, Benyapa
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    González-King Garibotti, Hernán
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Jing, Yujia
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Maugeri, Marco
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Safety Innovations, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, Gothenburg, Mölndal, Sweden.
    Kohl, Franziska
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden ; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Solna, Sweden.
    Hultin, Leif
    BioPharmaceuticals R&D, Clinical Pharmacology and Safety Science, Imaging and Data Analytics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Reyahi, Azadeh
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Kull, Bengt
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Christoffersson, Jonas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Grimsholm, Ola
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Austria.
    Jennbacken, Karin
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Sundqvist, Martina
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Wiseman, John
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Bidar, Abdel Wahad
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Lindfors, Lennart
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Valadi, Hadi
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions2023In: Advanced Science, E-ISSN 2198-3844, Vol. 10, no 12, article id 2206187Article in journal (Refereed)
    Abstract [en]

    Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF-A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF-A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP-mRNAs between cells is functionally extended by cells’ own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF-A mRNA delivery to cells via LNPs, a fraction of internalized VEGF-A mRNA is secreted via EVs. The overexpressed VEGF-A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA-Seq analysis reveals that as cells’ response to LNP-VEGF-A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF-A mRNA in vitro and in vivo. Upon equal amount of VEGF-A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF-A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF-A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF-A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this mRNA differently than LNPs. 

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  • 17.
    Nguyen, Duong T.
    et al.
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    O'Hara, Matthew
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Granéli, Cecilia
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Miliotis, Tasso
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Nyström, Ann-Christin
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hansson, Sara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Davidsson, Pia
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Gan, Li-Ming
    Early Clinical and Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Magnone, Maria Chiara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Althage, Magnus
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Humanizing Miniature Hearts through 4-Flow Cannulation Perfusion Decellularization and Recellularization2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 7458Article in journal (Refereed)
    Abstract [en]

    Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.

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  • 18.
    Olofsson, Peder S.
    et al.
    Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden / Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Steinberg, Benjamin E.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA / The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Sobbi, Roozbeh
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
    Cox, Maureen A.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Ahmed, Mohamed N.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Oswald, Michaela
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Szekeres, Ferenc
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Hanes, William M.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Introini, Andrea
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Liu, Shu Fang
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Holodick, Nichol E.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Rothstein, Thomas L.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Lövdahl, Cecilia
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Chavan, Sangeeta S.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Yang, Huan
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Pavlov, Valentin A.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Broliden, Kristina
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Andersson, Ulf
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Diamond, Betty
    The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Miller, Edmund J.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Arner, Anders
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Gregersen, Peter K.
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Backx, Peter H.
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada / Department of Biology, York University, Toronto, Ontario, Canada.
    Mak, Tak W.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Tracey, Kevin J.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Blood pressure regulation by CD4lymphocytes expressing choline acetyltransferase2016In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 34, no 10, p. 1066-1071Article in journal (Refereed)
    Abstract [en]

    Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4(+) T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals(1). Here we show that these CD4(+)CD44(hi)CD62L(Io) T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 T-ChAT). Mice lacking ChAT expression in CD4(+) cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JT(ChAT)) decreased blood pressure when infused into mice. Co-incubation of JT(ChAT) and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 T-ChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.

  • 19.
    Sartipy, Peter
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Göteborg, Sweden.
    Björquist, Petter
    Cellectis AB, Göteborg, Sweden / NovaHep AB, Göteborg, Sweden.
    Employment of the Triple Helix concept for development of regenerative medicine applications based on human pluripotent stem cells2014In: Clinical and translational medicine, ISSN 2001-1326, Vol. 3, p. 1-7, article id 9Article, review/survey (Refereed)
    Abstract [en]

    Using human pluripotent stem cells as a source to generate differentiated progenies for regenerative medicine applications has attracted substantial interest during recent years. Having the capability to produce large quantities of human cells that can replace damaged tissue due to disease or injury opens novel avenues for relieving symptoms and also potentially offers cures for many severe human diseases. Although tremendous advancements have been made, there is still much research and development left before human pluripotent stem cell derived products can be made available for cell therapy applications. In order to speed up the development processes, we argue strongly in favor of cross-disciplinary collaborative efforts which have many advantages, especially in a relatively new field such as regenerative medicine based on human pluripotent stem cells. In this review, we aim to illustrate how some of the hurdles for bringing human pluripotent stem cell derivatives from bench-to-bed can be effectively addressed through the establishment of collaborative programs involving academic institutions, biotech industries, and pharmaceutical companies. By taking advantage of the strengths from each organization, innovation and productivity can be maximized from a resource perspective and thus, the chances of successfully bringing novel regenerative medicine treatment options to patients increase.

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  • 20.
    Saxenborn, Patricia
    University of Skövde, School of Health and Education.
    Investigating the Effect of 1,25-Dihydroxyvitamin D3 and Retinoic acid on Viability, Differentiation and Migration in NB69 and T47D cells.2016Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Cancer is a well-known disease that many people encounter in their lifetime. There is constantly research being performed on cancer to find treatments for those types where none has been found, or even find better or more efficient treatments for those cancer types where there already is treatment available. Two types of cancer that have been studied in this thesis are neuroblastoma, which is a form of cancer that affects children and infants, and breast cancer. The 13-cis retinoic acid is presently used as treatment for neuroblastoma post-surgery and post-chemo therapy, but the treatment is quite invasive. It has been shown that 1,25-dihydroxyvitamin D3 is a good candidate for cancer treatment, and the aim of this study was to investigate whether a combination of 1,25-dihydroxyvitamin D3 and two forms of retinoic acid, all-trans and 13-cis, could cause synergistic effects on cell viability, invasion, and differentiation of the cells. The two vitamins were combined at different concentrations and ratios to make the different treatments. A proliferation assay with absorbance measurement was performed to determine cell viability, and a migration assay was performed to observe the migratory properties of the cells after treatment. The results concluded that the combined treatments had greater effect than the single treatments on cell viability in both neuroblastoma and breast cancer cells. The results showed that single treatment of 13-cis retinoic acid and combined treatments had the highest effect on invasion and differentiation on neuroblastoma cells.

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    Patricia Saxenborn - Bachelor Thesis
  • 21.
    Shunnar, Batoul
    University of Skövde, School of Bioscience.
    Different concentrations of GSK3 inhibitor fail to suppress interleukin-6 in stimulated THP-1 macrophage2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Inflammation is a defensive process that allows immune cells to be mobilized to help with infection removal and tissue regeneration. Inflammasomes are multiprotein oligomers in the cytoplasm and components of the innate immune system that have a role in inflammation. Glycogen synthase kinase 3 (GSK3) is a critical molecule involved in a wide range of inflammatory reactions. It has been reported to suppress the production of pro-inflammatory mediators in response to LPS when it is inhibited. The aim of this project was to study the effect of GSK3 inhibition in a concentration-dependent manner on the production of IL-6 as well as ASC-speck formation in THP1 ASC GFP cells stimulated with LPS and activated using nigericin. Using the cell culture supernatant ELISA was performed to quantify the IL-6 protein secreted by THP-1 macrophages. Using reverse-transcribed cDNA, qPCR was performed to measure the IL-6 gene expression. Finally, live-cell imaging was done to visualize the ASC-speck formation. It was found that upon stimulation of THP-1 cells a remarkable increase in the production of IL-6 was observed, however, the inhibitor did not suppress the production of IL-6 as hypothesized. This could be primarily due to the presence of another NF-κB pathway which is not mediated by GSK3 and therefore could not be inhibited using the GKS3 inhibitor. Future studies could decrease the LPS concentration to see if the uninhibited pathway can be observed at lower stimulation. Another probable solution could be lowering the FBS percentage to avoid potential inhibition.

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  • 22.
    Soufieh, Nadieh
    University of Skövde, School of Bioscience.
    Biogenesis and secretion of beta cell Synaptic-Like Micro-Vesicles2022Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Pancreatic β-cells produce insulin that balances the level of blood glucose. These cells also produce Synaptic-like micro-vesicles (SLMV) in which γ-aminobutyric acid (GABA) is stored; a metabolite known to be effective in the control of pancreatic endocrine functions in human islets of Langerhans. It is demonstrated in the previous studies conducted by researchers that biogenesis of SLMVs is strongly dependent on a group of Adaptor Protein complex known as AP3, and intracellular trafficking will be impaired in absence of AP3. In this study in order to understand the components of SLMVs better and to assess the role of AP3 in SLMV production and secretion, the exocytosis mechanisms of these vesicles were studied in rat pancreatic β-cell INS1 cell line in both wild type and knocked out AP3 cells using CRISPR/Cas9 technology. Cells were also transfected with plasmids expressing proteins related to SLMVs and their fusion site on the plasma membrane. Samples, either fixed or live, were imaged using fluoroscent microscopes. Based on the results, a moderate correlation was found for colocalization of AP3 and SLMVs. Moreover, exocytosis events, before and after glucose stimulation, were imaged by TIRF microscope and the results suggested an increase in fusion events for SLMVs onto the plasma membrane, immediately after glucose addition. We propose here a possible relationship between AP3 and SLMVs biogenesis and secretion which may contribute to future development of an explanatory model if confirmed with larger samples.

  • 23.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Améen, Caroline
    Cellartis, Gothenburg, Sweden.
    Lindahl, Anders
    Dept of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Sweden.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Gothenburg, Sweden .
    Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue2011In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 10, p. 581-594Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.

  • 24.
    Theodorou, Maria Panagiota
    University of Skövde, School of Bioscience.
    Factors and mechanisms associating the mobilisation of Ca2+ with the activation of the NLRP3 inflammasome: A systematic review2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Inflammasomes are multiprotein complexes that play a critical role in the regulation of inflammation and the inflammatory responses against pathogens. NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3) is among the molecules involved in the homonymous and well-studied NLRP3 inflammasome that accounts for the release of the pro-inflammatory cytokines interleukin (IL) 1-β and 18. Two signals (priming and activation) that include molecular and cellular events lead to the activation of the complex; the main events involved during the activation phase are ionic fluxes, mitochondrial dysfunction, and lysosomal damage. Calcium mobilisation belongs to the signalling events of ionic fluxes associated with the complex assembly initiation. Although no consensus has been established regarding the ionic Ca2+ fluxes and the exact mechanisms contributing to NLRP3 activation, several sources agree that Ca2+ mobilisation homeostasis is essential for the canonical function of the NLRP3 inflammasome, and other cellular processes associated with it. This systematic review aimed to determine the factors and mechanisms related to Ca2+ mobilisation contributing to inflammasome activation, examine NLRP3-associated pathologies, and propose potential therapeutic targets. The literature sources found were evaluated using the CASP tool. The obtained information revealed an intertwined relation of Ca2+ flux with the calcium-sensing receptor, reactive oxygen species (ROS) generation, lysosome rupture, Ca2+-permeable channels and K+ efflux contributing to NLRP3 inflammasome activation. The summarised knowledge in this review has led to the proposal of future studies through references to different NLRP3-related diseases such as Alzheimer’s and diabetes type II, while potential therapeutic targets were also discussed.

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